(12) Patent Application Publication (10) Pub. No.: US 2017/0119913 A1 Osterkamp Et Al

US 201701 1991.3A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0119913 A1 Osterkamp et al. (43) Pub. Date: May 4, 2017

(54) CONJUGATE COMPRISINGA the first targeting moiety is capable of binding to a first NEUROTENSIN RECEPTOR LIGAND AND target, AD1 is a first adapter moiety or is absent, LM is a USE THEREOF linker moiety or is absent, AD2 is a second adapter moiety or is absent, and TM2 is a second targeting moiety, wherein (71) Applicant: 3B PHARMACEUTICALS GMBH, the second targeting moiety is capable of binding to a second target; wherein the first targeting moiety and/or the second Berlin (DE) targeting moiety is a compound of formula (2): wherein R' (72) Inventors: Frank Osterkamp, Berlin (DE); is selected from the group consisting of hydrogen, methyl Christian Haase, Berlin (DE); Ulrich and cyclopropylmethyl: AA-COOH is an amino acid Reineke, Berlin (DE); Christiane selected from the group consisting of 2-amino-2 adamantane Smerling, Berlin (DE); Matthias carboxylic acid, cyclohexylglycine and 9-amino-bicyclo3. Paschke, Berlin (DE); Jan Ungewi?, 3.1 nonane-9 carboxylic acid; R is selected from the group Berlin (DE) consisting of (C-C)alkyl, (C-C)cycloalkyl, (CCs)cy cloalkylmethyl, halogen, nitro and trifluoromethyl: ALK" is (21) Appl. No.: 15/317,598 (C-Cs)alkylidene, R, R and R are each and indepen dently selected from the group consisting of hydrogen and (22) PCT Filed: Jun. 10, 2015 (C-C)alkyl under the proviso that one of R, R and R is of the following formula (3) wherein ALK" is (C-Cs) (86). PCT No.: PCT/EP201S/OO1166 alkylidene; R is selected from the (2) group consisting of S 371 (c)(1), hydrogen and (C-C)alkyl; and R is a bond; or a pharma (2) Date: Dec. 9, 2016 cologically acceptable salt, Solvate or hydrate thereof. (30) Foreign Application Priority Data

(2) Jun. 10, 2014 (EP) ...... 14001992.8 Jun. 11, 2014 (EP) ...... 140O2OO2.5 AA-COOH

Publication Classification (51) Int. Cl. A6 IK 5L/04 (2006.01) A6 IK 49/00 (2006.01) A6 IK3I/337 (2006.01) (52) U.S. Cl. CPC. A61 K5I/0482 (2013.01); A61K 47/48061 (2013.01); A61 K3I/337 (2013.01); A61 K 47/48.184 (2013.01); A61K 49/0043 (2013.01); A61K 47/48146 (2013.01); A61K 47/48369 (2013.01) (3) (57) ABSTRACT The present invention is related to a conjugate comprising a structure of general formula (1) ITM1-AD1-LM-IAD2 ITM2 (1), wherein TM1 is a first targeting moiety, wherein Patent Application Publication May 4, 2017. Sheet 1 of 15 US 2017/01 19913 A1

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CONUGATE COMPRISING A protein coupled. NTR3 has a single transmembrane domain NEUROTENSIN RECEPTOR LIGAND AND and is encoded by the SORT1 gene. USE THEREOF 0005. The neurotensin receptor 1 (NTR1) was cloned in 0001. The present invention is related to a conjugate; a 1990 from rat brain and found to act as a high affinity, composition comprising the conjugate; the conjugate and levocabastine insensitive receptor for neurotensin (Tanaka et composition, respectively, for use in a method for the al., Neuron, 1990, 4, 847-854). The affinity of neurotensin diagnosis of a disease; the conjugate and composition, for the receptor could be decreased by both sodium ions and respectively, for use in a method for the treatment of a guanosine triphosphate (GTP) (Vincent et al., Trends Phar disease; the conjugate and composition, respectively, for use macol. Sci., 1999, 20, 302-309). NTR1 is expressed pre in a method of diagnosis and treatment of a disease which is also referred to as “thera(g)nosis” or “thera(g)nostics': the dominantly in the central nervous system and intestine conjugate and composition, respectively, for use in a method (Smooth muscle, mucosa and nerve cells). In the central for the identification of a subject, wherein the subject is nervous system, expression has been found in the diagonal likely to respond or likely not to respond to a treatment of band of Broca, medial septal nucleus, nucleus basalis mag a disease; the conjugate and composition, respectively, for nocellularis, Suprachiasmatic nucleus, Supramammillary use in a method for the selection of a Subject from a group area, Substantia nigra and Ventral tegmental area. The recep of subjects, wherein the subject is likely to respond or likely tor is also expressed in the dorsal root ganglion neurones of not to respond to a treatment of a disease; the conjugate and the spinal cord. The predominant response upon activation composition, respectively, for use in a method for the of the receptor by neurotensin is activation of phospholipase stratification of a group of Subjects into Subjects which are C, causing an increase in intracellular calcium levels. The likely to respond to a treatment of a disease, and into receptor can also stimulate cAMP formation, MAP kinase Subjects which are not likely to respond to a treatment of a activation and the induction of growth related genes. Such as disease; the conjugate and the composition, respectively, for kroX-24 (Vincent et al., Trends Pharmacol. Sci., 1999, 20, use in a method for delivering an effector to a neurotensin 302-309). receptor expressing tissue; a method for the diagnosis of a disease using the conjugate and the composition, respec 0006 Neurotensin receptor 2 (NTR2) is a protein that in tively; a method for the treatment of a disease using the humans is encoded by the NTSR2 gene (Vincent et al., conjugate and the composition, respectively; a method for Trends Pharmacol. Sci., 1999, 20, 302-309; Mazella et al., the diagnosis and treatment of a disease which is also J. Neurosci., 1996, 16, 5613-5620; Ramez et al., J. Invest. referred to as “thera(g)nosis' or “thera(g)nostics, using the Dermatol., 2001, 117,687-693). The protein encoded by this conjugate and the composition, respectively; a method for gene belongs to the G protein-coupled receptor family that the delivery of an effector to a neurotensin receptor express activates a phosphatidylinositol-calcium second messenger ing tissue using the conjugate and the composition, respec system. Binding and pharmacological studies demonstrate tively; and a kit comprising the compound and composition, that this receptor binds neurotensin as well as several other respectively. ligands already described for NTR1. However, unlike 0002 Neurotensin NT is a 13 amino acid neuropeptide NTR1, NTR2 recognizes, with high affinity, levocabastine, (pyroGlu'-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg a histamine H1 receptor antagonist previously shown to Pro'-Tyr-Ile-Leu-OH) (SEQID NO: 1) that is impli compete with neurotensin for low-affinity binding sites in cated in the regulation of luteinizing hormone and prolactin the central nervous system. These activities Suggest that this release and has significant interaction with the dopaminergic receptor may be of physiological importance and that a system. Neurotensin was first isolated from extracts of natural agonist for the receptor may exist. bovine hypothalamus based on its ability to cause a visible vasodilation in the exposed cutaneous regions of anesthe 0007 Neurotensin receptor 3 (NTR3) is a non-G-protein tized rats (Carraway et al., J. Biol. Chem., 1973, 248, coupled receptor. The cDNA encodes an 833-amino acid 6854-6861). protein 100% identical to the recently cloned gp95/sortilin 0003) Neurotensin is distributed throughout the central and was then designated NTR3/gp95/sortilin (Mazella, Cell nervous system, with highest levels in the hypothalamus, Signal., 2001, 13, 1-6; Vincent et al., Trends Pharmacol. amygdala and nucleus accumbens. It induces a variety of Sci., 1999, 20, 302-309). NTR3 is a sorting protein involved effects, including analgesia, hypothermia and increased in cellular trafficking and neuropeptide signalling. The locomotor activity. It is also involved in regulation of physiological and cellular roles of sortilin/NTR3 are puta dopamine pathways. In the periphery, neurotensin is found tive in many aspects and still under discussion. in endocrine cells of the small intestine, where it leads to secretion and Smooth muscle contraction (Friry et al., Bio 0008. Apart from the central nervous system, NTR1 is chem. Biophys. Res. Commun., 2002, 290, 1161-1168). highly expressed in a mammalian body and a human body 0004 Neurotensin is bound by neurotensin receptors. in particular on several neoplastic cells in several tumor Three neurotensin receptors are known, namely neurotensin indications, whereas the expression of NTR1 in most other receptor 1, also referred to as NTR1, neurotensin receptor 2, tissues of the mammalian and the human body is either not also referred to as NTR2, and neurotensin receptor 3, also existent or low. Only for colon weak or moderate expression referred to as NTR3. These neurotensin receptors are trans membrane receptors that bind the neurotransmitter neuro under physiological conditions is described. tensin (Vincent et al., Trends Pharmacol. Sci., 1999, 20, 0009. The following table summarizes the expression of 302-309; Pelaprat, Peptides, 2006, 27, 2476-2487). NTR1 NTR1 as described in the prior art indicating the tissue, and NTR2 which are encoded by the NTSR1 and NTSR2 degree of expression, detection method and the respective genes, contain seven transmembrane helices and are G references. US 2017/01 19913 A1 May 4, 2017

Detection method Tissue Expression Reference Central Nervous System (e.g. ------Autoradiography, immunohistochemistry, in Substantia nigra, situ hybridization Suprachiasmatic nucleus) e.g. Boudin et al., J Comp. Neurol., 1996, 373, 76-89 (and references herein) Colon (mucosa, normal) +f- In situ hybridization Gui et al., Peptides, 2008, 29, 1609-15 Colon (Smooth muscle, +++ Autoradiography normal) Rettenbacher et al., Naunyn Schmiedebergs Arch. Pharmacol., 2001, 364, 291-304 Ductal pancreatic ------Autoradiography, RT-PCR, adenocarcinoma Immunohistochemistry, cell line studies Reubi et al., Gut, 1998, 42, 546-50; Ehlers et al., Ann. Surg., 2000, 231, 838–48; Iwase et al., Cancer, 1997, 79, 1787-1793; Wang et al., Neuropeptides, 2011, 45, 151-156: Wang et al., Clin. Cancer Res., 2000, 6, 566-571 Small cell lung cancer ---- Autoradiography, cell line studies Reubi et al., Int. J. Cancer, 1999, 82, 213–218: Moody et al., Peptides, 2001, 22, 109-115 Prostate cancer ---- RT-PCR (xenografts), functional studies, Taylor et al., Prostate, 2012, 72, 523-32: Amorino et al., Oncogene, 2007, 26, 745-756; Valerie et al., Cancer Res., 2011, 71, 6817-6826; Swift et al., Cancer Res., 2010, 70, 347-356: Almeida et al., Peptides, 2010, 31, 242-247 Colorectal carcinoma +++++ RT-PCR, in situ hybridization, immunohistochemistry, mouse model, cell line studies Chao et al., J. Surg. Res., 2005, 129, 313-321; Gui et al., Peptides, 2008, 29, 1609-1615; Bossard et al., Peptides, 2007, 28, 2030-2035: Bugni et al., Int. J. Cancer, 2012, 130, 1798-1805; Haase et al., Anitcancer Res., 2006, 26, 3527-3533; Martin et al., Gastroenterology, 2002, 123, 135-1143 Breast cancer -- mmunohistochemistry Souaze et al., Cancer Res., 2006, 66, 6243-6249; Dupouy et al., PLoS One, 2009, 4, e4223 Meningioma ------Autoradiography Reubi et al., Int. J. Cancer, 1999, 82, 213–218 Ewing's Sarcoma ------Autoradiography Reubi et al., Int. J. Cancer, 1999, 82, 213–218 Pleural Mesothelioma ---- mmunohistochemistry Alifano et al., Biochimie, 2010, 92, 164-170 Head and Neck Cancer -- Functional study Shimizu et al., Ini. J. Cancer, 2008, 123, 816-1823 Lung Cancer ---- mmunohistochemistry, cell line studies, RT-PCR Alifano et al., Cin. Cancer Res., 2010, 16, 4401-4410; Moody et al., Panminerva Med., 2006, 48, 19-26: Ocelo-Garcia et al., Lung Cancer, 2001, 33, 1-9 Gastrointestinal Stromal ---- Gromova et al., PLoS One, 2011, 6, e14710 Tumors Uterine Leiomyoma ---- Immunohistochemistry, RT-PCR Rodriguez et al., Biol. Reprod., 2010, 83, 641-647: Rodriguez et al., Int. J. Gynecol Pathol, 2011, 30, 354-363 Cutaneous T-Cell Lymphoma ---- Flow cytometry Ramez et al., J. Invest. Dermatoi, 2001, 117, 687-693

0010. These NTR1 expressing tumor indications include cutaneous T-cell lymphoma. A preferred group of NTR1 but are not limited to ductal pancreatic adenocarcinoma, expressing tumor indications are ductal pancreatic adeno Small cell lung cancer, prostate cancer, colorectal cancer, carcinoma, Small cell lung cancer, prostate cancer, colorectal breast cancer, meningioma, Ewing's sarcoma, pleural meso cancer, breast cancer, meningioma and Ewings sarcoma. thelioma, head and neck cancer, non-Small cell lung cancer, 0011 Because of this selective expression of NTR1, gastrointestinal Stromal tumors, uterine leiomyoma and NTR1 is regarded as a suitable target for drugs and diag US 2017/01 19913 A1 May 4, 2017

nostic agents. Agonists and antagonists binding to NTR1 al., Nucl. Med. Biol., 2001, 28, 75-84: Garcia-Garayoa et al., have been described in the prior art. One class of such NTR1 J. Nucl. Med., 2002, 43, 374-383; Garcia-Garayoa et al., agonists are peptides binding to NTR1. Nucl. Med. Biol., 2006, 33, 495-503; Garcia-Garayoa et al., 0012 Most of these agonist peptides are derivatives of Eur: J. Nucl. Med. Mol. Imaging, 2009, 36, 37-47; Bergmann neurotensin, its C-terminal eight amino acids Lys-Pro et al., Nucl. Med. Biol., 2002, 29, 61-72; Bruehlmeier et al., Arg-Arg-Pro-Tyr-Ile-Leu' (NT6-13) (SEQID NO: Nucl. Med. Biol., 2002, 29, 321-327; Blauenstein et al., 2) or its C-terminal six amino acids Arg-Arg-Pro'-Tyr'- Cancer Biother. Radiopharm., 2004, 19, 181-188: Maes et Ile'°-Leu' (NT8-13) (SEQ ID NO: 3). Modifications al., J. Med. Chem., 2006, 49, 1833-1836), demotensins include for example N-methylations, reduced amide bonds, (Nocket al., J. Med. Chem., 2006, 49, 4767-4776; Maina et B-Ala or D-Lys at position 7, Gly(PipAm) at position 8, Dab al., Eur: J. Nucl. Med. Mol. Imaging, 2007, 34, 1804-1814), or Phe(4-Gu) at position 9, Dmitat position 11, Tle or tBuGly NT(6-13) analogs (Alshoukret al., Bioconjug. Chem., 2009, at position 12, D-Leu or Cha at position 13 as well as 20, 1602-1610; Alshoukret al., Bioconjug. Chem., 2011, 22. combinations thereof. U.S. Pat. No. 4,439.359 discloses 1374-1385) and neurotensin analogs developed by Biosyn cyclic octapeptide analogs of neurotensin. U.S. Pat. No. thema (Achileflu et al., J. Med. Chem., 2003, 46,3403-3411; 4.425,269 discloses metabolically protected analogs of neu de Visser et al., Eur: J. Nucl. Med. Mol. Imaging, 2003, 30. rotensin. WO 1999/052539 discloses neurotensin analogs 1134-1139; and Janssen et al., Cancer Biother. Radiopharm., with the novel non-natural amino acid Neo-tryptophan. WO 2007, 22, 374-381). 2000/078796 discloses labeled neurotensin derivatives, 0016. It was found that (most) neurotensin-derived metal Some of them with improved resistance to enzymatic deg labeled peptides have a very short circulation half-life due to radation. WO 1995/022341 discloses labeled peptide com rapid renal clearance as often observed for peptidic mol pounds. US 2010/0256055 discloses conjugates of neuro ecules. Consequently, tumor accumulation is rather limited tensin or neurotensin analogs and uses thereof. U.S. Pat. No. for Such molecules. 4.110.321 discloses a synthetic tridecapeptide Gln-neu (0017 International patent application WO 98/33531 dis rotensin having hormonal activity. WO 2011006985 dis closes methods for the detection and localization of malig closes neurotensin analogues for radioisotope targeting to nant human tumors using neurotensin, peptide NTR agonists neurotensin receptor-positive tumors. EP 0606804, WO and peptide NTR antagonists, respectively. The example 1996/031531, WO 1997/0043.11 and WO 1998/001472 dis part of WO 98/33531 shows the use of 'I labeled and close marker for the neurotensin receptor including fluores unlabeled neurotensin and fragments thereof acting as ago cently labeled markers. U.S. Pat. No. 5,407,916 discloses nists in receptor autoradiography of cryostat sections of neurotensin mimetics as central nervous system agents. tumor samples. 0013 These peptides as well as the further ligands of 0018 U.S. Pat. No. 5,723,483 discloses small molecule NTR1, namely neuromedin N and Xenin, can be used for compounds which are active as NTR1 antagonists such as imaging purposes and therapeutic purposes. Typically, the SR142948. These small molecule compounds and agonist carries a therapeutically or diagnostically active SR142948 in particular, however, cross the blood-brain effector such as a chelated metal label and more specifically barrier and are thus suitable neither for the radionuclide a chelated radiolabel Suitable for therapy and diagnosis, therapy of tumors nor for the radioactive diagnosis of tumors respectively. The effector bearing agonist binds to the recep and imaging in particular, whereby the tumors are preferably tor and, upon binding to the receptor, the effector bearing those expressing NTR1, since irradiation of the central agonist is internalized by the receptor and the effector nervous system or any other non-radioactive cell-killing bearing agonist thus trapped in the target cell. It will be effect may have detrimental effects on the patient. Addition understood by a person skilled in the art that such trapping ally, the radiolabeling of these compounds is difficult. Even of the effector bearing agonist may go along with the release more difficult is designing and synthesizing a radiolabeled of the effector from the agonist. Additionally, upon such derivative of these compounds without diminishing or trapping, the effector and/or the agonist may be subject to destroying the original and desired high NTR1 affinity. metabolic conversion. Such metabolic conversion may 0019. The above overview of the prior art attempting to occur through the metabolism and enzymatic activities in provide a compound which can be used in the diagnosis particular of the organism to which the effector bearing and/or therapy of NTR1-expressing tumors, whereby such agonist has been administered and more specifically the diagnosis and therapy typically makes use of a radiolabeled metabolism of the cell and tissue, respectively, into which version of such compound, illustrates the difficulties in the effector bearing agonist has been internalized. designing this kind of compounds being effective and thus 0014. The potential utility of metal labeled neurotensin Suitable for Such diagnostic and therapeutic purpose. It is receptor specific peptidic agonists for Scintigraphic or imperative that the compound has appropriate in vivo tar SPECT or PET imaging and radiotherapy is exemplified by geting and pharmacokinetic properties. It is, however, well the "Tc-labelled neurotensin (NT) analog NT-XI (Bucheg known that the radionuclide chemistry and associated link ger et al., J. Nucl. Med., 2003, 44, 1649-1654) or "Tc ages are crucial particularly with respect to the attachment to labelled neurotensin (NT) analog "Tc-Demotensin VI the compound of an effector which provides the signal (Gabriel et al., Cancer Biother. Radiopharm., 2011, 26, needed for diagnosis or which provides the therapeutically 557-563). effective activity. Such effector can be attached to the 00.15 Metal labeled neurotensin receptor specific ligands compound either directly or through a connecting moiety. In have also been used for preclinical tumor imaging for case the effector is a radiolabel and the radiolabel is attached example of NTR1-expressing HT29 xenograft tumors using to the compound by a connecting moiety Such as, for "Tc-NTXIX (Garcia-Garayoa et al., Eur: J. Nucl. Med. example, a chelator, the labeling of Such a connecting Mol. Imaging, 2009, 36, 37-47). Such neurotensin receptor moiety and chelator, respectively, is a further crucial step in specific ligands are NT(8-13) analogs (Garcia-Garayoa et the identification of a suitable compound (Fritzberg et al., J. US 2017/01 19913 A1 May 4, 2017

Nucl. Med., 1992, 33, 394-397). Hence the type of radio 0021. These and other problems are solved by the subject nuclide, the type of compound which mediates target bind matter of the attached independent claims. Preferred ing, and the method used for linking them to one another embodiments may be taken from the attached dependent may have unpredictable effects on the properties of the claims. radiolabeled version of the compound. Theoretically, a high 0022. Furthermore, these and other problems are solved affinity of the compound as such, i.e. without the radiolabel, by the following embodiments. a connecting moiety and/or chelator, respectively, if any, for the target receptor facilitates retention of the compound and EMBODIMENT 1 the radiolabeled version thereof in particular in target recep 0023. A conjugate comprising a structure of general tor expressing tissues. However, it is well known that the formula (1) affinity and receptor specificity of the compound as such, i.e. without the radiolabel and the linker and chelator, respec TM1-AD1-LM-IAD2-TM2) (1), tively, if any, may be completely altered during chemical wherein modification and radionuclide labeling (Fani et al., J. Nucl. TM1 is a first targeting moiety, wherein the first targeting Med., 2012, 53, 1481-1489). Therefore, an optimal com moiety is capable of binding to a first target, pound and even more so a radiolabeled version thereof AD1 is a first adapter moiety or is absent, Suitable for diagnosis and therapy, respectively, of a disease LM is a linker moiety or is absent, is a matter of luck rather than of a rational and predictable AD2 is a second adapter moiety or is absent, and development process. This even more so in case Such TM2 is a second targeting moiety, wherein the second compound is part of a conjugate and wherein the conjugate targeting moiety is capable of binding to a second target; comprises said compound targeting the receptor expressing wherein the first targeting moiety and/or the second targeting tissues thus acting as a first targeting moiety, and a second moiety is a compound of formula (2): compound capable of binding to a second target, whereby the second target may be, but does not have to be, different from the first target. (2) 0020. The problem underlying the present invention is AA-COOH the provision of a compound which is Suitable as a diag nostic agent and/or a pharmaceutical agent, particularly if said compound comprises a diagnostically and/or therapeu tically active effector. A further problem underlying the present invention is the provision of a compound which is Suitable as a diagnostic agent and/or a pharmaceutical agent, particularly if conjugated to a diagnostically and/or thera peutically active effector, and which does not penetrate the blood-brain barrier. A further problem underlying the pres ent invention is the provision of a compound which is Suitable as a diagnostic agent and/or a pharmaceutical agent, particularly if conjugated to a diagnostically and/or thera peutically active effector, in the diagnosis and/or therapy of a disease where the diseased cells and/or diseased tissues express NTR1. A still further problem underlying the instant wherein invention is the provision of a compound which is Suitable R" is selected from the group consisting of hydrogen, methyl for delivering a diagnostically and/or therapeutically effec and cyclopropylmethyl; tive agent to a diseased cell and/or diseased tissue, respec AA-COOH is an amino acid selected from the group con tively, and more particularly an NTR1-expressing diseased sisting of 2-amino-2-adamantane carboxylic acid, cyclohex cell and/or diseased tissue. Also, a problem underlying the ylglycine and 9-amino-bicyclo[3.3.1 nonane-9-carboxylic present invention is the provision of a method for the diagnosis of a disease, of a method for the treatment and/or acid; prevention of a disease, and a method for the combined R is selected from the group consisting of (C-C)alkyl, diagnosis and treatment of a disease; preferably Such disease (C-C)cycloalkyl, (C-C)cycloalkylmethyl, halogen, nitro is a disease involving NTR1-expressing cells and/or tissues. and trifluoromethyl: ALK is (C-Cs)alkylidene: A still further problem underlying the present invention is R. R. and Rare each and independently selected from the the provision of a method for the identification of a subject, group consisting of hydrogen and (C-C)alkyl under the wherein the subject is likely to respond or likely not to proviso that one of R. RandR is of the following formula respond to a treatment of a disease, a method for the (3) selection of a subject from a group of Subjects, wherein the Subject is likely to respond or likely not to respond to a treatment of a disease. Also, a problem underlying the (3) present invention is the provision of a pharmaceutical com position containing a compound having the characteristics as outlined above. Furthermore, a problem underlying the present invention is the provision of a kit which is suitable for use in any of the above methods. US 2017/01 19913 A1 May 4, 2017

0024 wherein EMBODIMENT 9 0025 ALK" is (C-C)alkylidene; I0038. The conjugate of embodiment 8, wherein R is I0026 R is selected from the group consisting of selected from the group consisting of hydrogen and methyl. hydrogen and (C-C)alkyl; and 0027 R’ is a bond; EMBODIMENT 10 or a pharmacologically acceptable salt, Solvate or hydrate thereof. 0039. The conjugate of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8 and 9, wherein R, R and R are each and EMBODIMENT 2 independently methyl under the proviso that one of R. R. and R is of the following formula (3): 0028. The conjugate of embodiment 1, wherein the con jugate comprises an Effector moiety, wherein the Effector moiety comprises or is capable of comprising an Effector, (3) wherein the Effector is selected from the group comprising R7 a diagnostically active agent, a therapeutically active agent -ALK-N1 and a combination thereof. k EMBODIMENT 3 0040 wherein 0029. The conjugate of any one of embodiments 1 and 2. 0041 ALK" is (C-Cs)alkylidene: wherein the R' is methyl. I0042 R is selected from the group consisting of EMBODIMENT 4 hydrogen and methyl. 0030 The conjugate of any one of embodiments 1, 2 and EMBODIMENT 11 3, wherein AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantane carboxylic acid 0043. The conjugate of any one of embodiments 1, 2, 3, and cyclohexylglycine. 4, 5, 6, 7, 8, 9 and 10, preferably any one of embodiments 1, 2 and 10, wherein ALK and ALK" are both propylene, or EMBODIMENT 5 wherein either ALK is propylene and ALK" is (C-C) alkylidene or ALK is (C-Cs)alkylidene and ALK" is pro 0031. The conjugate of embodiment 4, wherein AA pylene. COOH is 2-amino-2-adamantane carboxylic acid. EMBODIMENT 12 EMBODIMENT 6 0044) The conjugate of any one of embodiments 1 and 2. 0032. The conjugate of embodiment 4, wherein AA wherein COOH is cyclohexylglycine. (0.045 R' is methyl: EMBODIMENT 7 0046 AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantane carboxylic 0033. The conjugate of any one of embodiments 1, 2, 3, acid and cyclohexylglycine; and 4, 5 and 6, preferably any one of embodiments 1 and 2. 0047 R’ is isopropyl. wherein R is isopropyl. EMBODIMENT 13 EMBODIMENT 8 0034. The conjugate of any one of embodiments 1, 2, 3, 0048. The conjugate of any one of embodiments 1, 2 and 4, 5, 6 and 7, preferably any one of embodiments 1 and 2. 12, wherein wherein R3, R4 and R5 are each and independently selected 0049 R, R and R are each and independently from the group consisting of hydrogen and methyl under the Selected from the group consisting of hydrogen and proviso that one of R3, R4 and R5 is of the following methyl under the proviso that one of R, R and R is formula (3) of the following formula (3):

(3) (3) R7 -ALK-N1 R7, -ALK-N1 k

0035 wherein 0050 wherein 0036) ALK" is (C-C)alkylidene; 0051 ALK" is (C-C)alkylidene: I0037 R is selected from the group consisting of 0.052 R is selected from the group consisting of hydrogen and (C-C)alkyl. hydrogen and methyl. US 2017/01 19913 A1 May 4, 2017

EMBODIMENT 14 (0071) R' is isopropyl; and 0053. The conjugate of any one of embodiments 1 and 2. 0.072 ALK and ALK" are both propylene, or wherein wherein either ALK is propylene and ALK" is (C-Cs)alkylidene 0054) R' is methyl: or ALK is (C-C)alkylidene and ALK" is propylene. 0055 AA-COOH is an amino acid selected from the EMBODIMENT 18 group consisting of 2-amino-2-adamantane carboxylic acid and cyclohexylglycine; 0073. The conjugate according to any one of embodi 0056 R is isopropyl: ments 1 and 2, wherein 0057 R, R and R are each and independently 0074) R' is methyl: Selected from the group consisting of hydrogen and 0075 AA-COOH is an amino acid selected from the methyl under the proviso that one of R. R. and R is group consisting of 2-amino-2-adamantane carboxylic of the following formula (3): acid and cyclohexylglycine; 0.076 R is isopropyl: 0.077 R. R. and R are each and independently (3) Selected from the group consisting of hydrogen and R7 methyl under the proviso that one of R. R. and R is -ALK-N1 of the following formula (3)

(3) 0058 wherein R7 0059 ALK" is (C-C)alkylidene; and -ALK-N1 I0060 R is selected from the group consisting of k hydrogen and methyl. 0078 wherein EMBODIMENT 15 0079 R is selected from the group consisting of 0061. The conjugate of any one of embodiments 1, 2, 3, hydrogen and methyl; and 4, 5, 6, 7, 8, 9, 10, 11, 13 and 14, preferably any one of 0080 ALK and ALK" are both propylene, or wherein embodiments 12, 13 and 14, wherein either ALK is propylene and ALK" is (C-Cs)alkylidene 0062 R. Rand Rare each and independently methyl or ALK is (C-Cs)alkylidene and ALK" is propylene. under the proviso that one of R. R. and R is of the following formula (3): EMBODIMENT 19 I0081. The conjugate of any one of embodiments 1 to 18, (3) wherein the first targeting moiety is selected from the group R7 consisting of a compound of formula (4), a compound of -ALK-N1 formula (5) and a compound of formula (6), wherein the compound of formula (4) is

0063 wherein (4) 0064 ALK" is (C-Cs)alkylidene; and I0065 R is selected from the group consisting of hydrogen and methyl.

EMBODIMENT 16 0066. The conjugate of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, preferably of any one of embodiments 12, 13, 14 and 15, wherein 0067 ALK and ALK" are both propylene, or wherein either ALK is propylene and ALK" is (C-Cs)alkylidene or ALK is (C-C)alkylidene and ALK" is propylene.

EMBODIMENT 17 0068. The conjugate according to any one of embodi ments 1 and 2, wherein 0069) R' is methyl: 0070 AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantane carboxylic acid and cyclohexylglycine; US 2017/01 19913 A1 May 4, 2017 7 the compound of formula (5) is EMBODIMENT 21 I0083. The conjugate of embodiment 20, wherein the first targeting moiety is selected from the group comprising (5) a compound of formula (4)

(4) O

OH

O

OH

R7; O ~~~~ the compound of formula (6) is O ~ ~ -R,

(6)

a compound of formula (5) is

(5)

O

OH

EMBODIMENT 20 0082. The conjugate of any one of embodiments 1 to 19, wherein the second targeting moiety and the first targeting moiety is a targeting moiety as defined in any one of embodiments 1 to 19. US 2017/01 19913 A1 May 4, 2017 8 and a compound of formula (5) is a compound of formula (6) is

(5) (6)

O

OH

R7 O ~~~~

and NH a compound of formula (6) is

and (6) wherein the second targeting moiety is selected from the group comprising a compound of formula (4)

(4)

OH

an 1-1N1\-1N1 R7, EMBODIMENT 22 I0084. The conjugate of any one of embodiments 20 and 21, wherein the first targeting moiety is a compound of formula (4) US 2017/01 19913 A1 May 4, 2017

(4) (4)

OH OH

and and wherein the second targeting moiety is a compound of wherein the second targeting moiety is a compound of formula (4) formula (5)

(4) (5)

EMBODIMENT 23 EMBODIMENT 24 0085. The conjugate of any one of embodiments 20 and I0086. The conjugate of any one of embodiments 20 and 21, wherein the first targeting moiety is a compound of 21, wherein the first targeting moiety is a compound of formula (4) formula (4) US 2017/01 19913 A1 May 4, 2017

(4) (7)

OH OH

EMBODIMENT 26 and I0088. The conjugate of any one of embodiments 1 to 25, wherein the second targeting moiety is a compound of preferably any one of embodiments 20 to 25, wherein the formula (6) first targeting moiety and the second targeting moiety are separated by 4 to 1000 covalent bonds, preferably 5 to 150 covalent bonds, more preferably 10 to 40 covalent bonds.

(6) EMBODIMENT 27 I0089. The conjugate of any one of embodiments 1 to 26, preferably any one of embodiments 20 to 26, wherein the linker moiety LM is of general formula:

—X Y—Z - (VIII) wherein DX, is a building block moiety formed of “a” building blocks X, or is absent Y is a branching moiety or is absent, IZ, is a building block moiety formed of “b' building blocks Z, or is absent and wherein “a” and “b' are individually and independently any integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 under the proviso that a+b is 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0; preferably “a” and “b' are individually and indepen dently any integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, more preferably any integer from 0, 1, 2, 3, 4 and 5.

EMBODIMENT 28 0090 The conjugate of embodiment 27, wherein building block moiety X, is linked to an adjacent moiety through a linkage, wherein the linkage is individually and indepen dently selected from the group comprising an amide linkage, a urea linkage, a carbamate linkage, an ester linkage, an ether linkage, a thioether linkage and a disulfide linkage, and EMBODIMENT 25 wherein the adjacent moiety is selected from the group comprising branching moiety Y, building block moiety 0087. The conjugate of any one of embodiments 1 to 24, Z, Second adapter moiety AD2, Second targeting moiety wherein the first targeting moiety and/or the second targeting TM2, first adapter moiety AD1 and first targeting moiety moiety is different from a compound of formula (7) TM1. US 2017/01 19913 A1 May 4, 2017

EMBODIMENT 29 EMBODIMENT 32 0091. The conjugate of any one of embodiment 27 and 0096. The conjugate of embodiment 31, wherein the 28, wherein the building block X is of general formula building block Z is of general formula --Lin'-R-Lin- (8) --Lin'-R-Lin- (8) wherein, wherein, 0092. Lin, if present, and Lin, if present, are each I0097. Lin, if present, and Lin, if present, are each individually and independently selected from the group individually and independently selected from the group comprising CO , NRO , S—, CO comprising CO , NRO , S—, CO NR' , —CS NR' , —O , -succinimide- and NR' , —CS NR' , —O-, -succinimide- and CH CO. NR' : CH CO. NR' : wherein wherein 0093. “-succinimide-” means 0.098 “-succinimide-” means vict (9) vict (9) R" is selected from the group consisting of hydrogen and R" is selected from the group consisting of hydrogen and (C-C)alkyl. (C-C)alkyl; and the nitrogen of all nitrogen containing fragments is and the nitrogen of all nitrogen containing fragments is linked to R. linked to R: and wherein R is selected from selected from —(C-Clio) and wherein R is selected from selected from —(C-Clio) alkylidene-, -(C-C)carbocyclo-, -arylene-, -(C-Co) alkylidene-, -(C-C)carbocyclo-, -arylene-, -(C-Co) alkylidene-arylene-, -arylene-(C-C)alkylidene-, -(C- alkylidene-arylene-, -arylene-(C-Co.)alkylidene-, -(C- Co)alkylidene-arylene-(C-C)alkylidene-, -(C-C) Co)alkylidene-arylene-(C-C)alkylidene-, -(C-C) alkylidene-(C-C)carbocyclo-, -(C-Cs)carbocyclo-(C- alkylidene-(C-C)carbocyclo-, -(C-Cs)carbocyclo-(C- Co)alkylidene-, -(C-C)alkylidene-(C-C)carbocyclo Co)alkylidene-, -(C-C)alkylidene-(C-C)carbocyclo (C-Co.)alkylidene-, -(C-Cs)heterocyclo-, (C-Co) (C-Co.)alkylidene-, -(C-Cs)heterocyclo-, (C-Co) alkylidene-(C-Cs)heterocyclo-, -(C-Cs)heterocyclo-(C- alkylidene-(C-Cs)heterocyclo-, -(C-Cs)heterocyclo-(C- Co)alkylidene-, -(C-Co.)alkylidene-(C-Cs)heterocyclo Co)alkylidene-, -(C-Co.)alkylidene-(C-Cs)heterocyclo (C-C)alkylidene-, -(CH2CH2O), , and —(CH) - (C-Co.)alkylidene-, -(CH2CH2O), , and —(CH2) - (CH2CH2O), (CH) : (CH2CH2O), (CH) : and wherein and wherein r is any integer from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; r is any integer from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; S is any integer from 0, 1, 2, 3 and 4; and S is any integer from 0, 1, 2, 3 and 4; and t is any integer from 0, 1, 2, 3 and 4. t is any integer from 0, 1, 2, 3 and 4.

EMBODIMENT 30 EMBODIMENT 33 0094. The conjugate of any one of embodiments 27 to 29, 0099. The conjugate of any one of embodiments 27 to 32, wherein the building block moiety X, is a peptide. wherein the building block moiety Z, is a peptide.

EMBODIMENT 31 EMBODIMENT 34 0095. The conjugate of any one of embodiments 27 to 30, 0100. The conjugate of any one of embodiments 27 to 33, wherein building block moiety Z, is linked to an adjacent wherein the branching moiety Y is linked to an adjacent moiety through a linkage, wherein the linkage is individu moiety through a linkage, wherein the linkage is individu ally and independently selected from the group comprising ally and independently selected from the group comprising an amide linkage, a urea linkage, a carbamate linkage, an an amide linkage, a urea linkage, a carbamate linkage, an ester linkage, an ether linkage, a thioether linkage and a ester linkage, an ether linkage, a thioether linkage and a disulfide linkage, and wherein the adjacent moiety is disulfide linkage, and wherein the adjacent moiety is selected from the group comprising branching moiety Y. selected from the group comprising building block moiety building block moiety XI, first adapter moiety AD1, first DX, first adapter moiety AD1, first targeting moiety TM1, targeting moiety TM1, second adapter moiety AD2 and building block moiety Z, Second adapter moiety AD2 and second targeting moiety TM2. second targeting moiety TM2. US 2017/01 19913 A1 May 4, 2017

EMBODIMENT 3.5 (C-C)alkylidene-, -(C-Co.)alkylidene-(C-Cs) carbocyclo, -(C-Cs)carbocyclo-(C-Co)alkylidene-, 0101 The conjugate of embodiment 34, wherein the —(C-Cs)heterocyclo-, (C-Co.)alkylidene-(C-Cs) branching moiety Y is of a structure as described in any heterocyclo- —(C-C)heterocyclo-(C-Co.)alky one of embodiment 28 to 33 for building block moiety X lidene-, -(CH2CH2O), , and -(CH2CH2O), and building block moiety Z. CH ; and wherein r is any integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; EMBODIMENT 36 preferably R8 is 0102) The conjugate of any one of embodiments 34 and a) —(CH, CH, O), CH - with r being an integer 35, wherein the branching moiety Y comprises a reactive from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, preferably r is 2; or group which allows, together with a corresponding comple b) —(C-Co.)alkylidene-, more preferably -(CH2), ; mentary reactive group, forming of a linkage individually wherein n is an integer from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. and independently selected from the group comprising an preferably n is 1, 2, 3, 4, and 5. amide linkage, a urea linkage, a thiourea linkage and an amine linkage. EMBODIMENT 40 0109. The conjugate of any one of embodiments 1 to 39, EMBODIMENT 37 wherein the second adapter moiety AD2 mediates linkage to (0103) The conjugate of any one of embodiments 1 to 36, the second targeting moiety TM2 and to an adjacent moiety, wherein the first adapter moiety AD1 mediates linkage to the wherein the adjacent moiety is selected from the group first targeting moiety TM1 and to an adjacent moiety, comprising linker moiety LM, building block moiety Za. wherein the adjacent moiety is selected from the group branching moiety Y, building block moiety XI first comprising linker moiety LM, building block moiety X. adapter moiety AD1 and first targeting moiety TM1. branching moiety Y, building block moiety Z. second adapter moiety AD2 and second targeting moiety TM2. EMBODIMENT 41 0110. The conjugate of embodiment 40, wherein the EMBODIMENT 38 linkage is individually and independently selected from the 01.04 The conjugate of embodiment 37, wherein the group comprising an amide linkage, a sulfonamide linkage, linkage is individually and independently selected from the a urea linkage, a thioether linkage, an ether linkage, a group comprising an amide linkage, a sulfonamide linkage, carbamate linkage, an amine linkage, a triazole linkage, an a urea linkage, a thioether linkage, an ether linkage, a oxime linkage, a hydrazone linkage, a disulfide linkage, a carbamate linkage, an amine linkage, a triazole linkage, an pyrazine linkage and a dihydropyrazine linkage. oxime linkage, a hydrazone linkage, a disulfide linkage, a pyrazine linkage and a dihydropyrazine linkage. EMBODIMENT 42 0111. The conjugate of any one of embodiments 40 to 31, EMBODIMENT 39 wherein the second adapter moiety AD2, preferably prior to 0105. The conjugate of any one of embodiments 37 to 38, forming any linkage, is of the following structure: wherein the first adapter moiety AD1, preferably prior to forming any linkage, is of the following structure: RG3-R8-RG4 (10) 0.112 wherein RG3 is a reactive group as described RG3-R8-RG4 (10) herein, preferably a reactive group as indicated in Table 0106 wherein RG3 is a reactive group as described 2 or selected from the group comprising amino, car herein, preferably a reactive group as indicated in Table boxylic acid, activated carboxylic acid, chloro, bromo, 2 or selected from the group comprising amino, car iodo, sulfhydryl, hydroxyl, sulfonic acid, activated sul boxylic acid, activated carboxylic acid, chloro, bromo, fonic acid, sulfonic acid esters like mesylate or tosylate. iodo, sulfhydryl, hydroxyl. Sulfonic acid, activated Sul Michael acceptors, strained alkenes like trans fonic acid, sulfonic acid esters like mesylate or tosylate, cyclooctene, isocyanate, isothiocyanate, aldehyde, Michael acceptors, strained alkenes like trans ketone, aminooxy, hydrazide, hydrazine, azide, alkyne cyclooctene, isocyanate, isothiocyanate, aldehyde, and tetrazine; ketone, aminooxy, hydrazide, hydrazine, azide, alkyne 0113 wherein RG4 is a reactive group as described and tetrazine; herein, preferably a reactive group as indicated in Table 0107 wherein RG4 is a reactive group as described 2 or selected from the group comprising amino, car herein, preferably a reactive group as indicated in Table boxylic acid, activated carboxylic acid, chloro, bromo, 2 or selected from the group comprising amino, car iodo, sulfhydryl, hydroxyl, sulfonic acid, activated sul boxylic acid, activated carboxylic acid, chloro, bromo, fonic acid, sulfonic acid esters like mesylate or tosylate. iodo, sulfhydryl, hydroxyl, sulfonic acid, activated Sul Michael acceptors, strained alkenes like trans fonic acid, sulfonic acid esters like mesylate or tosylate, cyclooctene, isocyanate, isothiocyanate, aldehyde, Michael acceptors, strained alkenes like trans ketone, aminooxy, hydrazide, hydrazine, azide, alkyne cyclooctene, isocyanate, isothiocyanate, aldehyde, and tetrazine; and ketone, aminooxy, hydrazide, hydrazine, azide, alkyne 0114 wherein R8 is selected from —(C-C)alky and tetrazine; and lidene-, -(C-C)carbocyclo-, -O-(C-Cs)alkyl-, 0.108 wherein R8 is selected from —(C-C)alky -arylene-, -(C-Co.)alkylidene-arylene-, -arylene lidene-, -(C-C)carbocyclo-, -O-(C-Cs)alkyl-, (C-C)alkylidene-, -(C-Co)alkylidene-(CCs)car -arylene-, -(C-Co.)alkylidene-arylene-, -arylene bocyclo, -(C-Cs)carbocyclo-(C-Co)alkylidene-, US 2017/01 19913 A1 May 4, 2017

—(C-Cs)heterocyclo-, (C-Co.)alkylidene-(C-C) EMBODIMENT 48 heterocyclo- —(C-Cs)heterocyclo-(C-Co.)alky 0.120. The conjugate of embodiment 47, wherein the lidene-, -(CH2CH2O), , and —(CH2CH2O), adapter moiety AD3 mediated the linkage between the CH ; and wherein second targeting moiety TM2 and the effector moiety EM. r is any integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; EMBODIMENT 49 preferably R8 is I0121 The conjugate of embodiment 48, wherein the a) —(CH2—CH2—O), CH - with r being an integer second targeting moiety TM2 is different from a compound from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, preferably r is 2; or of formula (2) and/or different from a compound of formula b) —(C-Co.)alkylidene-, more preferably —(CH), ; (7) wherein n is an integer from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, preferably n is 1, 2, 3, 4, and 5. (7)

EMBODIMENT 43 0115 The conjugate of any one of embodiments 2 to 42, wherein the Effector moiety EM is linked, preferably cova lently linked to the branching moiety Y.

EMBODIMENT 44 OH 0116. The conjugate of any one of embodiments 2 to 42, wherein the Effector moiety EM is linked, preferably cova lently linked to the second targeting moiety TM2.

EMBODIMENT 45 0117 The conjugate of embodiment 44, wherein the second targeting moiety TM2 is different from a compound of formula (2) and/or different from a compound of formula O 1N1a1n-1a N -R. (7) H H

EMBODIMENT SO (7) 0.122 The conjugate of any one of embodiments 47 to 49, wherein the linkage is selected from the group comprising an amide linkage, a Sulfonamide linkage, a urea linkage, a thiourea linkage, a thioether linkage, an ether linkage, a

carbamate linkage, an amine linkage, a triazole linkage, an Oxime linkage, a hydrazone, a disulfide linkage, a pyrazine linkage and a dihydro-pyrazine linkage. EMBODIMENT 51 I0123. The conjugate of any one of embodiments 46 to 50, wherein the third adapter moiety AD3 is a structure of formula -Lin-R-Lin- (11): wherein R is selected from selected from —(C-Co.)alkylidene-, —(C-C)carbocyclo-, -arylene-, -(C-C)alkylidene arylene-, -arylene-(C-Co.)alkylidene-, -(C-Co.)alky lidene-arylene-(C-C)alkylidene-, -(C-C)alkylidene (C-C)carbocyclo- —(C-C)carbocyclo-(C-C) alkylidene-, -(C-C)alkylidene-(C-C)carbocyclo-(C- Co)alkylidene-, —(C-Cs)heterocyclo- (C-Co) alkylidene-(C-C)heterocyclo-, -(C-C)heterocyclo-(C- Co)alkylidene-, -(C-Co.)alkylidene-(C-Cs)heterocyclo EMBODIMENT 46 (C-Co.)alkylidene-, -(CH2CH2O), , and —(CH2) - 0118. The conjugate of any one of embodiments 1 to 45, (CH2CH2O), (CH) ; wherein the conjugate comprises a third adapter moiety and wherein AD3. r is any integer from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; S is any integer from 0, 1, 2, 3 and 4; and t is any integer from 0, 1, 2, 3 and 4: EMBODIMENT 47 Lin' is selected from the group comprising —CO , 0119 The conjugate of embodiment 46, wherein the NR' CO NR' CS NR' CH and adapter moiety AD3 mediates the linkage between branch a bond, preferably a covalent bond, more preferably a single ing moiety Y and the effector moiety EM. bond; US 2017/01 19913 A1 May 4, 2017

wherein R' is selected from the group consisting of hydro EMBODIMENT 57 gen and (C-C)alkyl, and; Lin is selected from the group comprising-CO-, -S , I0131 The conjugate of embodiment 56, wherein the NRO , CO. NR , CS NR' , O—, Acceptor is a chelator, preferably the chelator is selected —CH2—, -SO. , -succinimide-, -CH2 CO-NR' , from the group comprising DOTA, NOTA, DTPA, TETA, —C=C- (in case of for example triazole), =N-O-, EDTA, NODAGA, NODASA, TRITA, CDTA, BAT, DFO, —N N —N N CO —N=N N (in case of or HYNIC, more preferably the chelator is DOTA. for example triazole), —HC– and RC= (of oxime and hydraZone); EMBODIMENT 58 wherein R' is selected from the group consisting of hydro 0.132. The conjugate of any one of embodiments 56 to 57, gen and (C-C)alkyl. wherein the Acceptor comprises an aromatic moiety, EMBODIMENT 52 wherein the aromatic moiety is selected from the group 0.124. The conjugate of any one of embodiments 1 to 51, comprising indole and benzene, preferably benzene is Sub wherein both the first adaptor moiety AD1 and the second stituted with at least one heteroatom, wherein the heteroa adaptor moiety AD2 are present. tom is selected from the group comprising an O, an N and S. EMBODIMENT 53 0.125. The conjugate of any one of embodiments 1 to 52, EMBODIMENT 59 wherein the linker moiety LM is present. I0133. The conjugate of any one of embodiments 2 to 58, EMBODIMENT 54. preferably embodiment 57, wherein the Effector is a diag 0126 The conjugate of any one of embodiments 1 to 53, nostically active nuclide, preferably a diagnostically active wherein the linker moiety LM is present, wherein the linker radionuclide, or a therapeutically active nuclide, preferably moiety LM is a peptide and wherein the peptide is inserted a therapeutically active radionuclide. into formula (1) either in N->C direction or in C->N direction. EMBODIMENT 60 EMBODIMENT 55 I0134. The conjugate of any one of embodiments 1 to 59, wherein one of the first targeting moiety TM1 and the 0127. The conjugate of any one of embodiments 1 to 54, second targeting moiety TM2 is selected from the group wherein the conjugate further comprises a third adaptor comprising an antibody, an antigen-binding antibody frag moiety AD3, wherein the third adaptor moiety is mediat ment, a camelid heavy chain IgG (hcIgG), a cartilaginous ing the linkage of the Effector moiety to the conjugate. fish IgNAR antibody, a protein scaffold, a target-binding EMBODIMENT 56 peptide, a peptide nucleic acid (PNA), a target-binding 0128. The conjugate of any one of embodiments 2 to 55, polypeptide or protein, a target binding nucleic acid mol wherein the Effector moiety is selected from the group ecule, a carbohydrate, a lipid and a target-binding Small comprising an Effector, Acceptor and -Acceptor-Effector. molecule. wherein I0129. Acceptor is a moiety which mediates linking of EMBODIMENT 61 an Effector to the third adapter moiety AD3, if present, 0.135 The conjugate of any one of embodiments 1 to 60, or Acceptor is a moiety which mediates linking of an wherein the conjugate is selected from the group comprising Effector to the branching moiety Y, and a conjugate of formulae (12), (12a), (13), (13a), (14), (14a). 0.130. Effector is selected from the group comprising a (15), (15a), (16), (16a), (17), (17a), (18), (18a), (19), (19a). diagnostically active agent and a therapeutically active (20), (20a), (21), (21a), (22), (22a), (23), (23a), (24), (24a). agent. (25), (25a), (26), (26a), (27), (27a), (28), (29) and (30):

(12)

NHDOTA

O r^-run non-rr O US 2017/01 19913 A1 May 4, 2017 15

-continued

NH OH ( \, N1 NHDOTA

O /

O 11-1a GABA-N1 N1,N1 N1)-N O O

(13a)

OH

O US 2017/01 19913 A1 May 4, 2017 16

-continued

NHDOTA

NHDOTA

US 2017/01 19913 A1 May 4, 2017 19

-continued

O ^^ Yau-tan

(20)

US 2017/01 19913 A1 May 4, 2017 25

-continued (29)

O

OH

O N1N1,N1 N1)-N-glutards-NH ) / \--- MAB1909 CONH2 (30)

O

OH

O 1N-11N1a n Ttds N // \--on- MAB3035: CONH preferably the conjugate is a conjugate of formulae (12), giogenic agent, a cytostatic agent, a cytotoxic agent, an (13), (14), (15), (16), (17), (18), (21), (22), (23), (24), (25), antithrombotic agent, an anti-inflammatory agent, an (26), and (27) and the diagnostically active radionuclide and antiphlogistic agent, an anticoagulative agent, an antibacte the therapeutically active radionuclide is chelated by the rial agent, an antiviral agent, an antimycotic agent, an chelator of formulae (12), (13), (14), (15), (16), (17), (18), endogenous fluorophore, a polycyclic aromatic, a coumarin, (21), (22), (23), (24), (25), (26), and (27); more preferably a quinoline, an indole, an imidazole, an UV-excited fluoro the diagnostically active radionuclide and the therapeuti phore, a fluorescein, a rhodamine, a naphthoxanthene dye, a cally active radionuclide is selected from the group com phenanthridine, a BODIPY dye, a cyanine, a phthalocya prising In, 177Lu, 7Ga, Ga, Cu and Y. nine, a Xanthene, an acridine, an oxazine, a polyene, an oxonol, a benzimidazole, an azamethine, a styryl, a thiazole, EMBODIMENT 62 an anthraquinone, a naphthalimide, an aza18 annulene, a 0136. The conjugate of any one of embodiments 2 to 61, porphin, a metal-ligand-complexe, a squaraine, an 8-hy wherein the Effector is selected from the group comprising droxyquinoline-derivative, a polymethin, a nanocrystal, a a small molecule, an antibody, an antigen-binding fragment fluorescent protein, a protein, a perylene, a phthalocyanine, of an antibody, an anticalin, an aptamer, a spiegelmer, an an upconversion dye, a diketopyrrolopyrrole, a molecule of anti-proliferative agent, an antimigration agent, an antian the porphyrin family, including but not limited to a hemato US 2017/01 19913 A1 May 4, 2017 26 porphyrin derivative and a molecule based on a hematopor EMBODIMENT 68 phyrin derivative, a benzoporphyrin derivative, a 5-amin olevulinic acid, and texaphyrin, a molecule of the 0142. The conjugate of any one of embodiments 1 to 67, chlorophyll family, including but not limited to a chlorin, a wherein the target targeted by the second targeting moiety is purpurin, and a bacteriochlorin; a dye, including but not a target expressed by tumor cells. limited to phtalocyanine and naphthalocyanine, a small mononuclear or polynuclear paramagnetic chelate, a metal EMBODIMENT 69 loporphyrin, a polymeric or macromolecular carrier, prefer ably covalently or noncovalently labeled with a paramag 0143. The conjugate of embodiment 68, wherein the netic chelate), a particulate CA including a fluorinated or a tumor is selected from group A, wherein group A comprises nonfluorinated paramagnetic micelle or liposome and a Neoplasms; Neoplasm, benign; Neoplasm, uncertain paramagnetic or a Superparamagnetic particle e.g. an iron whether benign or malignant; Neoplasm, malignant; Neo oxide, a Gd3+-labeled zeolite, a diamagnetic CEST poly plasm, metastatic; Neoplasm, malignant, uncertain whether mer, a diamagnetic hyperpolarization probe including but primary or metastatic; Tumor cells, benign; Tumor cells, not limited to gases and aerosols, a C-labeled compound uncertain whether benign or malignant; Tumor cells, malig or ion, an ultrasound contrast enhancing agent comprising a nant; Malignant tumor, Small cell type; Malignant tumor, shell an a core, whereby the shell preferably consista of a giant cell type; Malignant tumor, fusiform cell type: Epi material selected from the group comprising a phospholipid, thelial neoplasms; Epithelial tumor, benign; Carcinoma in a poly-D.L-lactide-co-glycolide acid (PLGA), serum albu situ; Carcinoma; Carcinoma, metastatic; Carcinomatosis: min, a polymer, a perflutren, a carbon-based phase shift Epithelioma, benign; Epithelioma, malignant; Large cell colloid, a perflexane, a lipid/galactose, a Sulphur hexafluo carcinoma; Carcinoma, undifferentiated type; Carcinoma, ride, a perfluorocyl bromide, a surfactant, anoligopeptide, anaplastic type; Pleomorphic carcinoma, Giant cell and and galactose and the core preferably consists of a material spindle cell carcinoma; Giant cell carcinoma; Spindle cell selected from the group comprising air, a perfluorocarbon, a carcinoma; Pseudosarcomatous carcinoma; Polygonal cell decafluorobutane, an octafluoropropane, a dodecafluoropen carcinoma; Spheroidal cell carcinoma; Tumorlet; Small cell tane and a perfluorobutane, a carbon nanotube, preferably a carcinoma; Oat cell carcinoma; Small cell carcinoma, fusi single-walled carbon nanotube or a multi-walled carbon form cell type; Papillary and squamous cell neoplasms; nanotube, a fullerene, a dendrimer, a quantum dot, a lipo Papilloma (except Papilloma of urinary bladder M81201): Some, a silica nanoparticle, a magnetic nanoparticle, a lipid Papillary carcinoma in situ; Papillary carcinoma; Verrucous nanoparticle including but not limited to a nanoemulsion, a papilloma; Verrucous carcinoma; Squamous cell papilloma; polymeric nanoparticle, a albumin-based nanoparticle and a Papillary Squamous cell carcinoma; Inverted papilloma; nanocrystal and a nucleic acid, a small molecule, an amino Papillomatosis; Squamous cell carcinoma in situ; Squamous acid, a peptide, a protein, a carbohydrate, a lipid, glycopro cell carcinoma; Squamous cell carcinoma, metastatic; tein, a glycan or lipoproteins preferably having antiprolif Squamous cell carcinoma, keratinizing type; Squamous cell erative, antimigration, antiangiogenic, cytostatic and/or carcinoma, large cell, nonkeratinizing type; Squamous cell cytotoxic properties. carcinoma, Small cell, nonkeratinizing type; Squamous cell carcinoma, spindle cell type; Adenoid squamous cell carci EMBODIMENT 63 noma; Squamous cell carcinoma in situ with questionable stromal invasion; Squamous cell carcinoma, microinvasive; 0.137 The conjugate of any one of embodiments 1 to 62, Queyrats erythroplasia; Bowen's disease; Lymphoepithe wherein the first target is same as the second target. lial carcinoma; Basal cell neoplasms; Basal cell tumor; Basal cell carcinoma; Multicentric basal cell carcinoma; EMBODIMENT 64 Basal cell carcinoma, morphea type; Basal cell carcinoma, 0.138. The conjugate of any one of embodiments 1 to 63, fibroepithelial type; Basosquamous carcinoma, Metatypical wherein the first targeting moiety and the second targeting carcinoma; Intraepidermal epithelioma of Jadassohn, moiety are targeting the same target. Trichoepithelioma: Trichofolliculoma; Tricholemmoma; Pilomatrixoma, Transitional cell papillomas and carcino EMBODIMENT 65 mas; Transitional cell papilloma; Urothelial papilloma; Transitional cell carcinoma in situ; Transitional cell carci 0.139. The conjugate of any one of embodiments 1 to 64, noma; Schneiderian papilloma; Transitional cell papilloma, wherein the first targeting moiety and the second targeting inverted type; Schneiderian carcinoma; Transitional cell moiety are targeting the same target molecule. carcinoma, spindle cell type; Basaloid carcinoma; Cloaco genic carcinoma; Papillary transitional cell carcinoma; EMBODIMENT 66 Adenomas and adenocarcinomas; Adenoma; Bronchial 0140. The conjugate of any one of embodiments 1 to 62, adenoma; Adenocarcinoma in situ; Adenocarcinoma; wherein the second targeting moiety TM2 is targeting a Adenocarcinoma, metastatic; Scirrhous adenocarcinoma; target different from the target targeted by the first targeting Linitis plastic; Superficial spreading adenocarcinoma; moiety. Adenocarcinoma, intestinal type; Carcinoma, diffuse type; Monomorphic adenoma; Basal cell adenoma; Islet cell adenoma; Islet cell carcinoma; Insulinoma; Insulinoma, EMBODIMENT 67 malignant: Glucagonoma, Glucagonoma, malignant, Gastri 0141. The conjugate of embodiment 66, wherein the noma, Gastrinoma, malignant; Mixed islet cell and exocrine second targeting moiety is targeting a target different from adenocarcinoma; Bile duct adenoma; Cholangiocarcinoma; neurotensin receptor 1, preferably the first targeting moiety Bile duct cystadenoma; Bile duct cystadenocarcinoma; TM1 is targeting NTR, preferably NTR1, and wherein. Liver cell adenoma; Hepatocellular carcinoma; Hepatocho US 2017/01 19913 A1 May 4, 2017 27 langioma, benign; Combined hepatocellular carcinoma and adenoma. Mucinous adenocarcinoma; Pseudomyxoma peri cholangiocarcinoma; Trabecular adenoma; Trabecular tonei; Mucin-producing adenocarcinoma; Signet ring cell adenocarcinoma; Embryonal adenoma; Eccrine dermal carcinoma, Metastatic signet ring cell carcinoma; Ductal, cylindroma; Adenoid cystic carcinoma; Cribriform carci lobular, and medullary neoplasms; Intraductal carcinoma, noma; Adenomatous polyp. Adenocarcinoma in adenoma noninfiltrating; Infiltrating duct carcinoma; Comedocarci tous polyp; Tubular adenoma; Tubular adenocarcinoma; noma, noninfiltrating; Comedocarcinoma, Juvenile carci Adenomatous polyposis coli; Adenocarcinoma in adenoma noma of the breast; Intraductal papilloma; Noninfiltrating tous polyposis coli, Multiple adenomatous polyps; Solid intraductal papillary adenocarcinoma; Intracystic papillary carcinoma; Carcinoma simplex; Carcinoid tumor; Carcinoid adenoma; Noninfiltrating intracystic carcinoma; Intraductal tumor, malignant; Carcinoid tumor, argentaflin; Carcinoid papillomatosis; Subareolar duct papillomatosis; Medullary tumor, argentaflin, malignant; Carcinoid tumor, nonargen carcinoma; Medullary carcinoma with amyloid stroma; taffin: Carcinoid tumor, nonargentaflin, malignant; Muco Medullary carcinoma with lymphoid stroma: Lobular car carcinoid tumor, malignant; Composite carcinoid; Pulmo cinoma in situ; Lobular carcinoma; Infiltrating ductular nary adenomatosis; Bronchiolo-alveolar adenocarcinoma; carcinoma; Inflammatory carcinoma; Paget’s disease, mam Alveolar adenoma; Alveolar adenocarcinoma; Papillary mary; Paget’s disease and infiltrating duct carcinoma of adenoma; Papillary adenocarcinoma; Villous adenoma; breast; Paget’s disease, extramammary (except Paget’s dis Adenocarcinoma in villous adenoma; Villous adenocarci ease of bone); Acinar cell neoplasms; Acinar cell adenoma; noma; Tubulovillous adenoma; Chromophobe adenoma; Acinar cell tumor, Acinar cell carcinoma; Complex epithe Chromophobe carcinoma; Acidophiladenoma; Acidophil lial neoplasms; Adenosquamous carcinoma; Adenolym carcinoma; Mixed acidophil-basophiladenoma; Mixed aci phoma; Adenocarcinoma with squamous metaplasia; dophil-basophil carcinoma; Oxyphilic adenoma; Oxyphilic Adenocarcinoma with cartilaginous and osseous metaplasia; adenocarcinoma; Basophiladenoma; Basophil carcinoma; Adenocarcinoma with spindle cell metaplasia; Adenocarci Clear cell adenoma; Clear cell adenocarcinoma, Hyper noma with apocrine metaplasia; Thymoma, benign; Thy nephroid tumor; Renal cell carcinoma; Clear cell adenofi moma, malignant; Specialized gonadal neoplasms; Sex broma; Granular cell carcinoma; Chief cell adenoma; Water cord-stromal tumor; Thecoma; Theca cell carcinoma; clear cell adenoma, Water-clear cell adenocarcinoma; Mixed Luteoma; Granulosa cell tumor; Granulosa cell tumor, cell adenoma; Mixed cell adenocarcinoma; Lipoadenoma; malignant; Granulosa cell-theca cell tumor; Androblastoma, Follicular adenoma; Follicular adenocarcinoma; Follicular benign; Androblastoma, Androblastoma, malignant; Sertoli adenocarcinoma, well differentiated type: Follicular adeno Leydig cell tumor; Gynandroblastoma; Tubular androblas carcinoma, trabecular type; Microfollicular adenoma, Mac toma; Sertoli cell carcinoma; Tubular androblastoma with rofollicular adenoma; Papillary and follicular adenocarci lipid storage; Leydig cell tumor, benign, Leydig cell tumor; noma; Nonencapsulated Sclerosing carcinoma, Multiple Leydig cell tumor, malignant; Hilar cell tumor; Lipid cell endocrine adenomas; Juxtaglomerular tumor; Adrenal cor tumor of ovary; Adrenal rest tumor; Paragangliomas and tical adenoma; Adrenal cortical carcinoma; Adrenal cortical glomus tumors; Paraganglioma, Paraganglioma, malignant: adenoma, compact cell type; Adrenal cortical adenoma, Sympathetic paraganglioma; Parasympathetic paragan heavily pigmented variant, Adrenal cortical adenoma, clear glioma; Glomus jugulare tumor, Aortic body tumor; Carotid cell type; Adrenal cortical adenoma, glomerulosa cell type; body tumor, Extra-adrenal paraganglioma: Extra-adrenal Adrenal cortical adenoma, mixed cell type; Endometrioid paraganglioma, malignant; Pheochromocytoma, Pheochro adenoma; Endometrioid adenoma, borderline malignancy; mocytoma, malignant; Glomangiosarcoma; Glomus tumor; Endometrioid carcinoma; Endometrioid adenofibroma; Glomangioma; Nevi and melanomas; Pigmented nevus: Endometrioid adenofibroma, borderline malignancy; Endo Malignant melanoma; Nodular melanoma; Balloon cell metrioid adenofibroma, malignant. Adnexal and skin nevus: Balloon cell melanoma; Halo nevus: Fibrous papule appendage neoplasms; Skin appendage adenoma; Sweat of the nose; Neuronevus: Magnocellular nevus: Nonpig gland adenoma; Sweat gland tumor, Sweat gland adenocar mented nevus: Amelanotic melanoma; Junctional nevus: cinoma; Apocrine adenoma; Apocrine adenocarcinoma; Malignant melanoma in junctional nevus; Precancerous Eccrine acrospiroma; Eccrine spiradenoma, Hidrocystoma; melanosis; Malignant melanoma in precancerous melanosis: Papillary hydradenoma; Papillary syringadenoma, Syrin Hutchinson's melanotic freckle, Malignant melanoma in goma; Sebaceous adenoma; Sebaceous adenocarcinoma; Hutchinson's melanotic freckle; Superficial spreading mela Ceruminous adenoma; Ceruminous adenocarcinoma; noma; Intradermal nevus; Compound nevus: Giant pig Mucoepidermoid neoplasms; Mucoepidermoid tumor; mented nevus, Malignant melanoma in giant pigmented Mucoepidermoid carcinoma, Cystic, mucinous, and serous nevus: Epithelioid and spindle cell nevus: Epithelioid cell neoplasms; Cystadenoma, Cystadenocarcinoma; Serous melanoma; Spindle cell melanoma; Spindle cell melanoma, cystadenoma; Serous cystadenoma, borderline malignancy; type A; Spindle cell melanoma, type B; Mixed epithelioid Serous cystadenocarcinoma; Papillary cystadenoma, Papil and spindle cell melanoma; Blue nevus; Blue nevus, malig lary cystadenoma, borderline malignancy; Papillary cysta nant; Cellular blue nevus; Soft tissue tumors and sarcomas; denocarcinoma; Papillary serous cystadenoma, Papillary Soft tissue tumor, benign; Sarcoma; Sarcomatosis; Spindle serous cystadenoma, borderline malignancy; Papillary cell sarcoma; Giant cell sarcoma (except of bone M92503); serous cystadenocarcinoma; Serous Surface papilloma; Small cell sarcoma; Epithelioid cell sarcoma; Fibromatous Serous Surface papilloma, borderline malignancy; Serous neoplasms; Fibroma: Fibrosarcoma; Fibromyxoma; Fibro Surface papillary carcinoma; Mucinous cystadenoma, Muci myxosarcoma; Periosteal fibroma; Periosteal fibrosarcoma; nous cystadenoma, borderline malignancy. Mucinous cys Fascial fibroma; Fascial fibrosarcoma; Infantile fibrosar tadenocarcinoma; Papillary mucinous cystadenoma; Papil coma; Elastofibroma; Aggressive fibromatosis; Abdominal lary mucinous cystadenoma, borderline malignancy; fibromatosis: Desmoplastic fibroma: Fibrous histiocytoma; Papillary mucinous cystadenocarcinoma. Mucinous Atypical fibrous histiocytoma; Fibrous histiocytoma, malig US 2017/01 19913 A1 May 4, 2017 28 nant: Fibroxanthoma; Atypical fibroxanthoma; Fibrox malignant; Angiofibroma; Hemangioblastoma; Lymphatic anthoma, malignant; Dermatofibroma; Dermatofibroma pro vessel tumors; Lymphangioma, Lymphangiosarcoma; Cap tuberans; Dermatofibrosarcoma, Myxomatous neoplasms; illary lymphangioma, Cavernous lymphangioma: Cystic Myxoma, Myxosarcoma; Lipomatous neoplasms; Lipoma; lymphangioma: Lymphangiomyoma, Lymphangiomyoma Liposarcoma; Fibrolipoma; Liposarcoma, well differenti tosis; Hemolymphangioma; Osteomas and osteosarcomas; ated type; Fibromyxolipoma; Myxoid liposarcoma; Round Osteoma; Osteosarcoma; Chondroblastic osteosarcoma; cell liposarcoma; Pleomorphic liposarcoma; Mixed type Fibroblastic osteosarcoma; Telangiectatic osteosarcoma; liposarcoma; Intramuscular lipoma; Spindle cell lipoma; Osteosarcoma in Paget’s disease of bone; Juxtacortical Angiomyolipoma; Angiomyoliposarcoma; Angiolipoma; osteosarcoma; Osteoid osteoma; Osteoblastoma; Chon Angiolipoma, infiltrating: Myelolipoma; Hibernoma; Lipo dromatous neoplasms; Osteochondroma; Osteochondroma blastomatosis: Myomatous neoplasms; Leiomyoma; Intra tosis; Chondroma; Chondromatosis; Chondrosarcoma; JuX vascular leiomyomatosis: Leiomyosarcoma; Epithelioid tacortical chondroma; Juxtacortical chondrosarcoma; leiomyoma; Epithelioid leiomyosarcoma; Cellular leio Chondroblastoma; Chondroblastoma, malignant; Mesen myoma; Bizarre leiomyoma; Angiomyoma; Angiomyosar chymal chondrosarcoma; Chondromyxoid fibroma; Giant coma, Myoma, Myosarcoma; Rhabdomyoma; Rhabdomyo cell tumors; Giant cell tumor of bone; Giant cell tumor of sarcoma; Pleomorphic rhabdomyosarcoma; Mixed type bone, malignant: Giant cell tumor of Soft parts; Malignant rhabdomyosarcoma; Fetal rhabdomyoma; Adult rhab giant cell tumor of Soft parts; Miscellaneous bone tumors; domyoma; Embryonal rhabdomyosarcoma; Alveolar rhab Ewing's sarcoma; Adamantinoma of long bones; Ossifying domyosarcoma; Complex mixed and stromal neoplasms; fibroma; Odontogenic tumors; Odontogenic tumor, benign; Endometrial stromal sarcoma; Endolymphatic stromal myo Odontogenic tumor; Odontogenic tumor, malignant, Denti sis; Adenomyoma; Pleomorphic adenoma; Mixed tumor, noma; Cementoma; Cementoblastoma, benign; Cementify malignant; Mullerian mixed tumor; Mesodermal mixed ing fibroma; Gigantiform cementoma; Odontoma; Com tumor; Mesoblastic nephroma; Nephroblastoma; Epithelial pound odontoma; Complex odontoma; Ameloblastic fibro nephroblastoma; Mesenchymal nephroblastoma; Hepato odontoma; Ameloblastic odontosarcoma; Adenomatoid blastoma; Carcinosarcoma; Carcinosarcoma, embryonal odontogenic tumor; Calcifying odontogenic cyst; Amelo type: Myoepithelioma; Mesenchymoma, benign; Mesenchy blastoma; Ameloblastoma, malignant, Odontoameloblas moma; Mesenchymoma, malignant; Embryonal sarcoma; toma; Squamous odontogenic tumor; Odontogenic myxoma; Fibroepithelial neoplasms; Brenner tumor; Brenner tumor, Odontogenic fibroma; Ameloblastic fibroma; Ameloblastic borderline malignancy; Brenner tumor, malignant: Fibroad fibrosarcoma; Calcifying epithelial odontogenic tumor; Mis enoma; Intracanalicular fibroadenoma; Pericanalicular cellaneous tumors; Craniopharyngioma; Pinealoma; Pine fibroadenoma; Adenofibroma; Serous adenofibroma; Muci ocytoma; Pineoblastoma; Melanotic neuroectodermal nous adenofibroma; Cellular intracanalicular fibroadenoma; tumor, Chordoma; Gliomas; Glioma, malignant; Gliomato Cystosarcoma phyllodes; Cystosarcoma phyllodes, malig sis cerebri; Mixed glioma; Subependymal glioma; Sub nant; Juvenile fibroadenoma; Synovial neoplasms; Syn ependymal giant cell astrocytoma; Choroid plexus papil ovioma, benign; Synovial sarcoma; Synovial sarcoma, loma; Choroid plexus papilloma, malignant, Ependymoma; spindle cell type: Synovial sarcoma, epithelioid cell type; Ependymoma, anaplastic type; Papillary ependymoma; Synovial sarcoma, biphasic type; Clear cell sarcoma of Myxopapillary ependymoma; Astrocytoma; Astrocytoma, tendons and aponeuroses; Mesothelial neoplasms; Mesothe anaplastic type; Protoplasmic astrocytoma; Gemistocytic lioma, benign; Mesothelioma, malignant: Fibrous mesothe astrocytoma; Fibrillary astrocytoma; Pilocytic astrocytoma; lioma, benign; Fibrous mesothelioma, malignant; Epithe Spongioblastoma; Spongioblastoma polare; Astroblastoma; lioid mesothelioma, benign: Epithelioid mesothelioma, Glioblastoma; Giant cell glioblastoma; Glioblastoma with malignant; Mesothelioma, biphasic type, benign; Mesothe sarcomatous component; Primitive polar spongioblastoma; lioma, biphasic type, malignant, Adenomatoid tumor; Germ Oligodendroglioma; Oligodendroglioma, anaplastic type; cell neoplasms; Dysgerminoma, Seminoma, Seminoma, Oligodendroblastoma; Medulloblastoma; Desmoplastic anaplastic type; Spermatocytic seminoma; Germinoma; medulloblastoma; Medullomyoblastoma; Cerebellar sar Embryonal carcinoma; Endodermal sinus tumor, Polyem coma; Monstrocellular sarcoma; Neuroepitheliomatous neo bryoma; Gonadoblastoma; Teratoma, benign, Teratoma; plasms; Ganglioneuroma; Ganglioneuroblastoma; Gangli Teratoma, malignant; Teratocarcinoma; Malignant teratoma, oneuromatosis; Neuroblastoma; Medulloepithelioma: undifferentiated type; Malignant teratoma, intermediate Teratoid medulloepithelioma; Neuroepithelioma; Spon type; Dermoid cyst; Dermoid cyst with malignant transfor gioneuroblastoma; Ganglioglioma; Neurocytoma; Pacinian mation; Struma ovarii; Struma ovarii, malignant; Strumal tumor; Retinoblastoma; Retinoblastoma, differentiated type: carcinoid; Trophoblastic neoplasms; Hydatidiform mole; Retinoblastoma, undifferentiated type; Olfactory neurogenic Invasive hydatidiform mole; Choriocarcinoma; Choriocar tumor, Esthesioneurocytoma; Esthesioneuroblastoma; cinoma combined with teratoma; Malignant teratoma; tro Esthesioneuroepithelioma, Meningiomas; Meningioma; phoblastic; Mesonephromas; Mesonephroma, benign; Meningiomatosis; Meningioma, malignant; Meningothe Mesonephric tumor; Mesonephroma, malignant; Endosal liomatous meningioma; Fibrous meningioma; Psammoma pingioma; Blood vessel tumors; Hemangioma, Heman tous meningioma: Angiomatous meningioma; Hemangio giosarcoma; Cavernous hemangioma; Venous hemangioma; blastic meningioma; Hemangiopericytic meningioma; Racemose hemangioma; Kupffer cell sarcoma; Heman Transitional meningioma; Papillary meningioma, Menin gioendothelioma, benign; Hemangioendothelioma; Heman geal sarcomatosis: Nerve sheath tumor; Neurofibroma; Neu gioendothelioma, malignant; Capillary hemangioma; Intra rofibromatosis; Neurofibrosarcoma; Melanotic neurofi muscular hemangioma; Kaposi's sarcoma; Angiokeratoma; broma; Plexiform neurofibroma; Neurilemmoma; Verrucous keratotic hemangioma; Hemangiopericytoma, Neurinomatosis; Neurilemmoma, malignant; Neuroma; benign; Hemangiopericytoma; Hemangiopericytoma, Granular cell tumors and alveolar soft part sarcoma; Granu US 2017/01 19913 A1 May 4, 2017 29 lar cell tumor; Granular cell tumor, malignant; Alveolar soft leukemia; Miscellaneous myeloproliferative and lymphop part sarcoma, Lymphomas; NOS or diffuse, Lymphomatous roliferative disorders: Polycythemia vera; Acute panmyelo tumor, benign, Malignant lymphoma; Malignantlymphoma, sis; Chronic myeloproliferative disease; Myelosclerosis with non Hodgkin’s type; Malignant lymphoma, undifferentiated myeloid metaplasia; Idiopathic thrombocythemia; Chronic cell type; Malignant lymphoma, stem cell type; Malignant lymphoproliferative disease; and Acute Lymphoblastic Leu lymphoma, convoluted cell type; Lymphosarcoma, Malig kemia (ALL), Acute Myeloid Leukemia (AML), Adreno nant lymphoma, lymphoplasmacytoid type; Malignant lym cortical Carcinoma, AIDS-Related Cancers, Kaposi Sar phoma, immunoblastic type; Malignant lymphoma, mixed coma, Lymphoma, Anal Cancer, Appendix Cancer, lymphocytic-histiocytic; Malignant lymphoma, centroblas Astrocytomas, Childhood, Atypical Teratoid/Rhabdoid tic-centrocytic, diffuse; Malignant lymphoma, follicular Tumor, Basal Cell Carcinoma, Bile Duct Cancer, Extrahe center cell; Malignant lymphoma, lymphocytic, well differ patic, Bladder Cancer, Bone Cancer, Ewing Sarcoma Family entiated; Malignant lymphoma, lymphocytic, intermediate of Tumors, Osteosarcoma and Malignant Fibrous Histiocy differentiation; Malignant lymphoma, centrocytic; Malig toma, Brain Stem Glioma, Brain Tumor, Astrocytomas, nant lymphoma, follicular center cell, cleaved; Malignant Brain and Spinal Cord Tumors, Central Nervous System lymphoma, lymphocytic, poorly differentiated; Prolympho Atypical Teratoid/Rhabdoid Tumor, Central Nervous Sys cytic lymphosarcoma; Malignant lymphoma, centroblastic tem. Embryonal Tumors, Central Nervous System Germ Cell type; Malignant lymphoma, follicular center cell, non Tumors, Craniopharyngioma, Ependymoma, Breast Cancer, cleaved; Reticulosarcomas; Reticulosarcoma; Reticulosar Male Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, coma, pleomorphic cell type; Reticulosarcoma, nodular; Carcinoid Tumor, Gastrointestinal Cancer, Carcinoma of Hodgkin’s disease; Hodgkin’s disease; Hodgkin’s disease, Unknown Primary, Cardiac Tumors, Childhood, Central lymphocytic predominance; Hodgkin’s disease, mixed cel Nervous System, Atypical Teratoid/Rhabdoid Tumor, lularity; Hodgkin’s disease, lymphocytic depletion; Hodg Embryonal Tumors, Germ Cell Tumor, Childhood, Lym kin's disease, lymphocytic depletion, diffuse fibrosis; Hodg phoma, Primary, Cervical Cancer, Childhood Cancers, kin's disease, lymphocytic depletion, reticular type; Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Hodgkin’s disease, nodular Sclerosis; Hodgkin’s disease, Myelogenous Leukemia (CML), Chronic Myeloprolifera nodular Sclerosis, cellular phase; Hodgkin’s paragranuloma; tive Disorders, Colon Cancer, Colorectal Cancer, Cutaneous Hodgkin’s granuloma; Hodgkin’s sarcoma; Lymphomas, T-Cell Lymphoma, Extrahepatic Bile Duct Cancer, Ductal nodular or follicular, Malignant lymphoma, nodular, Malig Carcinoma In Situ (DCIS), Embryonal Tumors of the Cen nant lymphoma, mixed lymphocytic-histiocytic; nodular: tral Nervous System, Endometrial Cancer, Ependymoma, Malignant lymphoma, centroblastic-centrocytic, follicular, Childhood, Esophageal Cancer, Esthesioneuroblastoma, Malignant lymphoma, lymphocytic, well differentiated, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extrago nodular, Malignant lymphoma, lymphocytic, intermediate nadal Germ Cell Tumor, Eye Cancer, Intraocular Melanoma, differentiation, nodular, Malignant lymphoma, follicular Retinoblastoma, Malignant Fibrous Histiocytoma of Bone, center cell, cleaved, follicular, Malignant lymphoma, lym Osteosarcoma, Gallbladder Cancer, Gastric Cancer, Gastro phocytic, poorly differentiated, nodular, Malignant lym intestinal Carcinoid Tumor, Gastrointestinal Stromal phoma, centroblastic type, follicular, Malignant lymphoma, Tumors (GIST), Germ Cell Tumor, Central Nervous System follicular center cell, noncleaved, follicular; Mycosis fun Germ. Cell Tumor, Ovarian Germ. Cell Tumor, Testicular goides; Mycosis fungoides; Sezary's disease; Miscellaneous Germ Cell Tumor, Gestational Trophoblastic Disease, reticuloendothelial neoplasms; Microglioma; Malignant his Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart tiocytosis: Histiocytic medullary reticulosis: Letterer-Siwe's Cancer, Childhood, Hepatocellular Cancer. Histiocytosis, disease; Plasma cell tumors; Plasma cell myeloma; Plasma Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal cell tumor, benign; Plasmacytoma; Plasma cell tumor, Cancer, Islet Cell Tumors, Pancreatic Neuroendocrine malignant; Mast cell tumors; Mastocytoma; Mast cell Sar Tumors, Kidney, Renal Cell Cancer, Wilms Tumor, Langer coma; Malignant mastocytosis; Burkitt's tumor; Burkitt's hans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Lip tumor; Leukemias; Leukemias; Leukemia; Acute leukemia; and Oral Cavity Cancer, Liver Cancer (Primary), Lobular Subacute leukemia; Chronic leukemia; Aleukemic leuke Carcinoma In Situ (LCIS), Lung Cancer, Non-Small Cell mia; Compound leukemias; Compound leukemia; Lym Lung Cancer, Small Cell Lung cancer, AIDS-Related Lym phoid leukemias; Lymphoid leukemia; Acute lymphoid leu phoma, Non-Hodgkin Lymphoma, Primary Central Nervous kemia; Subacute lymphoid leukemia; Chronic lymphoid System (CNS) Lymphoma, Macroglobulinemia, Walden leukemia; Aleukemic lymphoid leukemia; Prolymphocytic ström, Melanoma, Intraocular (Eye), Merkel Cell Carci leukemia; Plasma cell leukemias; Plasma cell leukemia; noma, Mesothelioma, Malignant, Metastatic Squamous Erythroleukemias; Erythroleukemia; Acute erythremia; Neck Cancer with Occult Primary, Midline Tract Carcinoma Chronic erythremia; Lymphosarcoma cell leukemias; Lym Involving NUT Gene, Mouth Cancer, Multiple Endocrine phosarcoma cell leukemia; Myeloid leukemias; Myeloid Neoplasia Syndromes, Childhood, Multiple Myeloma/ leukemia; Acute myeloid leukemia; Subacute myeloid leu Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplas kemia; Chronic myeloid leukemia; Aleukemic myeloid leu tic Syndromes, Myelodysplastic/Myeloproliferative Neo kemia; Neutrophilic leukemia; Acute promyelocytic leuke plasms, Myelogenous Leukemia, Chronic (CML), Myeloid mia; Basophilic leukemias; Basophilic leukemia; Leukemia, Acute (AML), Myeloma, Multiple, Myeloprolif Eosinophilic leukemias; Eosinophilic leukemia; Monocytic erative Disorders, Chronic, Nasal Cavity and Paranasal leukemias; Monocytic leukemia; Acute monocytic leuke Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Oral mia; Subacute monocytic leukemia; Chronic monocytic Cancer, Oral Cavity Cancer, Lip and, Oropharyngeal Can leukemia; Aleukemic monocytic leukemia; Miscellaneous cer, Osteosarcoma and Malignant Fibrous Histiocytoma of leukemias; Mast cell leukemia; Megakaryocytic leukemia; Bone, Ovarian Cancer, Epithelial, Low Malignant Potential Megakaryocytic myelosis; Myeloid sarcoma, Hairy cell Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine US 2017/01 19913 A1 May 4, 2017 30

Tumors (Islet Cell Tumors), Papillomatosis, Childhood, e.g. v6), CD44 receptor, CD52, CD70, CD77 (glycosphin Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, golipid Gb3), CD95, CD96, CDK1, CDK2, CDK2, CDK4, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, CDK4, CDK6, CDK7, CDK9, CEACAM cell adhesion Pheochromocytoma, Pituitary Tumor, Plasma Cell Neo molecule, CEACAM5 (carcinoembryonic antigen-related plasm/Multiple Myeloma, Pleuropulmonary Blastoma, cell adhesion molecule 5), Cell surface nucleolin, Cellular Childhood, Pregnancy and Breast Cancer, Prostate Cancer, tumor antigen p53, Centromeric protein E. Chemokine Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis receptor 4 (CXCR4), Cholecystokinin receptor subtype 2 and Ureter, Transitional Cell Cancer, Rhabdomyosarcoma, (CCK-2), Cholecystokinin type A (CCK-A) receptor, Cho Childhood, Salivary Gland Cancer, Sarcoma, Ewing, Kaposi, Osteosarcoma (Bone Cancer), Rhabdomyosarcoma, line kinase, Choline transporter, Choline transporter-like Soft Tissue, Uterine, Sézary Syndrome, Skin Cancer, Non protein 4, Chondroitin sulphate proteoglycan TENB2, Chro melanoma, Small Intestine Cancer, Soft Tissue Sarcoma, mogranin A (CgA), CIF. CK2, Claudin 4 receptor, Claudin Squamous Cell Carcinoma—see Skin Cancer (Nonmela 18, Claudin-6, Clusterin, c-MET, c-MYC, Collagen, colla noma), Squamous Neck Cancer with Occult Primary, Meta gen XXIII, Colon cancer Surface glycoprotein, Colony static, Stomach (Gastric) Cancer, T-Cell Lymphoma, Cuta stimulating factor-1 receptor (CSF-1R), Copper transporter neous—see Mycosis Fungoides and Sézary Syndrome, 1, Corticotropin-releasing factor receptor 1 (CRFR1), Cor Testicular Cancer. Throat Cancer, Thymoma and Thymic ticotropin-releasing factor receptor 2 (CRFR2), COX-2, Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Coxsackie-adenovirus receptor (CAR), CTLA4, Cyclin-de Renal Pelvis and Ureter, Unknown Primary, Carcinoma of pendent kinase, Cystine/glutamate exchanger, Cytochrome Unusual Cancers of Childhood, Ureter and Renal Pelvis, p450 (Hypoxic tissue), Cytochrome P450 family 11B Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, enzymes, de2-7 epidermal growth factor receptor, Delta-like Endometrial, Uterine Sarcoma, Vaginal Cancer, Vulvar Can 4. Disialoganglioside 2 (GD2), Disialogangliosides, DKK2 cer, Waldenström Macroglobulinemia and Women's Can protein, DNA topoisomerase I, DNA topoisomerase II, Dop amine D2 receptor, DPPIV, DR5, E2F1, E-Cadherin, ED-A CS. fibronectin, ED-B fibronectin, EGF HER2 receptor, EGFR (HER1), EGFR Tyrosine kinase, EGFR2, EGFRivIII, EMBODIMENT 70 EGFRVIII, EGP-1 (epithelial glycoprotein-1), eIF4E, Elon 0144. The conjugate of any one of embodiments 1 to 69, gation factor 1A, EMMPRIN (CD147), endosialin, Endosta wherein the target is selected from the group comprising tin receptor, Endothelin A (ETA) receptor, Endothelin B targets expressed in any tumor, cancer, tumor disease, cancer receptor, ENG protein, EpCAM (epithelial cell adhesion disease, tumor indication or cancer indication, preferably the molecule), EphA2 receptor, EphrinB4 receptor, Epidermal target is selected from group B, wherein group B comprises growth factor domain-like-7 (EGFL7), Epidermal growth 14C5 antigen, 18-22 kDa cell surface antigen for human factor receptor 3, Epidermal growth factor receptor deletion squamous-cell carcinoma, 3H11 antigen, A33 antigen, Abl variant, de2-8, ErbB2, ErbB-2 extracellular domain, Eryth kinase, Activated leukocyte cell adhesion molecule (AL ropoitin receptor, E-selectin, Estrogen receptor (ER), FAK, CAM), Activin receptor-like kinase-1, AKT1, AKT2, AKT3. Farnesyl protein transferase, Ferritin, FGF receptor, FGF-3 Aldehyde oxidase, Aldosterone synthase, ALK, Alkaline receptor, Fibrin, alpha-chain, Fibrin?fibronectin complexes, phosphatase, Alpha folate receptor, Alpha(3)beta(1) integ Fibrinogen, Fibroblast activation protein-alpha (FAPa), rin, Alpha(4)beta(1) integrin, Alpha(5)beta(1), Alpha(v)beta Fibronectin, Flt3, Foetal antigen-2, folate hydrolase, Folate (3) integrin, Alpha(V)beta(6) integrin, Alpha-1A adrenergic receptor, G protein-coupled estrogen receptor, Galactose receptor, Alpha-3 integrin receptor, Amino acid transporter receptor, Galectin-3, Gamma-secretase, Gamma-seminopro ASC, Amino acid transporter ASCT2, Amino acid trans tein, Gastric Mucin, gastrin receptors, Gastrin releasing porter L, Aminopeptidase N (ANP, CD13), Androgen recep peptide (GRP) receptor, Gastrin/cholecystokinin-2 (CCK-2, tor (AR), Angiopoietin-f-2, Angiopoietin-1, Angiopoietin-1 CCK-B) receptor, GD3 antigen, Gelatinase B (matrix met receptor, Antiapoptotic protein BCL-XL, Anti-dansyl (DNS) alloproteinase 9, MMP-9), Gelatinases (MMP-2), GIP (gas receptor, Antigen OC183B2. Aromatic Lamino acid decar tric inhibitory polypeptide), Glucagon like peptide 1 recep boxylase (AAAD), Atrial natriuretic peptide receptor 1, tor, Glucocorticoid receptor (GR), Glucose transporter, Atrial natriuretic peptide receptor 2, A-type amino acid Glucose transporter (GLUT1), Glucose transporter transporter, Aurora C, Aurora-A, Aurora-B, Avidin, B7-H3. (GLUT5), Glucosidase, GLUT transporter system, gluta BAFF, Bcl-2, Bcr-Abl tyrosine kinase, Beta-2-microglobu mate carboxypeptidase II (GCP II), Glutamate transporters, lin (B2M), Beta-galactosidase, Beta-glucuronidase, Beta Glutamine transporter, Glycogen synthase kinase-3 beta, human chorionic gonadotropin (Beta-hCG), Biotin, Bomb Glycoprotein IIb/IIIa receptor (GPIb/IIIa receptor), Glypi esin receptor, Bombesin receptor subtype-3, BRAF, Btk, CA can 3, GnRH. Gonadotropin releasing hormone receptor, 125 antigen, CA19.9, CA27.29, CAAG-1/KAAG-1, Cad gpA33, GPNMB, GPR54 receptor, Guanylate cyclase C herin 2, Calcitonin, Calcitonin receptor, Calcium-activated (GC-C) receptor, Haptoglobin-?3 chain derived from prostate chloride channel, Calpain, Cancer cell Surface-bound nucle cancer cells, HB-EGF, HDM2, HE4, Heat shock protein osomes, Carbonic Anhydrase II, Carbonic anhydrase IX, HSP 90, Heparan sulfate proteoglycans(HSPG), Hepara Carcinoembryonic antigen (CEA), Cartilage proteoglycans, nase, Heparin cofactor II (neovascular endothelium), Caspase-3, Caspase-7, catenin, Cathepsin, Cathepsin B, Hepatocyte growth factor (HGF), Hepatocyte growth factor Cathepsin D. Cathepsin E. Cathepsin K, Cathepsins H, CBP, receptor, Hepsin, HER3, Hexokinase, High-density lipopro CC49, CCK-1 receptor (CCK-A), CCND1 (cyclin D1), tein receptor (HDLR). Histone deacetylase (HDAC). His CD105 (Endoglin, EDG), CD117 (c-kit), CD1111b, CD123, tone deacetylase 4. Histone deacetylase 6, HLA-DR antigen, CD13, CD137 antigen, CD14 antigens, CD15, CD16a, HLA-DR10, HMW-MAA (high molecular weight mela CD16b, CD19, CD20, CD21, CD22, CD25, CD27, CD3, noma-associated antigen), hsp70, Human glioma cell-sur CD30, CD33, CD37, CD4, CD40, CD44 (splice variants, face antigen, Human sperm protein 17, Hyaluronidase (HA US 2017/01 19913 A1 May 4, 2017

dase), Hypoxia-inducible factor 1 (HIF-1), IGF1R, IgG1. vator inhibitor (PAI-1), Plectin-1, P1GF, PLK-1, PNK3 IL-13 receptor, IL-1 (3, IL-4R, IL-6, IL-6R, IL-8RB, Induc (protein kinase N3), Polo-like kinase 1 (PLK1), Poly ADP ible nitric oxide synthase (iNOS), insulin like-growth-factor ribose polymerase 1, Polyamine receptor, Progesterone binding protein 7 (IGFBP7). Insulin receptor, Insulin-like receptor (PR), Progestin receptor, Programmed cell death-1 growth factor, Insulin-like growth factor 1 receptor (IGF ligand 1 (PD-L1), Prolactin receptor, Propressophysin-like 1R), Integrin a23 ul. Integrin CVB4. Integrins CVB5, Inter protein cell Surface antigen, Prostate specific antigen, Pros cellular adhesion molecule 1 (ICAM-1), Interleukin 11 tate stem cell antigen (PSCA), Prostate-specific membrane receptor (IL-11R), Interleukin 11 receptor, alpha-chain, antigen (PSMA), Protein kinase B, Protein kinase C. Protein Interleukin 13 receptor alpha 2. Interleukin 18 receptor kinase D. Protein-tyrosine phosphatase SHP-1, Proto-onco (IL-18R), Interleukin 2 receptor (IL-2R), Interleukin 6 gene c-Kit; tyrosine-protein kinase kit; mast/stem cell receptor (IL-6R), Interleukin-18, Interleukin-7 receptor, growth factor receptor; CD117, PSCA, PTPN1, Puromycin Intestinal alkaline phosphatase, JAK1, JAK2, JAK3, JNK1/ sensitive aminopeptidase (PSA), Raf-1, RANKL, Ras, MAPK8, kinase insert domain receptor (KDR), Kinesin Receptor for advanced glycation endproducts (RAGE), Spindle Protein, KIR, L1 cell adhesion protein, L1-CAM Renin, Retinoic acid receptor alpha, Ribosyldihydronicoti antigen, La antigen, Lactate dehydrogenase, Lactoferrin namide dehydrogenase, Robol, Robo4, RON. Secretin, Ser receptor, LAG3, Laminin, Laminin receptor, L-Amino acid ine protease matriptase, Serine Racemase, Serine/threonine transporter (LAT), LAT1, LAT2, Lectin, Lectin, Legumain/ kinase (Akt). Serine/threonine-protein kinase Chikl, Serine/ Asparaginyl endopeptidase, Leukotriene A4 Hydrolase, threonine-protein kinase Chk2, Serine/threonine-protein Leukotriene B4 receptor 1, Lewis Y antigen, Low-density kinase PLK, Siglec-15, Sigma 2 receptor, Sigma receptor, lipoprotein receptor (LDLR), Low-density lipoprotein receptor-related protein-1, LRRC15, Luteinizing hormone SIRT1, Smoothened, somatostatin receptor. Somatostatin releasing hormone receptor, Luteinizing hormone/chorionic receptor 1 (SSTR1), Somatostatin receptor 2 (SSTR2), gonadotropin (LH/CG) receptor, Lymphatic vessel endothe Somatostatin receptor 3 (SSTR3). Somatostatin receptor lial hyaluronan receptor-1 (LYVE-1), Macrophage colony sub-type 4, Somatostatin receptor type 5, Sortilin (NTR3), stimulating factor 1, Mammaglobin-A, MAP kinase p38, Sphingosine kinase, Src, STAT3, Stathim, STEAP1, Steryl MARK3, Matrix metalloproteinase 2 (MMP-2), Matrix met sulfatase, Substance P receptor (NK-1R), Substance-K alloproteinase 7 (MMP-7), Matrix metalloproteinase-12, receptor (NK-2R), Survivin, Syk, TAG 72, Telomerase, Matrix metalloproteinase-13, Matrix metalloproteinase-9, TEM5, TEM8, Tenascin, Tenascin-C, TENB2, TFPI, TGF Matrix metalloproteinases (membrane type-1), Mcl-1, beta 1, TGF-beta 2. TGF-beta 3. Thioredoxin, Thioredoxin MCT1, MCT4, Mdrl. MEK1, MEK2, Melancortin-1 recep reductases, Thomsen-Friedenreich antigen, Thymidine tor (MC1R), Melanin, Melanin, phenomelanin, Melanocyte kinase, Thymidine phosphorylase, Thyroglobulin, Tissue stimulating hormone receptor, Melanocyte-stimulating hor factor, Toll-like receptor 9, topoisomerase, TORC1, Trans mone receptor, Mesenchymal-epithelial transition factor ferrin receptor (TfR), Translocator protein, TRPM8 protein, (c-Met), Mesothelin, Mesothelin-ADC, Microsomal epox Tubulin (microtubules), Tumor associated glycoprotein 72 ide hydrolase, Microtubules, MIF, Mindin/RG-1 extracellu (TAG-72), Tumor endothelial marker 1 (TEM1), Tumor lar matrix protein, Mitotic kinesin Eg5, MMP14, MMP-3, necrosis factor receptor, Tumor necrosis factor-related apop Monoamine oxidase B (MAO-B), Monosialoganglioside tosis-inducing ligand receptor 1 (TRAIL-R1), Tumor necro (sialosylated Lea antigen), MTF-1, mTOR, MTORC1, sis factor-related apoptosis-inducing ligand receptor 2 MTORC2, MUC1, Mucin MUC2, Multidrug resistance (TRAILR2), Tumor necrosis factor-a, Tumor specific gly associated protein 1, Na+-dependent myo-inositol cotrans coprotein antigen IOR C2, TWEAK, TYK2, Tyrosine porter-1/2 (SMIT-1/2), N-acetyl C-linked acidic dipeptidase hydroxylase, Underglycosylated mucin-1 antigen (uMUC (NAALADase), N-acetylated alpha-linked L-amino dipep 1), Uridine-cytidine kinase 2 (UCK2), Urokinase, Urokinase tidase, NAD-dependent deacetylase sirtuin-1, NADH oxi plasminogen activator receptor, Urokinase-type plasmino dase, NCAM, Nectin-4, Neprilysin, Neural cadherin, Neural gen activator receptor (uPAR), Vascular cell adhesion mol cell adhesion molecule (NCAM), Neuroblastoma-specific ecule 1 (VCAM-1), Vascular endothelial growth factor cell surface antigen, Neurokinin 1 (NK1) receptor, Neuro (VEGF), Vascular endothelial growth factor receptor medin-B receptor (NMBR), Neuromedin-K receptor (NK (VEGFR), Vascular endothelial growth factor receptor 2 3R), neuropeptide Y receptor 1 (NPY1-R), neuropeptide Y (VEGFR2), Vascular endothelial growth factor receptor 3, receptor 2 (NPY2-R), Neuropeptide Y receptor type 4 Vasoactive intestinal peptide receptor (VPAC1), Vasoactive (NPY4-R), Neuropeptide Y receptor type 4 (NPY4-R), intestinal polypeptide receptor 2 (VPAC2), VEGF A iso Neuropilin-1, neuropilin-1 receptors, Neurotensin, Neuro form, VEGFB, VEGF-C, Voltage-dependent anion-selective tensin receptor, Neurotensin receptor 1 (NTSR1), Neuro channel protein 2 (VDAC2), Voltage-dependent anion-se tensin receptor 2 (NTSR2), Nicotinic acetylcholine receptor, lective channel protein 3 (VDAC3), Wee1A kinase, XIAP alpha-4beta2, Non-camptothecin topol, Notch, NPY. NRH C.-Fetoprotein (AFP), B-D-galactose receptor and B-Glu dehydrogenase quinone 2, NRP1, NTRK1, Nuclear factor curonidase. NF-kappa-B. Nuclear matrix protein 22, Nucleolin, NY ESO-1, OX40, Oxytocin receptor, P70-S6 Kinase 1, PARP EMBODIMENT 71 1, PD-1, PDGFR, PDGFRA, PDGFRB, Peripheral benzo diazepine receptor (PBR), Peroxiredoxin I, Peroxisome 0145 The conjugate of any one of embodiments 1 to 70, proliferator-activated receptor-gamma (PPARgamma), wherein the second targeting moiety is selected from the P-glycoprotein (Pgp), phosphatidylethanolamine, Phospha group comprising an antibody, an antigen-binding antibody tidylserine, PI3K, PIGF, PIK-1, PIM kinase, Pituitary fragment, a camelid heavy chain IgG (hcIgG), a cartilagi adenylate cyclase-activating polypeptide type I receptor, nous fish IgNAR antibody, a protein scaffold, a target Placental alkaline phosphatase (PLAP), plasminogen acti binding peptide, a peptide nucleic acid (PNA), a target US 2017/01 19913 A1 May 4, 2017 32 binding polypeptide or protein, a target binding nucleic acid ICs of 100 nM or less, preferably 50 nM or less for NTR, molecule, a carbohydrate, a lipid and a target-binding Small more preferably for NTR1. molecule. EMBODIMENT 72 EMBODIMENT 76 0146 The conjugate of any one of embodiments 2 to 71, 0150. The conjugate of any one of embodiments 1 to 75, wherein the Effector is a diagnostically active nuclide or a wherein the targeting moiety is different from a glycoside. therapeutically active nuclide, wherein the diagnostically active nuclide and the therapeutically active radionuclide is individually and independently selected from the group EMBODIMENT 77 comprising "In, Tc, 9.7Ga Fe, Ga, 7°As, In, 7Ru, 208Pb, 62Cu, Cu, 5 Cr, 52"Mn, 157Gd, Cu, 89Zr, 0151. The conjugate of embodiment 76, wherein the and 77Lu, 18.Re, 90Y. 7Cu, Ga, 69Er, 12'Sn, 127Te, 142 Pr glycoside is a N-glycoside, C-glycoside, O-gylcoside or an 143Pr 198Au, 199Au, 161Tb, 109Pd, 188Rd, 188Re, 77As, 166Dy, S-glycoside, preferably the glycoside is N-glycoside. 166Ho, 149Pm, 15Pm, 'Sim, 15°Gd, 72Tm, 90Y. 169Yb, 175Yb, 105Rh, '''Ag, 213Bi, 225Ac, 177mSn and 227.Th. EMBODIMENT 78 EMBODIMENT 73 0152 The conjugate of any one of embodiments 1 to 77, 0147 The conjugate of any one of embodiments 1 to 72, wherein the conjugate is different from compound (89), wherein the conjugate interacts with a neurotensin receptor, including the F analog of this compound:

(89)

OH

O ry,N Z51 r" S. OH wherein the neurotensin receptor is preferably selected from EMBODIMENT 79 the group comprising neurotensin receptor 1 (NTR1) and O153 The conjugate of any one of embodiments 1 to 78, neurotensin receptor 2 (NTR2). for use in a method for the diagnosis of a disease.

EMBODIMENT 74 EMBODIMENT 80 0148 The conjugate of embodiment 73, wherein the 0154 The conjugate of embodiment 79, wherein the disease is a disease involving a target targeted by the first conjugate is an antagonist for NTR, preferably NTR1. targeting moiety TM1 or by the second targeting moiety TM2, preferably the disease is one involving neurotensin EMBODIMENT 75 receptor, more preferably the disease is a disease involving neurotensin receptor 1. 0149 The conjugate of any one of embodiments 1 to 74. wherein the conjugate has an ICs of 100 nM or less, EMBODIMENT 81 preferably 50 nM or less, for a target targeted by either the 0155 The conjugate of embodiment 80, wherein the first targeting moiety TM1 or the target targeted by the disease is a disease not involving tissue of the central second targeting target TM2, preferably the conjugate has an nervous system and/or cells of the central nervous system. US 2017/01 19913 A1 May 4, 2017

EMBODIMENT 82 EMBODIMENT 90 0156 The conjugate of any one of embodiments 79 to 81, 0164. The conjugate of any one of embodiments 79 to 89, wherein the disease is selected from the group comprising wherein the method for the diagnosis is an imaging method. tumors and hematological malignancies. EMBODIMENT 91 EMBODIMENT 83 0.165. The conjugate of embodiment 90, wherein the 0157. The conjugate of embodiment 82, wherein the imaging method is selected from the group consisting of tumor is selected from the group comprising ductal pancre Scintigraphy, Single Photon Emission Computed Tomogra atic adenocarcinoma, Small cell lung cancer, prostate cancer, phy (SPECT) and Positron Emission Tomography (PET). colorectal cancer, breast cancer, meningioma, Ewing's sar coma, pleural mesothelioma, head and neck cancer, non EMBODIMENT 92 Small cell lung cancer, gastrointestinal stromal tumors, uter ine leiomyoma and cutaneous T-cell lymphoma, preferably 0166 The conjugate of any one of embodiments 79 to 91, ductal pancreatic adenocarcinoma, Small cell lung cancer, wherein the method comprises the administration of a diag prostate cancer, colorectal cancer, breast cancer, menin nostically effective amount of the compound to a Subject, gioma, Ewing's sarcoma, and indications subject to group A preferably to a mammal, wherein the mammal is selected as defined herein. from the group comprising man, companion animals, pets and livestock, more preferably the subject is selected from EMBODIMENT 84 the group comprising man, dog, cat, horse and cow, and most preferably the Subject is a human being. 0158. The conjugate of any one of embodiments 79 to 83, wherein Effector is a radioactive metal, wherein preferably EMBODIMENT 93 the radioactive metal is chelated by Acceptor, wherein Acceptor is a chelator. 0167. The conjugate of any one of embodiments 1 to 78, for use in a method for the treatment of a disease. EMBODIMENT 85 EMBODIMENT 94 0159. The conjugate of embodiment 84, wherein the radioactive metal is a diagnostically effective radioactive (0168 The conjugate of embodiment 93, wherein the metal. disease is a disease involving a target targeted by the first targeting moiety TM1 or by the second targeting moiety EMBODIMENT 86 TM2, preferably the disease is one involving neurotensin receptor, preferably the disease is a disease involving neu 0160 The conjugate of embodiment 85, wherein the rotensin receptor 1. radioactive metal is selected from the group comprising 113In, 99mTc, 7Ga, 52Fe, Ga, 7°As, Ill In, 7Ru, 208Pb, EMBODIMENT 95 °Cu, Cu, Cr, 5?"Mn, 157Gd, Cu, Zr, and 77Lu; more preferably the radioactive metal is selected from the group 0169. The conjugate of embodiment 94, wherein the comprising "Tc, 7 Ga, Ga, In, Zr and '77Lu; and disease is a disease not involving tissue of the central more preferably the radioactive metal is '''In, "77Lu or Zr. nervous system and/or cells of the central nervous system. EMBODIMENT 87 EMBODIMENT 96 0161 The conjugate of any one of embodiments 79 to 83, 0170 The conjugate of any one of embodiments 93 to 94, wherein Effector is a radionuclide, wherein preferably the wherein the disease is selected from the group comprising radionuclide is covalently bound by Acceptor, wherein tumors and hematological malignancies. Acceptor comprises an aromatic moiety, wherein the aro matic moiety is selected from the group comprising indole EMBODIMENT 97 and benzene, preferably benzene is substituted with at least one heteroatom, wherein the heteroatom is selected from the 0171 The conjugate of embodiment 96, wherein the group comprising O, N and S. tumor is selected from the group comprising ductal pancre atic adenocarcinoma, Small cell lung cancer, prostate cancer, EMBODIMENT 88 colorectal cancer, breast cancer, meningioma, Ewing's sar coma, pleural mesothelioma, head and neck cancer, non 0162 The conjugate of embodiment 87, wherein the Small cell lung cancer, gastrointestinal stromal tumors, uter radionuclide is a diagnostically effective radioactive halo ine leiomyoma and cutaneous T-cell lymphoma, preferably gen. ductal pancreatic adenocarcinoma, Small cell lung cancer, prostate cancer, colorectal cancer, breast cancer, menin EMBODIMENT 89 gioma, Ewing's sarcoma, and indications subject to group A defined herein. 0163 The conjugate of embodiment 88, wherein the radioactive halogen is selected from the group comprising EMBODIMENT 98 18F 123, 1241, 125I. 131I. 7SBr 7°Br, 77Br, 8Br, and 21 At more preferably the radionuclide is selected from the group 0172. The conjugate of any one of embodiments 95 to 97. comprising ‘I, 'I. wherein Effector is a therapeutically active agent. US 2017/01 19913 A1 May 4, 2017 34

EMBODIMENT 99 group of subjects, wherein the Subject is likely to respond or 0173 The conjugate of any one of embodiments 93 to 98, likely not to respond to a treatment of a disease, wherein the wherein the method comprises the administration of a thera method for the selection of a subject from a group of peutically effective amount of the conjugate to a subject, Subjects comprises carrying out a method of diagnosis using preferably to a mammal, wherein the mammal is selected the compound of any one of embodiments 1 to 78, prefer from the group comprising man, companion animals, pets ably a method for the diagnosis of a disease as described in and livestock, more preferably the subject is selected from any one of embodiments 79 to 92. the group comprising man, dog, cat, horse and cow, and most preferably the Subject is a human being. EMBODIMENT 107 0181. The conjugate of any one of embodiments 1 to 78, EMBODIMENT 100 for use in a method for the stratification of a group of 0.174. The conjugate of any one of embodiments 93 to 97. Subjects into Subjects which are likely to respond to a wherein Effector is a radioactive metal, wherein preferably treatment of a disease, and into Subjects which are not likely the radioactive metal is chelated by Acceptor, wherein to respond to a treatment of a disease, wherein the method Acceptor is a chelator. for the stratification of a group of Subjects comprises car rying out a method of diagnosis using the compound of any EMBODIMENT 101 one of embodiments 1 to 78, preferably a method for the 0.175. The conjugate of embodiment 100, wherein the diagnosis of a disease as described in any one of embodi radioactive metal is selected from the group comprising ments 79 to 92. 18.Re, 90Y. 7Cu, Ga, 69Er, 12'Sn, 127Te, 142 Pr. 14.Pr 198Au, 199Au, 161Tb, 109Pd, 188Rd, 188Re, 77As, 166Dy, EMBODIMENT 108 166Ho, 149Pm, 15Pm, Sm, 15°Gd, 72Tm, 90Y. In, 169b, 175Yb, 177Lu, 105Rh, '''Ag, 213Bi, 225Ac, 6.Cu, 177mSn and 0182. The conjugate of any one of embodiments 105 to ''Th, preferably the radioactive metal is selected from the 107, wherein the disease is a disease involving neurotensin group comprising Re, Re, 'Y. Sm, Ga, and receptor, preferably the disease is a disease involving neu '''Lu; and more preferably the radioactive metal is selected rotensin receptor 1. from the group comprising 'Y and ''Lu. EMBODIMENT 109 EMBODIMENT 102 0183 The conjugate of embodiment 108, wherein the 0176 The conjugate of any one of embodiments 93 to 99, disease is a disease not involving tissue of the central wherein Effector is a radionuclide, wherein preferably the nervous system and/or cells of the central nervous system. radionuclide is covalently bound by Acceptor, wherein Acceptor comprises an aromatic moiety, wherein the aro EMBODIMENT 110 matic moiety is selected from the group comprising indole and benzene, preferably benzene is substituted with at least 0.184 The conjugate of any one of embodiments 105 to one heteroatom, wherein the heteroatom is selected from the 109, wherein the disease is selected from the group com group comprising O, N and S. prising tumors and hematological malignancies.

EMBODIMENT 103 EMBODIMENT 111 0177. The conjugate of embodiment 102, wherein the 0185. The conjugate of embodiment 110, wherein the radionuclide is a radioactive halogen. tumor is selected from the group comprising ductal pancre atic adenocarcinoma, Small cell lung cancer, prostate cancer, EMBODIMENT 104 colorectal cancer, breast cancer, meningioma, Ewing's sar 0.178 The conjugate of embodiment 103, wherein the coma, pleural mesothelioma, head and neck cancer, non radioactive halogen is selected from the group comprising Small cell lung cancer, gastrointestinal stromal tumors, uter 123, 125 and 1291. ine leiomyoma and cutaneous T-cell lymphoma, preferably ductal pancreatic adenocarcinoma, Small cell lung cancer, EMBODIMENT 105 prostate cancer, colorectal cancer, breast cancer, menin 0179 The conjugate of any one of embodiments 1 to 78, gioma, Ewing's sarcoma, and indications subject to group A for use in a method for the identification of a subject, as defined herein. wherein the subject is likely to respond or likely not to respond to a treatment of a disease, wherein the method for EMBODIMENT 112 the identification of a Subject comprises carrying out a method of diagnosis using the compound of any one of 0186 The conjugate of any one of embodiments 105 to embodiments 1 to 78, preferably a method for the diagnosis 111, wherein the method of diagnosis is an imaging method. of a disease as described in any one of embodiments 79 to 92. EMBODIMENT 113 0187. The conjugate of embodiment 112, wherein the EMBODIMENT 106 imaging method is selected from the group comprising 0180. The conjugate of any one of embodiments 1 to 78, Scintigraphy, Single Photon Emission Computed Tomogra for use in a method for the selection of a subject from a phy (SPECT) and Positron Emission Tomography (PET). US 2017/01 19913 A1 May 4, 2017

EMBODIMENT 114 metal radioactive or a halogen radioactive, more preferably the effector is Effector of the compound of any one of 0188 The conjugate of any one of embodiments 105 to embodiments 1 to 78. 113, preferably any one of embodiments 112 and 113, wherein Effector is a radioactive metal, wherein preferably EMBODIMENT 121 the radioactive metal is chelated by Acceptor, wherein Acceptor is a chelator. 0.195 The conjugate of any one of embodiments 116 to 120, wherein the method comprises the administration of an EMBODIMENT 115 effective amount of the compound and/or of the effector to a subject, preferably to a mammal, wherein the mammal is 0189 The conjugate of any one of embodiments 105 to selected from the group comprising man, companion ani 113, preferably any one of embodiments 112 and 113, mals, pets and livestock, more preferably the Subject is wherein Effector is a radioactive halogen, wherein prefer selected from the group comprising man, dog, cat, horse and ably the radioactive halogen is covalently bound by Accep cow, and most preferably the Subject is a human being. tor, wherein Acceptor comprises an aromatic moiety, wherein the aromatic moiety is selected from the group EMBODIMENT 122 comprising indole and benzene, preferably benzene is Sub stituted with at least one heteroatom, wherein the heteroa 0196. The conjugate of any one of embodiments 116 to tom is selected from the group comprising O, N and S. 121, wherein the delivery is for diagnosis, treatment and/or a combination of diagnosis and treatment. EMBODIMENT 116 EMBODIMENT 123 0190. The conjugate of any one of embodiments 1 to 78, for use in a method for delivering an effector to neurotensin 0197) The conjugate of any one of embodiments 121 to receptor, preferably neurotensin receptor 1, or for use in a 122, wherein the effective amount is a diagnostically effec method for delivering an effector to a target targeted by tive amount and/or a therapeutically effective amount. either the first tarteing moiety TM1 or the second targeting EMBODIMENT 124 moiety TM2, wherein the effector is selected from the group comprising a diagnostically active agent and a therapeuti 0198 A composition, preferably a pharmaceutical com cally active agent. position, wherein the composition comprises a compound according to any one of embodiments 1 to 78 and a phar EMBODIMENT 117 maceutically acceptable excipient. 0191 The conjugate of embodiment 116, wherein the EMBODIMENT 125 neurotensin receptor is expressed by a cell and/or a tissue, wherein preferably the neurotensin expressing cell and/or 0199 The composition of embodiment 124 for use in any neurotensin expressing tissue is different from a cell of the method as defined in any of the preceding embodiments. central nervous system and/or tissue of the central nervous system. EMBODIMENT 126 0200. A method for the diagnosis of a disease in a subject, EMBODIMENT 118 wherein the method comprises administering to the Subject a diagnostically effective amount of a compound according 0.192 The conjugate of any one of embodiments 116 to 117, wherein the NTR1 expressing tissue is NTR1 express to any one of embodiments 1 to 78. ing tissue of a tumor or NTR1 expressing tissue of a hematological malignancy, and wherein the NTR1 express EMBODIMENT 127 ing cell is a NTR1 expressing tumor cell or an NTR1 0201 The method of embodiment 126, wherein the con expressing hematological malignancy cell. jugate comprises a diagnostically active agent, whereby the agent is preferably a radionuclide. EMBODIMENT 119 EMBODIMENT 128 0193 The conjugate of embodiment 118, wherein the tumor is selected from the group comprising ductal pancre 0202 Amethod for the treatment of a disease in a subject, atic adenocarcinoma, Small cell lung cancer, prostate cancer, wherein the method comprises administering to the Subject colorectal cancer, breast cancer, meningioma, Ewing's sar a therapeutically effective amount of a conjugate according coma, pleural mesothelioma, head and neck cancer, non to any one of embodiments 1 to 79. Small cell lung cancer, gastrointestinal stromal tumors, uter ine leiomyoma and cutaneous T-cell lymphoma, preferably EMBODIMENT 129 ductal pancreatic adenocarcinoma, Small cell lung cancer, 0203 The method of embodiment 128, wherein the con prostate cancer, colorectal cancer, breast cancer, menin jugate comprises a therapeutically active agent, whereby the gioma, Ewing's sarcoma, and indications subject to group A agent is preferably a radionuclide. as defined herein. EMBODIMENT 130 EMBODIMENT 120 0204 The method according to any one of embodiments 0194 The conjugate of any one of embodiments 105 to 126 to 129, wherein the disease is a disease involving 119, wherein the effector is a radionuclide, preferably a neurotensin receptor, preferably the disease is a disease US 2017/01 19913 A1 May 4, 2017 36 involving neurotensin receptor 1, or from a disease involv ing a target targeted by the first targeting moiety TM1 or by (2) the second targeting moiety TM2. O AA-COOH EMBODIMENT 131 0205 The method according to any one of embodiments 126 to 129, wherein the disease is selected from the group comprising tumors and hematological malignancies. R2

EMBODIMENT 132

0206 A kit comprising a conjugate according to any one R5 of embodiments 1 to 78, one or more optional excipient(s) O N-ALK-N1 and optionally one or more device(s), whereby the device(s) is/are selected from the group comprising a labeling device, a purification device, a handling device, a radioprotection wherein device, an analytical device or an administration device. R. R. and Rare each and independently selected from the group consisting of hydrogen and (C-C)alkyl under the proviso that one of R. RandR is of the following formula EMBODIMENT 133 (3) 0207. The kit of embodiment 132 for use in any method as defined in any of the preceding embodiments. (3) R7 0208 The present invention is based on the Surprising -ALK-N1 finding of the present inventors that the conjugate of the invention is not only binding to NTR1 with a high affinity, k but is also not crossing the blood-brain barrier. This char 0209 wherein acteristic allows the use of the conjugate of the invention in 0210 ALK" is (C-C)alkylidene; the diagnosis as well as in the treatment of diseases such as, 0211) R' is selected from the group consisting of but not limited to, tumors, particularly tumors different from hydrogen and (C-C)alkyl; and tumors of the central nervous system in its various forms, 0212 R is a bond. 0213. A further surprising finding underlying the present more particularly those forms thereof which require passage invention is that by linking the compound of formula (2) to of the diagnostically and/or therapeutically effective agent any one of the other moieties of the conjugate of the across the blood-brain barrier. Along with these character invention through a bond represented by R', such other istics go a high and persistent uptake by tumors and NTR1 moiety and other moieties, respectively, do not have an expressing tumors in particular as well as NTR1 expressing impact on the overall binding characteristics of the com pounds of the invention to NTR1, at least not to such extent hematological malignancies, combined with a low uptake which would render the binding of the conjugate of the and rapid clearance in non-target organs thus providing an invention unspecific Such as, preferably, resulting in an IC50 excellent tumor-to-background ratio. Using the compound value of the conjugate of the invention to NTR1 greater than of the invention, the tumor-to-background ratio is at least 10 uM or which would not allow the use of the conjugate of 1.5, preferably greater than 2, and more preferably greater the invention in the various methods disclosed herein and in than 5. The tumor-to-background ratio is preferably defined particular methods for the treatment and/or prevention of a disease as defined herein and methods for the diagnosis of a as the signal intensity of the tumor divided by the back disease as defined herein. Insofar, Surprisingly the position ground signal intensity. Signal intensities are typically mea of R", i.e. the forming of a bond represented by R', does not sured with a region-of-interest (ROI) analysis of the tumor seem to interfere with the binding of the conjugate of the and ROI analysis of Surrounding healthy tissue as back invention to NTR1. Because of this, the other moieties attached to the compound of formula (2) in the conjugate of ground (see Palmedo et al., Nucl Med Biol, 2002, 29. the invention can vary in a broad manner as is further 809-815). The above finding is insofar even more surprising Supported by the example part. as the conjugate of the invention comprises a second tar 0214. In light of these surprising characteristics it is geting moiety, whereby Such second targeting moiety does possible that, without wishing to be bound by any theory, not interfere with the binding characteristics of the first because of the two targeting moieties more patients can be targeting moiety. Without wishing to be bound by any positively diagnosed and treated, respectively, within an indication. Also, it is possible that more lesions can be theory, the present inventors assume that the binding of the diagnosed and treated, respectively, per patient. Also it is conjugate to NTR1 is mediated by a targeting moiety possible that a lesion can be treated more homogenously and wherein Such targeting moiety is a compound of formula (2): thereby more efficiently if the two targeting moieties of the US 2017/01 19913 A1 May 4, 2017 37 conjugate of the invention target different targets and if the 0216. In an embodiment the conjugate of the invention is targets are heterogeneously expressed within the lesion but an antagonist to NTR1. The suitability of an antagonist to each of the targets of the conjugate of the invention is NTR1 for use in the diagnosis and/or therapy of diseases and differently expressed as to its expression level and/or spatial diseases involving NTR1 expressing cells and NTR1 expression pattern. Additionally, it is thus possible to diag expressing tissue in particular, is a Surprising finding. The nose and treat, respectively, tumors expressing a target with prevailing understanding in the art is that in order to provide low density, such as, for example 5000 copies of the target a Suitable means for diagnosis and/or therapy of Such or less per tumor cell while said tumors express a second diseases an agonist to NTR1 is to be used, particularly if the target with high density, Such as, for example, more than diagnostically active agent or the therapeutically active 5000 copies of the second target per tumor cell. Additionally, agent, generally referred to as effector, is a radiolabel Such it is thus possible to diagnose and treat, respectively, tumors as a radionuclide. The rationale behind this understanding in expressing a first target with low density, Such as, for the art is that an effective in vivo diagnosis and therapy, example 5000 copies of the target or less per tumor cell particular in case such diagnosis and therapy makes use of while said tumors express any number of copies of a second a radiolabel Such as a radionuclide attached to a compound target targeted by a conjugate of the invention. Conse having an affinity to a target molecule Such as a receptor, quently, also due to avidity and re-binding effects a longer requires that such compound shows good internalization retention time is achieved which goes along with a higher properties leading to a high in vivo accumulation and effective dose and thus improvement in diagnosis and retention of the compound and thus of the effector in the therapy of the respective disease. Due to the binding char tissue and cells, respectively, expressing the target molecule. acterisitics of the conjugate of the invention it is also As well-known from molecular-pharmacologic investiga possible to target a first target targeted by the first targeting tions efficient internalization is usually provided predomi moiety and thus a cell, tissue and organ, respectively, nantly by agonists (Bodei et al., J. Nucl. Med., 2006, 47. expressing Such first target, independently from the targeting 375-377; Koenig et al., Trends Pharmacol. Sci., 1997, 18, of a second target targeted by the second targeting moiety 276-287: Cescato et al., J. Nucl. Med., 2006, 47, 502-511: and thus a cell, tissue and organ, respectively, expressing Ginjet al., Proc. Natl. Acad. Sci. USA, 2006, 103, 16436 Such second target; and vice versa. Finally, the target of the 16441) thus suggesting the use of target molecule agonists invention if conjugated to an effector provides Such effector rather than target molecule antagonists. In accordance there in an active form despite of the effector being linked to the with and as evident from the prior art recited above, the conjugate. compound Suitable for use in the diagnosis and/or therapy of a disease whereby the disease involves NTR1 expressing 0215 Depending on the characteristics of the first target cells and NTR1 expressing tissue, respectively, is to produce ing moiety of the conjugate of the invention in terms of or elicit a diagnostic or therapeutic effect by NTR1 upon whether Such first targeting moiety is an agonist or an interaction with NTR1, whereby the compound is subse antagonist of the target targeted by the first targeting moiety quently internalized into NTR1 expressing cells. Because of and the characteristics of the second targeting moiety of the this, this kind of compound of the prior art acts as an agonist conjugate of the invention in terms of whether Such second to NTR1. Such internalization preferably occurs by means targeting moiety is an agonist or an antagonist of the target of endocytosis. In contrast thereto, an antagonist to NTR1 as targeted by the second targeting moiety, the overall charac the conjugate of the invention counteracts the effect of an teristics of the conjugate of the invention be more of an agonist to NTR1 and is preferably not internalized into agonist or more of an antagonist. For example, in case the NTR1 expressing cells. In connection therewith it is note first targeting moiety is targeting NTR1 the first targeting worthy that the present inventors found that the conjugate of moiety is typically an antagonist; if under Such conditions the invention Surprisingly binds to a higher number of the second targeting moiety is targeting a second target binding sites compared to an agonist of comparable binding which, in an embodiment, is different from NTR1 or which, affinity. in an alternative embodiment is NTR1, and such second targeting moiety also acts as an antagonist of Such second 0217. The expression alkyl as preferably used herein target, the conjugate of the invention is typically regarded as refers each and individually to a saturated, straight-chain or an antagonist; if, however, the second targeting moiety is branched hydrocarbon group and is usually accompanied by targeting a second target which, in an embodiment, is a qualifier which specifies the number of carbon atoms it different from NTR1 or which, in an alternative embodi may contain. For example the expression (C-C)alkyl ment, is NTR1 and Such second targeting moiety acts as an means each and individually any of methyl, ethyl, n-propyl. agonist of Such second target, the conjugate of the invention isopropyl. n-butyl, isobutyl, Sec-butyl, tert-butyl, n-pentyl, inherently bears both the characteristic of an antagonist and 1-methyl-butyl, 1-ethyl-propyl, 3-methyl-butyl, 1,2-dim of an agonist. In an embodiment of the conjugate of the ethyl-propyl, 2-methyl-butyl, 1,1-dimethyl-propyl. 2,2-dim invention Such conjugate is internalized by a cell, whereby ethylpropyl, n-hexyl, 1,1-dimethyl-butyl and any other iso preferably such internalization renders the effector, i.e. the form of alkyl groups containing six saturated carbon atoms. diagnostically active effector and/or the therapeutically active effector, diagnostically effective and, respectively, 0218. In an embodiment and as preferably used herein, therapeutically effective. In a preferred embodiment of the (C-C)alkyl means each and individually any of methyl, conjugate of the invention the conjugate comprises a target ethyl, n-propyl, isopropyl. n-butyl, isobutyl, sec-butyl and ing moiety which acts as an agonist of the target targeted by tert-butyl. Such targeting moiety and wherein such agonist activity 0219. In an embodiment and as preferably used herein, leads to internalization into a cell of the conjugate of the (C-Cs)alkyl means each and individually any of ethyl, invention n-propyl, isopropyl. n-butyl, isobutyl, sec-butyl, tert-butyl,

US 2017/01 19913 A1 May 4, 2017 39 carbon atoms, heptane-1,7-diyl, any other isomer with 7 —NHR'. —NR' and —CN; where each R" is independently carbon atoms, octane-1,8-diyl, any other isomer with 8 selected from —(C-Cs)alkyl and aryl. carbon atoms, nonane-1,9-diyl, any other isomer with 9 0232. In an embodiment and as preferably used herein, carbon atoms, decane-1,10-diyl and any other isomer with (C-C)carbocyclo refers to a (C-C)carbocycle group 10 carbon atoms, preferably (C-C) alkylidene means each defined above wherein one of the carbocycles group hydro and individually any of ethane-1,2-diyl, propane-1,3-diyl. gen atoms is replaced with a bond. butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane 0233. In an embodiment and as preferably used herein, 1,7-diyl, octane-1,8-diyl. nonane-1,9-diyl and decane-1,10 (C-C)cycloalkylmethyl means each and individually any diyl. of cyclopropylmethyl, cyclobutylmethyl, cyclopentylm 0228. In an embodiment and as preferably used herein, ethyl, cyclohexylmethyl, cycloheptylmethyl and cyclooctyl (C-Co.)alkylidene means each and individually any of methyl. methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2- 0234. In an embodiment and as preferably used herein, diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl. arylene refers to an aryl group which has two covalent bonds 2-methyl-propane-1,2-diyl, 2-methyl-propane-1,3-diyl, pen and can be in the ortho, meta, or para configurations as tane-1,5-diyl, pentane-1,4-diyl, pentane-1,3-diyl, pentane-1, shown in the following structures: 2-diyl, pentane-2,3-diyl, pentane-2,4-diyl, any other isomer with 5 carbon atoms, hexane-1,6-diyl, any other isomer with 6 carbon atoms, heptane-1,7-diyl, any other isomer with 7 (31) carbon atoms, octane-1,8-diyl, any other isomer with 8 carbon atoms, nonane-1,9-diyl, any other isomer with 9 carbon atoms, decane-1,10-diyl and any other isomer with 10 carbonatoms, preferably (C-C) alkylidene means each and individually any of methylene, ethane-1,2-diyl, pro pane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1, 6-diyl, heptane-1,7-diyl, octane-1,8-diyl. nonane-1,9-diy1 and decane-1,10-diyl. A (C-Co.)alkylidene group can be unsubstituted or substituted with one or more groups, including, but not limited to, (C-Cs)alkyl, —O—(C-C) alkyl, -aryl, CO R', O CO R', CO OR', CO. NH CO. NHR', CO NR, NH CO R', -SO, R', SO R', —OH, -halogen, N, NH, —NHR'. —NR' and —CN; where each R" is independently selected from —(C1-C5)alkyl and aryl. in which the phenyl group can be unsubstituted or Substi 0229. In an embodiment and as preferably used herein, tuted with four groups, including, but not limited to, (C- "Aryl refers to a carbocyclic aromatic group. Examples of Cs)alkyl, —O—(C-Cs)alkyl, -aryl, -CO—R', —O— aryl groups include, but are not limited to, phenyl, naphthyl CO R', CO OR', CO. NH CO. NHR', and anthracenyl. A carbocyclic aromatic group or a hetero CO NR', NH CO. R', SO, R', SO R', cyclic aromatic group can be unsubstituted or Substituted —OH, -halogen, N, NH, -NHR'. —NR', and —CN: with one or more groups including, but not limited to, where each R" is independently selected from —(C-Cs) —(C-C)alkyl, —O—(C-C)alkyl, -aryl, -CO—R', alkyl and aryl. O CO. R', CO OR, CO. NH CO. NHR'. 0235. In an embodiment and as preferably used herein, CO NR, CO NR, NH CO. R', SO, R', (C-Cs)heterocycle refers to an aromatic or non-aromatic —SO—R', —OH, -halogen, —N —NH, —NHR'. —NR' (C-C)carbocycle in which one to four of the ring carbon and —CN; where each R" is independently selected from atoms are independently replaced with a heteroatom from —(C-Cs)alkyl and aryl. the group consisting of O, S and N. Representative examples of a (C-C)heterocycle include, benzofuranyl, benzothio 0230. In an embodiment and as preferably used herein, phene, indolyl, benzopyrazolyl, coumarinyl, isoquinolinyl, (C-C)cycloalkyl means each and individually any of pyrrolyl, thiophenyl, furanyl, thiazolyl, imidazolyl pyra cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep Zolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, pyrido tyl and cyclooctyl. nyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl and tet 0231. In an embodiment and as preferably used herein, razolyl. A (C-Cs)heterocycle can be unsubstituted or (C-C) carbocycle refers to a 3-, 4-, 5-, 6-, 7- or 8-mem Substituted with up to seven groups including, (C-Cs)alkyl, bered saturated or unsaturated non-aromatic carbocyclic —O (C-C)alkyl, -aryl, —CO R', —O CO R', ring. Representative (CCs)carbocycles include, but are not CO OR, CO. NH CO. NHR', CO NR', limited to, any of -cyclopropyl, -cyclobutyl, -cyclopentyl, NH CO R', —SO, R', —SO R', -OH, -halogen, -cyclopentadienyl, -cyclohexyl, -cyclohexenyl, -1,3-cyclo - N - NH, -NHR'. - NR', and CN; where each R" is hexadienyl, -1,4-cyclohexadienyl, -cycloheptyl, -1,3-cyclo independently selected from —(C-Cs)alkyl and aryl. heptadienyl, -1,3,5-cycloheptatrienyl, -cyclooctyl, and -cy 0236. In an embodiment and as preferably used herein, looctadienyl. A (C-C)carbocycle group can be (C-Cs)heterocyclo refers to a (C-Cs)heterocycle group unsubstituted or substituted with one or more groups, defined above wherein one of the carbocycles group hydro including, but not limited to, (C-Cs)alkyl, —O—(C-C) gen atoms is replaced with a bond. A (C-Cs)heterocyclo can alkyl, -aryl, CO R', O CO R', CO OR', be unsubstituted or substituted with up to six groups includ CO. NH CO. NHR', CO NR, NH CO ing, (C-C)alkyl, —O—(C-Cs)alkyl, -aryl, -CO—R', R", —SO R', —SO R', —OH, -halogen, - N - NH, O CO R', CO OR, CO. NH CO. NHR'. US 2017/01 19913 A1 May 4, 2017 40

CO NR', NH CO R', -SO, R', SO R', provided herein. Conventional amino acids, also referred to —OH, -halogen, —N, NH, -NHR'. —NR', and —CN: as natural amino acids are identified according to their where each R" is independently selected from —(C-C) standard, one-letter or three-letter codes, as set forth in Table alkyl and aryl. 1. 0237. In an embodiment and as preferably used herein, the term “halogen' or “halogenide' means each and indi TABLE 1. vidually any of F, Cl, Br, I and At. 0238. In an embodiment and as preferably used herein, Conventional amino acids and their abbreviations the term '-succinimide- refer to a bivalent structure accord ing to formula (9) 3-letter 1-letter codes code Amino acids

(9) Ala A. Alanine Cys C Cysteine Asp D Aspartic acid Glu E Glutamic acid Phe Phenylalanine Gly G Glycine His H Histidine O Ile I Isoleucine Lys K Lysine Leu Leucine 0239. In an embodiment and as preferably used herein Met M Methionine atoms with unspecified atomic mass numbers in any struc ASn N Asparagine tural formula or in any passage of the instant specification Pro C Proline including the claims are either of unspecified isotopic com Gln Q Glutamine position, naturally occurring mixtures of isotopes or indi Arg R Arginine vidual isotopes. This applies in particular to halogen atoms, Ser S Serine including, but not limited to F Cl, Br, I and At and to metal Thr Threonine atoms, including but not limited to Sc, Cr, Mn, Co, Fe, Cu, Wall V Valine Ga, Sr, Zr, Y. Mo, Tc, Ru, Rh, Pd, Pt, Ag, In, Sb, Sn, Te, I, Trp W Tryptophan Pr, Pm, Dy, Sm, Gd, Tb, Ho, Dy, Er, Yb, Tm, Lu, Sn, Re, Rd, Tyr Y Tyrosine Os, Ir, Au, Pb, Bi, Po, Fr. Ra, Ac, Th and Fm. 0240. In an embodiment and as preferably used herein, a chelator is a compound which is capable of forming a 0242. Non-conventional amino acids, also referred to as chelate, whereby a chelate is a compound, preferably a non-natural amino acids, are any kind of non-oligomeric cyclic compound where a metal or a moiety having an compound which comprises an amino group and a carbox electron gap or a lone pair of electrons participates in the ylic group and is not a conventional amino acid. formation of the ring. More preferably, a chelator is this kind of compound where a single ligand occupies more than one 0243 Examples of non-natural amino acids, preferably coordination site at a central atom. used for the construction of the conjugates of the invention 0241. In some embodiments certain parts of the com are identified according to their abbreviation or name found pounds of the invention contain amino acid sequences as in Table 2. TABLE 2

Name Structure Abbreviation

pyro glutamic acid O O pyroGlu

OH

Amino (piperidinyl)acetic O Gly(PipAm) acid OH HN NH2

1,4-diaminobutyric acid H Dab OH HN O US 2017/01 19913 A1 May 4, 2017 41

TABLE 2-continued

Name Structure Abbreviation 4-guanidylphenylalanine Phe(4-Gu)

NH OH

HN ls N NH2 2 H

2,5-Dimethyltyrosine Dnt

OH

HO tertbutylglycine Tle

neo-tryptophane neo-Trp

OH

cyclohexylglycine Chg

2-amino-2-adamantane carboxylic acid

9-amino bicyclo[3.3.1 nonane-9- carboxylic acid

HN OH

N-(3-2-[2-(3-Amino Ttds propoxy)-ethoxy ethoxy)-propyl)- Succinamic acid O 1N1a N OH US 2017/01 19913 A1 May 4, 2017

TABLE 2-continued

Name Structure Abbreviation 3-alanine H O Bal

Ul OH Y-aminobutyric acid OH GABA or Gab O - - NH 2 aminopentanoic acid O

HN ~.OH aminohexanoic acid Ahx

O NH2 3-aminomethyl-benzoic NH2 acid HO

O

4-aminomethyl-benzoic O NH2 acid

O anthranilic acid HN HO

O

3-amino benzoic acid NH

4-amino benzoic acid HO

OX-()– NH2

1,3-diamino propionic O Dap or Dpr acid OH NiIII .

Homolysine

"\") {OH

2-aminoadipic acid O US 2017/01 19913 A1 May 4, 2017 43

TABLE 2-continued

Name Structure Abbreviation

C-aminosuberic acid

N-carboxymethyl-B- alanine

3(2- carboxyethylamino) propanoic acid

44-bis(N,N-dibutyric acid) O OH

HO r-r H O

N-(2-Aminoethyl)glycine HN O

\- HN )—on

N-(5-aminopentyl)-glycine O OH

H2 1)N-1)n-1\,H

4-amino-3- NH2 pyrrollidinecarboxylic acid s O

HN OH 3-amino-proline NH2 O

NH OH

4-amino-proline HN O

NH OH

2,3-dicarboxypyrrollidine OH O

HO NH May 4, 2017

TABLE 2-continued

Name Structure Abbreviation pyrrollidine-2,4- O dicarboxylate O HO

NH OH

3,5-diaminobenzoic acid HN O

OH HN

3,5-bis-aminomethyl- HN benzoic acid O

OH HN

5-aminoisophthalic acid HO O O

HO NH2

Citrulline NH2 Cit "N-N-n-"H s O O

Hydroxyproline HO OH Hyp

Xu N O H

Cyclohexylalanine Cha O

HN OH Ornithine --~~O Orn NH, octahydroindol-2-carbonic Oi HO C acid US 2017/01 19913 A1 May 4, 2017

TABLE 2-continued

Name Structure Abbreviation C.-methyl-L-phenylalanine HN Amf HO

O

D-2-Naphtylalanine O OH nal

'NH

N-(4-aminobutyl)-glycine O OH

2N-1-N-1a N H

2-Aminoindane-2- carboxylic acid HN HO

O Aminooxyacetic acid t O O OH 1-Amino-(4-N- piperidinyl)carboxylic HO HN acid O NH

N-(3-aminopropyl)- O glycine H 2N-1-N-N OH

D-AZetidine-2-carboxylic O acid

{O-(H OH

3-Homoglutamatic acid

B-Homolysine O HN H2N OH

B-Homoleucine

HOuulus 3-Homoasparagine O NH2 O US 2017/01 19913 A1 May 4, 2017 46

TABLE 2-continued

Name Structure Abbreviation

3-Homoglutamine

3-Homoarginine

B-Homoserine

HO

B-Homotyrosine OH

L-3-Benzothienylalanine

Carboxymethylen cysteine

L-Cyclopentylglycine

5,5-Dimethyl-D- thiazolidine-4-carboxylic acid

3,4- Dihydroxyphenylalanine HO OH NH2 HO

1-Amino-cyclopentane-1- OH carboxylic acid US 2017/01 19913 A1 May 4, 2017 47

TABLE 2-continued

Name Structure Abbreviation

1-amino-cyclohexane-1- HN carboxylic acid HO

O

L-methionine-Sulphone HN Moo

HO o ,

N-(cyclohexyl)-glycine HO

4-Nitrophenylalanine HN

O HO O

O

N-Methyl-asparagine O OH O Ns' NH2 H

Ornithine-(pyrazin N O OH carboxylate) 2 N C N -- NH2 O

Pipecolic acid HO HN

O

L-Tyrosinmethylether HO NH2

O V

L-Phosphotyrosine O On M. NH M PSNOH HO HO

O

N-Methylglycine O Nmg or Sar HN OH

US 2017/01 19913 A1 May 4, 2017 49

TABLE 2-continued

Name Structure Abbreviation norleucine Nle

t-butylalanine

phenylglycine Phg

3-homophenylalanine

HO 3-homoValine trOH NH2 O 2-propargylglycine H2N O

OH L-homophenylalanine HN

O

0244. The amino acid sequences of the peptides provided sequences without hyphens explicitly illustrated. Where an herein are depicted in typical peptide sequence format, as amino acid contains more than one amino and/or carboxy would be understood by the ordinary skilled artisan. For group in the amino acid side chain, all orientations of this example, the three-letter code or one-letter code of a con amino acids are in principle possible, otherwise preferred ventional amino acid, or the code including the abbrevia orientations are explicitly specified. tions for additional building blocks, indicates the presence 0245. For non-conventional amino acids, a 3-letter code of the amino acid or building block in a specified position was used where the first letter indicates the stereochemistry within the peptide sequence. The code for each non-con of the C-o-atom. For example, a capital first letter indicates ventional amino acid or building block is connected to the that the L-form of the amino acid is present in the peptide code for the next and/or previous amino acid or building sequence, while a lower case first letter indicating that the block in the sequence by a hyphen. Adjacent building blocks D-form of the correspondent amino acid is present in the are connected by a chemical bond (typically an amide peptide sequence. When one-letter code is used, a lower case linkage or thioether linkage). The formation of the chemical letter represents a D-amino acid, while an upper case letter bond removes a hydroxyl group from the 1-carboxyl group represents an L-amino acid. Unless indicated to the contrary, of the amino acid when it is located to the left of the adjacent the amino acid sequences are presented herein in N- to amino acid (e.g., Phe-adjacent amino acid), and removes a C-terminus direction. hydrogen from the amino group of the amino acid when it 0246 The C-termini of several conjugates of the inven is located on the right of the adjacent amino acid (e.g., tion described herein are explicitly illustrated by inclusion of adjacent amino acid-Phe). It is understood that both modi an OH, NH, or an abbreviation for a specific terminating fications can apply to the same amino acid and apply to amine linked to the C-terminal amino acid code via a adjacent conventional amino acids present in amino acid hyphen. The N-termini of several peptides described herein US 2017/01 19913 A1 May 4, 2017 50 are explicitly illustrated by inclusion of a hydrogen (for a diagnosis and diagnosing, respectively. In an embodiment free N-terminus), or an abbreviation for a specific terminat thereof, labeling means the interaction of a detectable label ing carboxylic acid like Ac for acetic acid or other chemical either directly or indirectly with the neurotensin receptor group or structural formula of chemical groups linked to the expressing cells and/or with the neurotensin receptor N-terminal amino acid code via a hyphen. expressing tissue; more preferably such interaction involves 0247. In an embodiment and as preferably used herein an or is based on the interaction of the label or a compound antagonist to NTR1 is a compound which inhibits the bearing such label with the neurotensin receptor. activity of a ligand on NTR1 such as neurotensin, and more 0258. In an embodiment and as preferably used herein, a specifically inhibits the receptor mediated effects which disease involving neurotensin receptor 1 (NTR1) is a disease arise from the binding of the ligand to NTR1. More pref where cells expressing NTR1 and tissue expressing NTR1. erably, the antagonist to NTR1 is binding to NTR1. respectively, are either a or the cause for the disease and/or 0248. In an embodiment and as preferably used herein, an the symptoms of the disease, or are part of the pathology effector is a compound which is diagnostically and/or thera underlying the disease. In an embodiment of the disease, peutically active in the diagnosis and therapy, respectively, preferably when used in connection with the treatment, of a disease. treating and/or therapy of the disease, affecting the cells, the 0249. In an embodiment and as preferably used herein, a tissue and pathology, respectively, results in cure, treatment diagnostically active compound is a compound which is or amelioration of the disease and/or the symptoms of the Suitable for or useful in the diagnosis of a disease. disease. In an embodiment of the disease, preferably when 0250 In an embodiment and as preferably used herein, a used in connection with the diagnosis and/or diagnosing of diagnostic agent or a diagnostically active agent is a com the disease, labeling of the NTR1 expressing cells and/or of pound which is suitable for or useful in the diagnosis of a the NTR1 expressing tissue allows discriminating or distin disease. guishing said cells and/or said tissue from healthy or NTR1 0251. In an embodiment and as preferably used herein, a non-expressing cells and/or healthy or NTR1 non-express therapeutically active compound is a compound which is ing tissue. More preferably such discrimination or distinc suitable for or useful in the treatment of a disease. tion forms the basis for said diagnosis and diagnosing, 0252. In an embodiment and as preferably used herein, a respectively, of the disease. In an embodiment thereof, therapeutic agent or a therapeutically active agent is a labeling means the interaction of a detectable label either compound which is suitable for or useful in the treatment of directly or indirectly with the NTR1 expressing cells and/or a disease. with the NTR1 expressing tissue; more preferably such 0253) In an embodiment and as preferably used herein, a interaction involves or is based on the interaction of the label theragnostically active compound is a compound which is or a compound bearing such label with the NTR1 receptor. suitable for or useful in both the diagnosis and therapy of a 0259. In an embodiment and as preferably used herein, a disease. target cell is a cell which is expressing NTR1 and is a or the 0254. In an embodiment and as preferably used herein, a cause for a disease and/or the symptoms of a disease, or are theragnostical agent or a theragnostically active agent is a part of the pathology underlying a disease. compound which is suitable for or useful in both the 0260. In an embodiment and as preferably used herein, a diagnosis and therapy of a disease. non-target cell is a cell which is either not expressing NTR1 0255. In an embodiment and as preferably used herein, and/or is nota or the cause for a disease and/or the symptoms theragonstics is a method for the combined diagnosis and of a disease, or is part of the pathology underlying a disease. therapy of a disease; preferably, the combined diagnostically 0261. In an embodiment and as preferably used herein, an and therapeutically active compounds used in theragnostics indication is a medical indication. are radiolabeled. 0256 In an embodiment and as preferably used herein, 0262. In an embodiment and as preferably used herein, a treatment of a disease is treatment and/or prevention of a target is a target molecule or targeted structure. disease. 0263. In an embodiment and preferably used herein a cell 0257. In an embodiment and as preferably used herein, a is involved in a disease or indication if such cell is or forms disease involving neurotensin receptor is a disease where part of the tissue and/or the organ afflicted by such disease cells expressing neurotensin receptor and tissue expressing or indication, or if such cell is causing the disease or neurotensin receptor, respectively, are either a or the cause indication, or if the cell is a diseased cell, wherein preferably for the disease and/or the symptoms of the disease, or are Such diseased cell is causing the disease or indication or part of the pathology underlying the disease. In an embodi wherein the diseased cell is or forms part of the tissue and/or ment of the disease, preferably when used in connection the organ afflicted by Such disease or indication. with the treatment, treating and/or therapy of the disease, 0264. In an embodiment and as preferably used herein the affecting the cells, the tissue and pathology, respectively, term “mediating a linkage” means that a linkage or a type of results in cure, treatment or amelioration of the disease linkage is established, preferably a linkage between two and/or the symptoms of the disease. In an embodiment of the moieties. In a preferred embodiment the linkage and the type disease, preferably when used in connection with the diag of linkage is as defined herein. nosis and/or diagnosing of the disease, labeling of the 0265. To the extent it is referred in the instant application neurotensin receptor expressing cells and/or of the neuro to a range indicated by a lower integer and a higher integer tensin receptor expressing tissue allows discriminating or Such as, for example, 1-4. Such range is a representation of distinguishing said cells and/or said tissue from healthy or the lower integer, the higher integer and any integer between neurotensin receptor non-expressing cells and/or healthy or the lower integer and the higher integer. Insofar, the range is neurotensin receptor non-expressing tissue. More preferably actually an individualized disclosure of said integer. In said Such discrimination or distinction forms the basis for said example, the range of 1-4 thus means 1, 2, 3 and 4. US 2017/01 19913 A1 May 4, 2017

0266 Preferably the terms conjugate of the invention and 0272 Based on such general formula, the conjugate of compound of the invention are used interchangeably. the invention may be realized in various embodiments such 0267. The conjugate of the invention comprises general as embodiments (I) to (VII) outlined in the following formula (1) TM1-AD1-LM-IAD2-TM2) (I); TM1-AD1-LM-IAD2-TM2) (1), wherein TM1-LM-IAD2-TM2) (II): TM1 is a first targeting moiety, wherein the first targeting TM1-AD2-TM2) (III): moiety is capable of binding to a first target, AD1 is a first adapter moiety or is absent, TM1-TM2) (IV); LM is a linker moiety or is absent, AD2 is a second adapter moiety or is absent, and TM1-AD1-LM-ITM2) (V): TM2 is a second targeting moiety, wherein the second targeting moiety is capable of binding to a second target; TM1-AD1-TM2) (VI); and wherein the first targeting moiety and/or the second targeting TM1-LM-ITM2) (VII); moiety is a compound of formula (2): wherein in each and any case TM1 is a first targeting moiety, wherein the first targeting (2) moiety is capable of binding to a first target, AA-COOH AD1 is a first adapter moiety, LM is a linker moiety, AD2 is a second adapter moiety, and TM2 is a second targeting moiety, wherein the second targeting moiety is capable of binding to a second target; wherein the first targeting moiety and/or the second targeting moiety is a compound of formula (2):

(2) wherein AA-COOH R" is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group con sisting of 2-amino-2-adamantane carboxylic acid, cyclohex ylglycine and 9-amino-bicyclo[3.3.1 nonane-9-carboxylic acid; R is selected from the group consisting of (C-C)alkyl, (C-C)cycloalkyl, (C-C)cycloalkylmethyl, halogen, nitro and trifluoromethyl; ALK is (C-Cs)alkylidene; R. R. and Rare each and independently selected from the group consisting of hydrogen and (C-C)alkyl under the proviso that one of R. RandR is of the following formula (3) wherein (3) R" is selected from the group consisting of hydrogen, methyl R7 -ALK-N1 and cyclopropylmethyl; k AA-COOH is an amino acid selected from the group con sisting of 2-amino-2-adamantane carboxylic acid, cyclohex ylglycine and 9-amino-bicyclo[3.3.1 nonane-9-carboxylic 0268 wherein 0269 ALK" is (C-Cs)alkylidene; acid; (0270 R is selected from the group consisting of R is selected from the group consisting of (C-C)alkyl, hydrogen and (C-C)alkyl; and (C-C)cycloalkyl, (CCs)cycloalkylmethyl, halogen, nitro (0271) R' is a bond. and trifluoromethyl; US 2017/01 19913 A1 May 4, 2017 52

ALK is (C-Cs)alkylidene; of the conjugate of the invention and in particular in embodi R. R. and Rare each and independently selected from the ments (I) to (VII) of the conjugate of the invention as group consisting of hydrogen and (C-C)alkyl under the disclosed herein. proviso that one of R. RandR is of the following formula 0280. It will be appreciated by a person skilled in the art (3) that the various moieties of the conjugate of the invention are linked to or connected with each other by a linkage. Such linkage is typically indicated in the formulae of the conju (3) gate of the invention Such as formulae (1) or in embodiments R7 -ALK-N1 (I) to (VII) of the conjugate of the invention or in embodi ments (VIII) to (XV) of the linker moiety by “ ”. k 0281. In an embodiment and as preferably used herein a linkage is an attachment of at least two atoms of two independent moieties and building blocks, respectively to 0273 wherein each other. Such moieties are the first target moiety TM1, the 0274 ALK" is (C-Cs)alkylidene; first adapter moiety AD1 I, the linker moiety LM, the second (0275) R' is selected from the group consisting of adaptor moiety AD2, the second targeting moiety TM2, the hydrogen and (C-C)alkyl; and third adapter moiety AD3 and the effector moiety EM, as (0276 R7 is a bond. well as building block moiety X, a building block moiety Z 0277 As also disclosed herein, the linker moiety LM, in and building block moiety Y. A preferred linkage is a an embodiment, is of the following general formula: chemical bond or a plurality of chemical bonds. More X-Y-Z - (VIII) preferably, a chemical bond is a covalent bond or a plurality of chemical bonds. Most preferably, the linkage is a covalent wherein bond or a coordinate bond. As preferably used herein, an DX, is a building block moiety formed of a building blocks, embodiment of a coordinate bond is a bond or group of Y is a branching moiety or is absent, bonds as realized when a metal is bound by a chelator. IZ, is a building block moiety formed ofb building blocks, Depending on the type of atoms linked and their atomic and environment different types of linkages are created. These wherein a and b are individually and independently any types of linkage are defined by the type of atom arrange integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, ments created by the linkage. For instance, the linking of a 16, 17, 18, 19 and 20 under the proviso that a+b is 20, 19, moiety comprising a primary or secondary amino with a 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or moiety comprising a carboxylic acid leads to a linkage O. named amide (which is also referred to as amide linkage, (0278. In light thereof, embodiments (VIII) to (XV) of the —CO N —N CO ). It will be appreciated by a linker moiety LM are as follows: person skilled in the art that the linking of a moiety com —DX Y—Z- (VIII), prising an isothiocyanate with a moiety comprising a pri mary or secondary amino leads to a linkage named thiourea —X, Y) (IX), (which is also referred to as a thiourea linkage. —N—CS— N—), and linking of a moiety comprising a halogen atom —DX (X), with a moiety comprising a sulfhydryl ( -SH) leads to thioether (which is also referred to as a thioether linkage, —DX, Z - (XI), —S—). —Y—Z - (XII), 0282. In an embodiment and as preferably used herein, an amine linkage is a linkage, wherein an Natom is bound to —DX, Z - (XIII), a C atom ( N-C ). A specific type of amine linkage is one, wherein an N atom is bound to an aliphatic C atom, —Y— (XIV), and whereby Such linkage is also referred to as alkylamine linkage ( N C ). In one embodiment the alkylamine —Z - (XV), linkage is formed by reacting a moiety comprising a primary DX is a building block moiety formed of “a building or secondary amino group with a moiety comprising an blocks X, or is absent aldehyde group or a ketone group either under reductive Y is a branching moiety or is absent, conditions or followed by subsequent reduction. IZ, is a building block moiety formed of “b' building 0283. In an embodiment a linkage with a plurality of blocks Z, or is absent chemical bonds is triazole, which is also referred to as and wherein “a” and “b' are individually and independently triazole linkage, wherein a triazole, preferably a 1.2.3- any integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, triazoles links two moieties. In one embodiment the triazole 15, 16, 17, 18, 19 and 20 under the proviso that a+b is 20, linkage is formed by reacting a moiety comprising an azide 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, with a moiety comprising an alkyne with or without cataly 1 or 0; preferably “a” and “b' are individually and indepen sis by preferably copper salts. dently any integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, more 0284. It is understood by a person skilled in the art that preferably any integer from 0, 1, 2, 3, 4 and 5. several different technical and mechanistical alternatives 0279. It is within the present invention that any embodi exist to realize a specific type of linkage, for instance an ment of the linker moiety as disclosed herein and in par amide bond. In this case usually specific reagents are used ticular embodiments of the linker moiety (VIII) to CXV) as for activation of at least one component, for instance the disclosed herein, can be realized in any of the embodiment carboxylic acid. These activated species like active esters or US 2017/01 19913 A1 May 4, 2017 53 carboxylic acid halides are in Some cases isolated and/or TABLE 3-continued purified prior to use; alternatively. Such activated species is/are formed in situ and reacted immediately, i.e. without Linkage Characteristic atom arrangement having been isolated and/or purified. Oxime 0285. In an embodiment and as preferably used herein the Na term “mediating a linkage” means that a linkage or a type of N linkage is established, preferably a linkage between two moieties. In a preferred embodiment the linkage and the type Hydrazone of linkage is as defined herein. 0286 A non-limiting list of linkages as preferably used in connection with the conjugate of the invention and the characteristic type of atom arrangement is presented Table 3. Disulfide TABLE 3 ". S s>, Linkage Characteristic atom arrangement Amide O Pyrazine

n vex r2N Sulfonamide V / O 2 N

Sn N Dihydro-pyrazine

U O n N (8. l N-NH NN N N O S NH Thioether ". S y and isomers 0287. The following are reactive groups and functional Ether ities which are utilized or amenable of forming linkages O between moieties as used in embodiments of the conjugate of the invention: Primary or secondary amino, carboxylic acid, activated carboxylic acid, chloro, bromo, iodo, Sulf Ester O hydryl, hydroxyl, Sulfonic acid, activated Sulfonic acid, Sulfonic acid esters like mesylate or tosylate, Michael accep O tors, strained alkenes like trans cyclooctene, isocyanate, isothiocyanate, aldehyde, ketone, aminooxy, hydrazide, hydrazine, azide, alkyne and tetrazine. Carbamate O 0288. As preferably used herein, the term “activated ul carboxylic acid refers to a carboxylic acid group with the O N general formula —CO—X, wherein X is a leaving group. For example, activated forms of a carboxylic acid group may include, but are not limited to, acyl chlorides, symmetrical Amine or unsymmetrical anhydrides, and esters. In some embodi 's ments, the activated carboxylic acid group is an ester with pentafluorophenol, nitrophenol, benzotriazole, aZabenzotri azole, thiophenol or N-hydroxysuccinimide (NHS) as leav Thiourea S ing group. ls 0289. As preferably used herein, the term “activated N N Sulfonic acid refers to a Sulfonic acid group with the general formula —SO X, wherein X is a leaving group. For Triazole example, activated forms of a Sulfonic acid may include, but N are not limited to, sulfonyl chlorides or sulfonic acid anhy N1 N drides. In some embodiments, the activated Sulfonic acid group is Sulfonylchloride with chloride as leaving group. 0290. As preferably used herein, the term “Michael acceptor refers to an olefin that is substituted with an electron deficient group which comprises the minimal char acteristic structure (32) US 2017/01 19913 A1 May 4, 2017 54

TABLE 4 (32) first n-EWG: reactive group Second reactive group (type of) linkage amino carboxylic acid amide wherein EWG is an electron withdrawing group, such as amino activated carboxylic acid amide CN, NO, CO R', —CO OR', -SO, R'. carboxylic acid amino amide sulfhydryl Michael acceptor (e.g. Maleimide) thioether 0291. A “Michael acceptor is capable of reacting with bromo sulfhydryl thioether nucleophiles especially Sulfhydryl groups in an addition aminooxy aldehyde Oxime reaction as exemplified as follows: isothiocyanate amino thiourea hydroxyl carboxylic acid ester azide alkyne triazole sulfhydryl sulfhydryl disulfide (33) sulfhydryl 2-Pyridine-disulfide disulfide amino aldehyde alkylamine

TM1 SH + N-W -- /u. 0295 The conjugate of the invention comprises at least one compound of formula (2) 0292 For example, Michael acceptors include, but are not limited to, C. B-unsaturated nitriles, C.B-unsaturated nitro compounds, C.B-unsaturated aldehydes, C.B-unsaturated (2) ketones and C.B-unsaturated carboxylic acid derivatives. In a preferred embodiment, the Michael acceptor is a maleim AA-COOH ide group. Linking Concept: 0293. The basic concept underlying the present invention in the forming of a linkage between two moieties, whereby, preferably, the two moieties, i.e. a first moiety and a second moiety, are equipped with complementary reactive groups, whereby preferably the first moiety provides a first reactive group and the second moiety provides a second reactive group. Upon the reactive groups having reacted, the reactive groups or the reaction product thereof and thus, ultimately, the two moieties are linked together by at least one covalent bond to form a linkage of a certain type. The nature of the formed linkage depends on the reactive groups involved in wherein the forming of the linkage, as will be appreciated by a person R" is selected from the group consisting of hydrogen, methyl skilled in the art. It will also be appreciated by a person and cyclopropylmethyl; skilled in the art that, in principle, any reactive group can be provided by any of the two moieties. In other words, the first AA-COOH is an amino acid selected from the group con reactive group can be provided by either the first moiety or sisting of 2-amino-2-adamantane carboxylic acid, cyclohex the second moiety under the proviso that the second reactive ylglycine and 9-amino-bicyclo[3.3.1 nonane-9-carboxylic group is either provided by the second moiety or the first acid; moiety, so that in each case the necessary reactive groups are R is selected from the group consisting of (C-C)alkyl, present or are formed, respectively, allowing the forming of (C-C)cycloalkyl, (CC8)cycloalkylmethyl, halogen, nitro the linkage. It will also be appreciated by a person skilled in and trifluoromethyl; the art that depending on the chemical nature of the first and ALK is (C-Cs)alkylidene; the second moiety on the one hand and the reactive groups involved in the forming of the linkage between the first and R. R. and Rare each and independently selected from the the second moiety on the other hand, some types of reactive group consisting of hydrogen and (C-C)alkyl under the group are preferably provided by the first moiety or the proviso that one of R. RandR is of the following formula second moiety. (3) 0294 Examples of reactive groups which, in some embodiments of the invention, are used in the forming of linkages which may be realized in embodiments the conju (3) gate of the invention are summarized in Table 4. It will, however, be understood by a person skilled in the art that neither the linkages which may be realized in embodiments the conjugate of the invention are limited to the ones of Table 4 nor the reactive groups forming Such linkages. US 2017/01 19913 A1 May 4, 2017 55

0296 wherein (Akram et al., Mol Cancer Res, 2014), (Hruby et al., Annu 0297 ALK" is (C-C)alkylidene: Rev Pharmacol Toxicol, 2013, 53, 557-580), (Tomasini et (0298) R' is selected from the group consisting of al., Chem Soc Rev. 2013, 42, 156-172). (Oishi et al., Org hydrogen and (C-C)alkyl; and Biomol Chem, 2012, 10, 5720-5731), (Dietrich et al., Curr 0299 R7 is a bond, in its various embodiments dis Pharm Biotechnol, 2013, 14, 501-512), (Wetzler et al., closed herein. Biopolymers, 2011, 96, 556-560), (Chongsiriwatana et al., 0300. In one embodiment of the conjugate of the inven Antimicrob Agents Chemother, 2011, 55, 5399-5402), tion a compound (2), in any of its embodiments, is present (Liskamp et al., Chembiochem, 2011, 12, 1626-1653), a in the conjugate of the invention as targeting moiety TM1. peptide nucleic acid (PNA) (Gambari, Expert Opin Ther In a further embodiment of the conjugate of the invention a Pat, 2014, 24, 267-294), (Sforza et al., Methods Mol Biol, compound of formula (2), in any of its embodiments, is 2014, 1050, 143-157), (Corradini et al., Curr Top Med present in the conjugate of the invention as targeting moiety Chem, 2011, 11, 1535-1554), (Nielsen, ArtifDNA PNA XNA, TM2. In a still further embodiment of the conjugate of the 2010, 1, 1), (Nielsen, Chem Biodivers, 2010, 7, 786-804), invention a compound of formula (2), in any of its embodi (Pensato et al., Expert Opin Biol. Ther; 2007, 7, 1219-1232), ments, is present in the conjugate of the invention as (Lundin et al., Adv. Genet, 2006, 56, 1-51), a target-binding targeting moiety TM1 and as targeting moiety TM2. In polypeptide or protein, a target binding nucleic acid mol connection with the latter embodiment of the conjugate of ecule, a carbohydrate (Balan et al., Cancers (Basel), 2010, the invention the embodiment of the compound of formula 2,592-610), a lipid (Helms et al., Traffic, 2004, 5, 247-254), (2) present in the conjugate of the invention as TM1 is (Resh, Subcell Biochem, 2004, 37, 217-232), (Kohli et al., J different from the embodiment of the compound of formula Control Release, 2014) and a target-binding Small molecule (2) present in the conjugate of the invention as TM2, (Book: Drug Discovery and Development Volumes 1 and 2. alternatively, the embodiment of the compound of formula edited by Mukund S. Chorghade, John Wiley & Sons, Inc., (2) present in the conjugate of the invention as TM1 is Hoboken, N.J., 2006), (Book: Optimization in Drug Dis identical to the embodiment of the compound of formula (2) covery—In vitro Methods, edited by Zhengyin Yan and present in the conjugate of the invention as TM2. Gary W. Caldwell, Humana Press, Totowa, N.J., 2004), 0301. It is within the present invention that the conjugate (Book: The Organic Chemistry of Drug Design and Drug of the invention comprises, under the proviso that either the Action, Richard B. Silverman, Academic Press Ltd., Lon first targeting moiety TM1 or the second targeting moiety don, 1992). It will be appreciated by a person skilled in the TM2 is a compound of formula (2), in any of its embodi art that any of the above, and further, compounds forming ments, a further targeting moiety. Such further targeting the or being contained in the conjugate of the invention are moiety is a second targeting moiety TM2 in those embodi known in the art as are methods for the preparation and ments of the conjugate of the invention where the compound identification, respectively, of Such compounds. of formula (2), in any of its embodiments, is present in the 0303. In an embodiment of the conjugate of the invention conjugate of the invention as targeting moiety TM1, and the antibody is a polyclonal or monoclonal antibody. In a Such further targeting moiety is a first targeting moiety TM1 further embodiment of the conjugate of the invention the in those embodiments of the conjugate of the invention antibody is a human antibody, a humanized antibody, a where the compound of formula (2), in any of its embodi chimeric antibody, a sub-primate antibody a murine anti ments, is present in the conjugate of the invention as body or an antibody from other species, i.e. species different targeting moiety TM2. from man and mouse. 0302) In an embodiment of the conjugate of the invention 0304. In a further embodiment of the conjugate of the the further targeting moiety is preferably selected from the invention the antigen-binding antibody fragment is selected group comprising an antibody (Book: Immunochemistry, from the group comprising Fab., Fab, scEv, bispecific schv, edited by Carel J. van Oss and Marc H. V. Van Regenmortel, schv-Fc, a minibody, a diabody, a triabody and a tetrabody. Marcel Dekker, New York 1994), an antigen-binding anti 0305. In a further embodiment of the conjugate of the body fragment (Moran, Nat Biotechnol, 2011, 29, 5-6), (Peer invention the antigen-binding antibody is selected from the et al., Nat Nanotechnol, 2007, 2, 751–760), (Hong et al., group comprising IgG, IgG1, IgG2, IgG3, IgG4, IgM, Ig|D. Biomark Insights, 2008, 3, 435-451), (Holliger et al., Nat IgE. IgA, IgA1, IgA2. Biotechnol, 2005, 23, 1126-1136), a camelid heavy chain 0306 In a further embodiment of the conjugate of the IgG (hcIgG) (Unciti-Broceta et al., Ther Deliv, 2013, 4, invention the camelid heavy chain IgG (hcIgG) may be 1321-1336), (De Vos et al., Expert Opin Biol Ther, 2013, 13, present as a full-length heavy chain IgG or as a fragment 1149-1160), (Vincke et al., Methods Mol Biol, 2012, 907, thereof. Such fragment may be a nanobody which is also 145-176), (Vincke et al., Methods Mol Biol, 2012, 911, known in the art as VHH. 15-26), a cartilaginous fish (e.g. shark) IgNAR antibody 0307. In a further embodiment of the conjugate of the (Dooley et al., Dev Comp Immunol, 2006, 30, 43-56), a invention the cartilaginous fish IgNAR antibody may be protein scaffold (Skerra, J Mol Recognit, 2000, 13, 167 present as a full-length IgNAR or as a fragment thereof. Such 187), (Zoller et al., Molecules, 2011, 16, 2467-2485), (Ge fragment may be VNAR. In an embodiment the cartilaginous bauer et al., Curr Opin Chem Biol, 2009, 13, 245-255), fish is shark. (Hosse et al., Protein Sci, 2006, 15, 14-27), a target-binding 0308. In a further embodiment of the conjugate of the peptide (Zhou et al., Curr Med Chem, 2013, 20, 1985-1996), invention the protein scaffold is selected from the group (Boohaker et al., Curr Med Chem, 2012, 19, 3794-3804), comprising a protein scaffold for molecular recognition; a (Aoki et al., Adv. Drug Deliv Rev, 2012, 64, 1220-1238), protein scaffold derived from naturally occurring protein (Pirogova et al., Curr Pharm Biotechnol, 2011, 12, 1117 domains; a protein scaffold derived from a venomous ani 1127), (Kliger, Biopolymers, 2010, 94, 701-710), a peptido mal, preferably Such venomous animal is one selected from mimetic (Avan et al., Chem Soc Rev. 2014, 43,3575-3594), the group comprising a spider, a Scorpion, a see anemonea, US 2017/01 19913 A1 May 4, 2017 56 an insect, a frog, a snail, a Snake and fish; a genetically 289, 1732-1741), (Doehn et al., IDrugs, 2006, 9, 565-572), engineered protein scaffold; an affibody, wherein the affi a cyclic peptide (Heckmann et al., Methods Enzymol, 2007, body is preferably based on the Z-domain of staphylococcal 426, 463-503), (Fliri et al., Ann N Y AcadSci, 1993, 696, protein A (Nord et al., Protein Eng, 1995, 8, 601-608), (Nord 47-53), (Schmid, Mol Cell Endocrinol, 2008, 286, 69-74); a et al., Nat Biotechnol, 1997, 15,772-777), (Gunneriusson et cyclic peptide (comprising at least one linkage of disulfide, al., Protein Eng, 1999, 12, 873-878), (Wikman et al., Protein amide, ester, hydrocarbon, thioether and triazole with in the Eng Des Sel, 2004, 17, 455-462); a scaffold based on cyclic part) (Roxin et al., Future Med Chem, 2012, 4, immunity protein ImmE7 (Chak et al., Proc Natl Acad Sci 1601-1618), (Cemazaret al., Curr Top Med Chem, 2012, 12, USA, 1996, 93, 6437-6442); a scaffold based on cytochrome 1534-1545), (Tam et al., J Biol Chem, 2012, 287, 27020 b562 (Ku et al., Proc Natl Acad Sci USA, 1995, 92, 27025), (White et al., Org Lett, 2012, 14, 2898-2901), 6552-6556); a scaffold based on peptide C2p8 (Barthe et al., (White et al., Nat Chem, 2011, 3, 509-524), (Gentilucci et Protein Sci., 2000, 9, 942-955); a scaffold based on the al., Curr Pharm Des, 2010, 16, 3185-3203), (Ovadia et al., ankyrin repeat (Mosavi et al., Proc Natl Acad Sci USA, Expert Opin Drug Discov, 2010, 5, 655-671), (Nestor, Curr 2002, 99, 16029-16034), (Binz et al., Nat Biotechnol, 2004, Med Chem, 2009, 16, 4399-4418), (Kopp et al., Nat Prod 22, 575-582), (Amstutz et al., J Biol Chem, 2005, 280, Rep, 2007, 24, 735-749), a bicyclic peptide, a tricyclic 24715-24722); a scaffold based on insect defensins such as peptide, a tetracyclic peptide, a pentacyclic peptide (Ma insect defensin A (1 ICA29) (Zhao et al., Peptides, 2004, 25, cLachlan et al., Methods Mol Biol, 1997, 60, 337-362), 629–635); a scaffold based on Kunitz domains, preferably (Cemazaret al., Curr Top Med Chem, 2012, 12, 1534-1545), BPTI/APPI (Roberts et al., Proc Natl AcadSci USA, 1992, (Heinis et al., Nat Chem Biol, 2009, 5,502-507), (Baeriswyl 89, 2429-2433), (Roberts et al., Gene, 1992, 121, 9-15), et al., ChemMedChem, 2012, 7, 1173-1176), a peptide (Dennis et al., J Biol Chem, 1994, 269, 22129-22136), composed of genetically encoded amino acids (Bernstein et (Dennis et al., J Biol Chem, 1994, 269, 22137-22144), al., Expert Rev Clin Immunol, 2010, 6, 29-39), (Dockal et al., (Stoop et al., Nat Biotechnol, 2003, 21, 1063-1068); a J Biol Chem, 2014, 289, 1732-1741), a peptide composed of scaffold based on PDZ domains, preferably the Ras binding unnatural, preferably non-naturally occurring, amino acids protein AF-6 (Schneider et al., Nat Biotechnol, 1999, 17, (Wei et al., Mol Pharm, 2014); a peptide composed of 170-175); a scaffold based on scorpion toxins such as genetically encoded and unnatural, preferably non-naturally charybdotoxin (Vita et al., Biopolymers, 1998, 47, 93-100); occurring, amino acids (Rhaleb et al., Eur J Pharmacol, a scaffold based on the fibronectin type III domain (Koide et 1992, 210, 115-120), (Hocket al., Br J Pharmacol, 1991, al., J Mol Biol, 1998, 284, 1141-1151), (Xu et al., Chem 102, 769-773), (Wirth et al., Br J Pharmacol, 1991, 102, Biol, 2002, 9,933-942); a scaffold based on the extracellular 774-777), (Dockal et al., J Biol Chem, 2014, 289, 1732 domain of CTLA-4 (Nuttall et al., Proteins, 1999, 36, 1741), a peptide conjugated with a non-proteinogenic moi 217-227), (Irving et al., J Immunol Methods, 2001, 248, ety (Guskey et al., Pharmacotherapy, 2010, 30, 80-94), a 31-45); a scaffold based on knottins such as Min-23 (Souriau lipopeptide (Grossman, Pharmacotherapy, 2009, 29, 25S et al., Biochemistry, 2005, 44, 7143-7155); a scaffold based 32S) and a glycopeptide (Maschauer et al., Mol Pharm, on the cellulose binding domain (Lehtio et al., Proteins, 2014, 11, 505-515). 2000, 41, 316-322); a scaffold based on neocarzinostatin 0310. In a further embodiment of the conjugate of the (Heydet al., Biochemistry, 2003, 42,5674-5683); a scaffold invention the target-binding nucleic acid molecule is based on CBM4-2 (Cicortas et al., Protein Eng Des Sel, selected from the group comprising an aptamer (Kang et al., 2004, 17, 213-221); a scaffold based on tendamistat (McCo Adv Biochem Eng Biotechnol, 2013, 131, 153-169), (Zhou et nnell et al., J Mol Biol, 1995, 250, 460-470), (Li et al., al. Front Genet, 2012, 3, 234), (Jeong et al., Biochem Protein Eng, 2003, 16, 65-72); an anticalin, preferably based Biophy's Res Commun, 2001, 281, 237-243), (Santulli-Ma on apolipoprotein D (Gebauer et al., Methods Enzymol, rotto et al., Cancer Res, 2003, 63, 7483-7489), (Roth et al., 2012, 503, 157-188), (Gebauer et al., J Mol Biol, 2013, 425, Cancer Res, 2012, 72, 1373-1383), (Chen et al., Proc Natl 780-802), (Vogt et al., Chembiochem, 2004, 5, 191-199); a AcadSci USA, 2003, 100,9226-9231), (Bell et al., In Vitro scaffold based on the bilin-binding protein (Beste et al., Proc Cell Dev Biol Anim, 1999, 35, 533-542), (Esposito et al., Natl AcadSci USA, 1999, 96, 1898-1903); a scaffold based PLOS One, 2011, 6, e24.071), a spiegelmer (Vater et al., Curr on FABP (Lamla et al., Protein Expr Purif, 2004, 33, 39-47), Opin Drug Discov Devel, 2003, 6, 253-261), (Darisipudi et (Lamla et al., J Mol Biol, 2003, 329, 381-388); a DARPin al., Am J Pathol, 2011, 179, 116-124), (Hoellenriegel et al., (Weidle et al., Cancer Genomics Proteomics, 2013, 10. Blood, 2014, 123, 1032-1039), (Schwoebel et al., Blood, 155-168), (Stumpp et al., Drug Discov Today, 2008, 13, 2013, 121, 2311-2315), a ribozyme (Mulhbacher et al., Curr 695-701), (Boersma et al., Curr Opin Biotechnol, 2011, 22, Opin Pharmacol, 2010, 10, 551-556), (Balke et al., Appl 849-857); and an adnectin (Lipovsek, Protein Eng Des Sel, Microbiol Biotechnol, 2014, 98, 3389-3399) and a spiegel 2011, 24, 3-9). Zym (Wyszko et al., PLoS One, 2014, 9, e86673), (Wyszko 0309. In a further embodiment of the conjugate of the et al., PLoS One, 2013, 8, e54741). invention the target-binding peptide is one selected from the 0311. In a further embodiment of the conjugate of the group comprising a peptide with 2 up 50 amino acids in invention the target-binding carbohydrate molecule is length, a peptide with 3 up 40 amino acids in length selected from the group comprising an natural carbohydrate (Manfredi et al., Curr Med Chem, 2006, 13, 2369-2384), a ligand for carbohydrate binding receptors (Yang et al., peptide with 5 up 30 amino acids in length (Harmar et al., Expert Rev Mol Med, 2008, 10, e17) and an unnatural BrJ Pharmacol, 2012, 166, 4-17), a peptide with 5 up 20 carbohydrate ligand (Ramstrom et al., Chembiochem, 2000, amino acids in length (Dockal et al., J Biol Chem, 2014, 289. 1, 41-48), (Liang et al., Science, 1996, 274, 1520-1522). 1732-1741), (Heckmann et al., Methods Enzymol, 2007, 0312. In a further embodiment of the conjugate of the 426, 463-503), (Schmid, Mol Cell Endocrinol, 2008, 286, invention the target-binding Small molecule is selected from 69-74); a linear peptide (Dockal et al., J Biol Chem, 2014, the group comprising a target-binding Small molecule full US 2017/01 19913 A1 May 4, 2017 57 filling the rule-of-five (Lipinski, J Pharmacol Toxicol Meth 1078-1085), flow cytometry (Chekhun et al., Exp Oncol, ods, 2000, 44, 235-249). (Lipinski et al., Adv. Drug Deliv 2013, 35, 174-179: Forster et al., Cytometry A, 2007, 71, Rev. 2001, 46, 3-26), (Lipinski, Drug Discov Today, 2003, 8, 945-950; Goodman et al., Biol Open, 2012, 1,329-340) and 12-16) and a target-binding Small molecule violating the Western blot (Schmidt et al., Anticancer Res, 2008, 28. rule-of-five. 1719-1724; Goodman et al., Biol Open, 2012, 1,329-340: 0313. It will be appreciated by a person skilled in the art Kusagawa et al., Br J Cancer, 1998, 77, 98-102). Samples to that the target recognized by the further targeting moiety, be analyzed with the above methods may originate from regardless of whether it is within the conjugate of the biopsies, Surgically resected specimens, circulating tumor invention the first targeting moiety TM1 or the second cells, blood, urine or fecal samples, Swabs and Smears, targeting moiety TM2, can, in principle, be any target under sputum; preferably such sample is obtained from biopsies, the proviso that the further targeting moiety is capable of Surgically resected specimens, circulating tumor cells. These binding to such target. It will be appreciated by a person methods are also Suitable for detecting and determining, skilled in the art that in particular an antibody, an antigen respectively, homogeneity and/or heterogeneity of expres binding antibody fragment, a camelid heavy chain IgG sion of a or the target, including expression of receptors such (hcIgG), a cartilaginous fish (e.g. shark) IgNAR antibody, a as NTR1 and NTR2, by a cell, a tissue, an organ, a tumor protein scaffold, a target-binding peptide, a peptide nucleic and/or an indication. These methods are also suitable for acid (PNA), a target-binding polypeptide or protein, and a detecting and determining, respectively, the density of a or target binding nucleic acid molecule can, in principle, be the target, including expression of receptors such as NTR1 identified and generated, respectively, against any target by and NTR2, by a cell, a tissue, an organ, a tumor and/or an using routine methods known in the art. indication. 0314. It is within the present invention that a target to 0317. It is within the present invention that a target to which the further targeting moiety of the conjugate of the which the further targeting moiety of the conjugate of the invention is capable of binding, is a target that is expressed invention is capable of binding, is a target that is expressed in any oncology indication, preferably in any indication in an indication, preferably a tumor indication, in which related to oncology, more preferably any tumor and/or more at least 75% or more, at least 50% or more, at least cancer disease, and even more preferably any cell. Such as 25% or more, or at least 10% or more of patients, preferably a diseased cell, involved in Such indication. the diseased cell, tissue, organ and/or indication express 0315. It is within the present invention that a target to NTR. In an embodiment thereof NTR is NTR1. In a further which the further targeting moiety of the conjugate of the embodiment NTR is NTR2. In a still further embodiment invention is capable of binding, is a target that is expressed NTR is NTR1 and NTR2, i.e. the patients and, preferably the in NTR-positive indications, preferably in a disease where diseased cell, tissue, organ and/or indication express both cells involved in the disease and/or diseased cells express NTR1 and NTR2. NTR. In a preferred embodiment the NTR-positive indica 0318. It is within the present invention that a target to tion is an NTR1-positive indication, preferably in a disease which the further targeting moiety of the conjugate of the where cells involved in the disease and/or diseased cells invention is capable of binding, is a target that is expressed express NTR1. In a preferred embodiment the NTR-positive in an indication, preferably a tumor indication, in which only indication is an NTR2-positive indication, preferably in a a small portion of the tumors, preferably a tumor indication disease where cells involved in the disease and/or diseased where only a small portion of the patients suffering from the cells express NTR2. In a further preferred embodiment the tumor indication, express NTR1. Preferably, a small portion NTR-positive indication is an NTR1 and an NTR2-positive of the tumors is about 10% or less of the tumors. indication, preferably in a disease where cells involved in 0319. Also preferably, a small portion of the patients is the disease and/or diseased cells express both NTR1 and about 10% or less of the patients. NTR2. 0320. It is within the present invention that a target to 0316. It is within the present invention that a target to which the further targeting moiety of the conjugate of the which the further targeting moiety of the conjugate of the invention is capable of binding, is a target that is expressed invention is capable of binding, is a target that is expressed homogeneously in an indication, preferably an oncology in an indication, preferably a tumor indication, whereby indication, more preferably in any indication related to such target can be identified by methods known in the art. oncology. In an embodiment thereof the indication is any Such methods comprise, but are not limited to, receptor tumor and/or cancer disease. In an embodiment thereof the autoradiography (Reubi et al., Int J Cancer, 1999, 81, target is expressed homogenously by a cell in Such indica 376-386: Waser et al., Eur J. Nucl Med Mol Imaging, 2014, tion, preferably the cell is involved in such indication and 41, 1166-1171), immunohistochemistry (Schmidt et al., more preferably the cell is a diseased cell. Anticancer Res, 2008, 28, 1719-1724; Patsenker et al., J 0321. It is within the present invention that a target to Hepatol, 2010, 52,362-369; Korner et al., Am J Surg Pathol, which the further targeting moiety of the conjugate of the 2012, 36, 242-252), immunocytochemistry (Chekhun et al., invention is capable of binding, is a target that is expressed Exp Oncol, 2013, 35, 174-179; Ghosh et al., J. Cytol, 2013, heterogeneously in an indication, preferably in an oncology 30, 151-155; Seymour et al., Am J Clin Pathol, 1990, 94, indication, more preferably in any indication related to S35-40), RT-PCR (Bernard et al., Clin Chem, 2002, 48, oncology. In an embodiment thereof the indication is any 1178-1185: Chang et al., Clin Cancer Res, 1999, 5, 2674 tumor and/or cancer disease. In an embodiment thereof the 2681; Kang et al., Cancer Genet Cytogenet, 2006, 164, target is expressed heterogenously by a cell in Such indica 32-38; Patel et al., Clin Cancer Res, 2004, 10, 75.11-7519), tion, preferably the cell is involved in such indication and in situ hybridization (Chang et al., Clin Cancer Res, 1999, 5, more preferably the cell is a diseased cell. 2674-2681; Kang et al., Cancer Genet Cytogenet, 2006, 164, 0322. It is within the present invention that a target to 32-38: Heinrich et al., Int J Gynecol Cancer, 2004, 14, which the further targeting moiety of the conjugate of the US 2017/01 19913 A1 May 4, 2017 invention is capable of binding, is a target that is expressed mucosa lip, commissure lip, overlapping lesion of lip, base in an indication, preferably in an oncology indication, more of tongue, dorsal Surface tongue, border of tongue, Ventral preferably in any indication related to oncology, where NTR Surface of tongue, anterior 2/3 of tongue, lingual tonsil, is expressed at a low density. In an embodiment thereof the overlapping lesion of tongue, tongue, upper gum, lower indication is any tumor and/or cancer disease. In an embodi gum, gum, anterior floor of mouth, lateral floor of mouth, ment thereof the target is expressed heterogenously by a cell overlapping lesion of floor of mouth, floor of mouth, hard in such indication, preferably the cell is involved in such palate, Soft palate, uvula, overlapping lesion of palate, indication and more preferably the cell is a diseased cell. As palate, cheek mucosa, Vestibule of mouth, retromolar area, preferably used herein low density means that less than 5000 overlapping lesion of other and unspecified parts of mouth, copies of NTR per cell are expressed. Suitable methods to mouth, parotid gland, Submaxillary gland, Sublingual gland, identify such indications are listed above. Preferred methods are receptor autoradiography (Reubi et al., Supra; Waser et overlapping lesion of major salivary glands, major salivary al., Supra) and cell binding studies (Kitabgi et al., Supra). gland, tonsillar fossa, tonsillar pillar, overlapping lesion of tonsil, tonsil, Vallecula, anterior Surface of epiglottis, lateral 0323. It is within the present invention that a target to wall oropharynx, posterior wall oropharynx, branchial cleft, which the further targeting moiety of the conjugate of the overlapping lesion of oropharynx, oropharynx, Superior wall invention is capable of binding, is a target that is expressed of nasopharynx, posterior wall nasopharynx, lateral wall in an indication, preferably in an oncology indication, more nasopharynx, anterior wall nasopharynx, overlapping lesion preferably in any indication related to oncology, where NTR of nasopharynx, nasopharynx, pyriform sinus, postcricoid is expressed in the primary tumor, in metastases, preferably region, hypopharyngeal aspect of aryepiglottic fold, poste metastases of the primary tumor, or in both the primary rior wall hypopharynx, overlapping lesion of hypopharynx, tumor and metastates, preferably metastases of the primary hypopharynx, pharynx, laryngopharynx, waldeyer's ring, tumor. In an embodiment thereof NTR is NTR1, NTR2 or overlapping lesion of lip oral cavity and pharynx, cervical both NTR1 and NTR2. esophagus, thoracic esophagus, abdominal esophagus, upper 0324. It is within the present invention that a target to third of esophagus, middle third of esophagus, esophagus which the further targeting moiety of the conjugate of the lower third, overlapping lesion of esophagus, esophagus, invention is capable of binding, is a target that is expressed cardia, fundus stomach, body stomach, gastric antrum, pylo in an indication, preferably in an oncology indication, more rus, lesser curvature of Stomach, greater curvature of stom preferably in any indication related to oncology, where NTR ach, overlapping lesion of stomach, stomach, duodenum, is not expressed. In an embodiment thereof NTR is NTR1. jejunum, ileum, meckel's diverticulum, overlapping lesion In another embodiment thereof NTR is NTR2. In still of Small intestine, Small intestine, cecum, appendix, ascend another embodiment thereof NTR is NTR1 and NTR2, i.e. ing colon, hepatic flexure of colon, transverse colon, splenic the indication does express neither NTR1 nor NTR2. In an flexure of colon, descending colon, sigmoid colon, overlap embodiment thereof NTR is not expressed by a cell involved ping lesion of colon, colon, rectosigmoid junction, rectum, in said indication and more preferably not expressed by a anus, anal canal, cloacogenic Zone, overlapping lesion of diseased cell involved in said indication. rectum anus and anal canal, liver, intrahepatic bile duct, 0325 It is within the present invention that a target to gallbladder, extrahepatic bile duct, ampulla of Vater, over which the further targeting moiety of the conjugate of the lapping lesion of biliary tract, biliary tract, head of pancreas, invention is capable of binding, is a target that is expressed body pancreas, tail pancreas, pancreatic duct, islets of in an indication, preferably in an oncology indication, more langerhans, neck of pancreas, overlapping lesion of pan preferably in any indication related to oncology, where at creas, pancreas, intestinal tract, overlapping lesion of diges least 20,000 or more copies of NTR or at least 10,000 or tive system, gastrointestinal tract, nasal cavity, middle ear, more copies of NTR or at least 5,000 or more copies of NTR maxillary sinus, ethmoid sinus, frontal sinus, sphenoid or at least 1,000 or more copies of NTR are expressed per sinus, overlapping lesion of accessory sinuses, accessory cell. In an embodiment thereof the cell is involved in such sinus, glottis, Supraglottis, Subglottis, laryngeal cartilage, indication and more preferably the cell is a diseased cell. In overlapping lesion of larynx, larynx, trachea, main bron an embodiment thereof NTR is NTR1, NTR2 or both NTR1 chus, upper lobe lung, middle lobe lung, lower lobe lung, and NTR2. Accordingly, the above copy numbers may refer overlapping lesion of lung, lung, thymus, heart, anterior to the copy number of NTR1 or the copy number of NTR2 mediastinum, posterior mediastinum, mediastinum, pleura, or the total copy number of NTR1 and NTR2 taken together. overlapping lesion of heart mediastinum and pleura, upper 0326. It is within the present invention that a target to respiratory tract, overlapping lesion of respiratory system which the further targeting moiety of the conjugate of the and intrathoracic organs, respiratory tract, upper limb long invention is capable of binding, is a target that is expressed bones joints, upper limb short bones joints, lower limb long in an indication, preferably in an oncology indication, more bones joints, lower limb short bones joints, overlapping preferably in any indication related to oncology, where the lesion of bones joints and articular cartilage of limbs, bone blood brain barrier is intact. limb, skull and facial bone, mandible, vertebral column, rib 0327. It is within the present invention that a target to Sternum clavicle, pelvic bone, overlapping lesion of bones which the further targeting moiety of the conjugate of the joints and articular cartilage, bone, blood, bone marrow, invention is capable of binding is a target that is expressed spleen, reticuloendothelial system, hematopoietic system, in an indication of group A as defined herein skin lip, eyelid, external ear, skin face, skin Scalp neck, skin 0328 Preferably the indication of group A as defined trunk, skin limb upper, skin limb lower, peripheral nerve herein is one which occurs in an organ and/or a tissue, head neck, peripheral nerve shoulder arm, peripheral nerve wherein the organ and/or the tissue is selected from group C, leg, peripheral nerve thorax, peripheral nerve abdomen, wherein group C comprises external upper lip, external peripheral nerve pelvis, peripheral nerve trunk, overlapping lower lip, external lip, upper lip mucosa, lower lip mucosa, lesion of peripheral nerves and autonomic nervous system, US 2017/01 19913 A1 May 4, 2017 59 autonomic nervous system, retroperitoneum, peritoneum, Melanoma, Laryngeal Cancer, Leukemia, Liver Cancer, peritoneum, overlapping lesion of retroperitoneum and peri Lobular Carcinoma In Situ (LCIS), Lung Cancer, Lym toneum, connective tissue head, connective tissue arm, phoma, Melanoma, Mouth Cancer, Multiple Myeloma, connective tissue leg, connective tissue thorax, connective Myelodysplastic Syndromes, Nasal Cavity and Paranasal tissue abdomen, connective tissue pelvis, connective tissue Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, trunk, overlapping lesion of connective Subcutaneous and Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, other soft tissues, connective tissue, nipple, central portion Oral Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic of breast, upper inner quadrant of breast, lower inner quad Cancer, Pancreatic Neuroendocrine Tumors, Paraganglioma, rant of breast, upper outer quadrant of breast, lower outer Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, quadrant of breast, axillary tail of breast, overlapping lesion Pheochromocytoma, Pituitary Tumor, Primary Lymphoma, of breast, breast, labium majus, labium minus, clitoris, Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Retino overlapping lesion of Vulva, Vulva, vagina, endocervix, blastoma, Salivary Gland Cancer, Sarcoma, Sézary Syn exocervix, overlapping lesion of cervix uteri, cervix uteri, drome, Skin Cancer, Small Cell Lung cancer, Small Intestine isthmus uteri, endometrium, myometrium, fundus uteri, Cancer, Squamous Cell Carcinoma, Testicular Cancer, Thy overlapping lesion of corpus uteri, corpus uteri, uterus, moma and Thymic Carcinoma, Thyroid Cancer, Urethral ovary, fallopian tube, broad ligament, round ligament, Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, parametrium, uterine adnexa, wolffian body, overlapping Wilms Tumor. lesion of female genital organs, female genital tract, pre 0331 Group E: Acute Lymphoblastic Leukemia (ALL), puce, glans penis, body penis, overlapping lesion of penis, Acute Myeloid Leukemia (AML), Anal Cancer, Astrocy penis, prostate gland, undescended testis, descended testis, tomas, Basal Cell Carcinoma, Bladder Cancer, Bone Cancer, testis, epididymis, spermatic cord, Scrotum, tunica vaginalis, Brain Tumor, Breast Cancer, Burkitt Lymphoma, Cervical overlapping lesion of male genital organs, male genital Cancer, Chronic Lymphocytic Leukemia (CLL), Chronic organs, kidney, renal pelvis, ureter, trigone bladder, dome Myelogenous Leukemia (CML), Colon Cancer, Colorectal bladder, lateral wall bladder, posterior wall bladder, ureteric Cancer, Endometrial Cancer, Esophageal Cancer, Ewing orifice, urachus, overlapping lesion of bladder, bladder, Sarcoma, Gallbladder Cancer, Gastric Cancer, Glioma, urethra, paraurethral gland, overlapping lesion of urinary Hairy Cell Leukemia, Head and Neck Cancer, Hepatocel organs, urinary system, conjunctiva, cornea, retina, choroid, lular Cancer, Hodgkin Lymphoma, Leukemia, Liver Cancer, ciliary body, lacrimal gland, orbit, overlapping lesion of eye Lung Cancer, Lymphoma, Melanoma, Multiple Myeloma, and adnexa, eye, cerebral meninges, spinal meninges, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin meninges, cerebrum, frontal lobe, temporal lobe, parietal Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, lobe, occipital lobe, ventricle, cerebellum, brain stem, over Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Pancre lapping lesion of brain, brain, spinal cord, cauda equina, atic Neuroendocrine Tumors, Paraganglioma, Parathyroid olfactory nerve, optic nerve, acoustic nerve, cranial nerve, Cancer, Pharyngeal Cancer, Pheochromocytoma, Primary overlapping lesion of brain and central nervous system, Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell nervous system, thyroid gland, adrenal gland cortex, adrenal Cancer, Sarcoma, Skin Cancer, Small Cell Lung cancer, gland medulla, adrenal gland, parathyroid gland, pituitary Squamous Cell Carcinoma, Testicular Cancer, Thyroid Can gland, craniopharyngeal duct, pineal gland, carotid body, cer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer. aortic body, overlapping lesion of endocrine glands and 0332 Group F: Acute Lymphoblastic Leukemia (ALL), related Structures, endocrine gland, head face or neck, tho Acute Myeloid Leukemia (AML), Anal Cancer, Bladder rax, abdomen, pelvis, upper limb, lower limb, other illde Cancer, Bone Cancer, Brain Tumor, Breast Cancer, Cervical fined sites, overlapping lesion of ill-defined sites, lymph Cancer, Chronic Lymphocytic Leukemia (CLL), Chronic node face head neck, intrathoracic lymph node, intra-ab Myelogenous Leukemia (CML), Colon Cancer, Colorectal dominal lymph nodes, lymph node axilla arm, lymph node Cancer, Endometrial Cancer, Esophageal Cancer, Ewing inguinal region leg, lymph node pelvic, lymph nodes of Sarcoma, Gastric Cancer, Glioma, Hairy Cell Leukemia, multiple regions, lymph node, unknown primary site. Head and Neck Cancer, Hepatocellular Cancer, Hodgkin 0329. It is within the present invention that a target to Lymphoma, Leukemia, Lung Cancer, Lymphoma, Mela which the further targeting moiety of the conjugate of the noma, Non-Hodgkin Lymphoma, Non-Small Cell Lung invention is capable of binding, is a target that is expressed Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, in an indication Subject to the following group D, group E, Pancreatic Neuroendocrine Tumors, Primary Lymphoma, group F, group G, group H, group I, group J, group K and/or Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Sar group L: coma, Skin Cancer, Small Cell Lung cancer, Squamous Cell 0330 Group D: Acute Lymphoblastic Leukemia (ALL), Carcinoma, Thyroid Cancer, Vaginal Cancer, Vulvar Cancer. Acute Myeloid Leukemia (AML), Adrenocortical Carci 0333 Group G: Bladder Cancer, Bone Cancer, Breast noma, Anal Cancer, Astrocytomas, Basal Cell Carcinoma, Cancer, Cervical Cancer, Colon Cancer, Colorectal Cancer, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Endometrial Cancer, Ewing Sarcoma, Gastric Cancer, Tumor, Breast Cancer, Burkitt Lymphoma, Carcinoid Hepatocellular Cancer, Hodgkin Lymphoma, Leukemia, Tumor, Carcinoma of Unknown Primary, Cervical Cancer, Lung Cancer, Lymphoma, Melanoma, Non-Hodgkin Lym Chronic Lymphocytic Leukemia (CLL), Chronic Myelog phoma, Non-Small Cell Lung Cancer, Ovarian Cancer, enous Leukemia (CML), Colon Cancer, Colorectal Cancer, Pancreatic Cancer, Prostate Cancer, Rectal Cancer, Renal Ductal Carcinoma In Situ (DCIS), Embryonal Tumors, Cell Cancer, Sarcoma, Small Cell Lung cancer, Squamous Endometrial Cancer, Esophageal Cancer, Ewing Sarcoma, Cell Carcinoma, Thyroid Cancer. Gallbladder Cancer, Gastric Cancer, Glioma, Hairy Cell 0334 group H: Pancreatic cancer (Ehlers et al., Ann Surg, Leukemia, Head and Neck Cancer, Hepatocellular Cancer, 2000, 231, 838-848; Reubi et al., Gut, 1998, 42, 546-550), Hodgkin Lymphoma, Hodgkin Lymphoma, Intraocular Small cell lung cancer (Moody, Panminerva Med, 2006, 48, US 2017/01 19913 A1 May 4, 2017 60

19-26; Oceo-Garcia et al., Lung Cancer, 2001, 33, 1-9), Cancer Res, 2011, 71, 6817-6826; Swift et al., Cancer Res, Non-small cell lung cancer (Alifano et al., Clin Cancer Res, 2010, 70, 347-356), Small cell lung cancer (Moody, Pan 2010, 16, 4401-4410; Moody et al., Life Sci., 2014, 100, minerva Med, 2006, 48, 19-26: Oceo-Garcia et al., Lung 25-34), Prostate cancer (Amorino et al. Oncogene, 2007, Cancer, 2001, 33, 1-9), Breast cancer (Dupouy et al., PLOS 26, 745-756; Taylor et al., Prostate, 2012, 72, 523-532: One, 2009, 4, e4223; Souaze et al., Cancer Res, 2006, 66, Valerie et al., Cancer Res, 2011, 71, 6817-6826; Swift et al., 6243-6249), Colorectal cancer (Chao et al., J Surg Res, Cancer Res, 2010, 70,347-356), Colorectal cancer (Chao et 2005, 129, 313-321; Gui et al., Peptides, 2008, 29, 1609 al., J Surg Res, 2005, 129, 313-321; Gui et al., Peptides, 1615; Bossard et al., Peptides, 2007, 28, 2030-2035); and 2008, 29, 1609-1615; Bossard et al., Peptides, 2007, 28, 0338 group L: Pancreatic cancer (Ehlers et al., Ann Surg, 2030-2035), Ewing's sarcoma (Reubi et al., Int J Cancer, 2000, 231, 838-848; Reubi et al., Gut, 1998, 42, 546-550), 1999, 82. 213-218), Meningioma (Reubi et al., Int J Cancer, Prostate cancer (Amorino et al., Oncogene, 2007, 26, 745 1999, 82, 213-218), Breast cancer (Dupouy et al., PLoS 756; Taylor et al., Prostate, 2012, 72, 523-532; Valerie et al., One, 2009, 4, e4223; Souaze et al., Cancer Res, 2006, 66, Cancer Res, 2011, 71, 6817-6826; Swift et al., Cancer Res, 6243-6249), Gastric cancer (Schulz et al., J. Endocrinol, 2010, 70, 347-356), Small cell lung cancer (Moody, Pan 2006, 191, 121-128; Thomas et al., Endocr Rev, 2003, 24, minerva Med, 2006, 48, 19-26: Ocejo-Garcia et al., Lung 571-599), Mesothelioma (Alifano et al., Biochimie, 2009), Cancer, 2001, 33, 1-9). Head and neck cancer (Shimizu et al., Int J Cancer, 2008, 0339. It is within the present invention that a target to 123, 1816-1823), Gastrointestinal stromal tumors (GIST) which the further targeting moiety of the conjugate of the (Gromova et al., PLoS One, 2011, 6, e14710), Neuroblas invention is capable of binding, is a target selected from the toma Tavares, Melanoma (Zhang et al., Mol Cell Biochem, group of target classes comprising a GPCR, an ion channel, 2014, 389, 1-8), Chronic B cell leukemia (Saada et al., J an adhesion molecule, an immunoglobulin Superfamily Immunol, 2012, 189, 5293-5303), Leiomyosarcoma (Rodri receptor, a receptor tyrosine kinase, a receptor tyrosine guez et al., Int J Gynecol Pathol, 2011, 30, 354-363; Rodri phosphatase, a member of the tumor necrosis factor receptor guez et al., Biol Reprod, 2010, 83, 641–647), and cutaneous family, an extracellular matrix protin, a transport, a matrix T-cell lymphoma Ramez: metallo proteinase and CD molecules. 0335 group I: Pancreatic cancer (Ehlers et al., Ann Surg, 0340. In an embodiment of the conjugate of the invention 2000, 231, 838-848: Reubi et al., Gut, 1998, 42, 546-550), the GPCR to which the further targeting moiety of the Small cell lung cancer (Moody, Panminerva Med, 2006, 48, conjugate of the invention is capable of binding, is selected 19-26; Ocelo-Garcia et al., Lung Cancer, 2001, 33, 1-9), from the group comprising a class AGPCR, a class B GPCR, Non-small cell lung cancer (Alifano et al., Clin Cancer Res, a class C GPCR, an adhesion class GPCR, a frizzled class 2010, 16, 4401-4410; Moody et al., Life Sci, 2014, 100, GPCR and other 7TM proteins. 25-34), Prostate cancer (Amorino et al. Oncogene, 2007, 0341. In an embodiment of the conjugate of the invention 26, 745-756; Taylor et al., Prostate, 2012, 72, 523-532: the ion channel to which the further targeting moiety of the Valerie et al., Cancer Res, 2011, 71, 6817-6826; Swift et al., conjugate of the invention is capable of binding, is selected Cancer Res, 2010, 70,347-356), Colorectal cancer (Chao et from the group comprising a voltage-gated ion channel, a al., J Surg Res, 2005, 129, 313-321; Gui et al., Peptides, ligand-gated ion channel and other ion channels. 2008, 29, 1609-1615; Bossard et al., Peptides, 2007, 28, 0342. In an embodiment of the conjugate of the invention 2030-2035), Ewings sarcoma (Reubi et al., Int J Cancer, the adhesion molecule to which the further targeting moiety 1999, 82,213-218), Meningioma (Reubi et al., IntJ Cancer, of the conjugate of the invention is capable of binding, is 1999, 82,213-218), Breast cancer (Dupouyet al., PLoS One, selected from the group comprising an integrin, a cell 2009, 4, e4223; Souaze et al., Cancer Res, 2006, 66, adhesion molecule (CAMs), a selectin, a cadherin, a lectin 6243-6249), Gastric cancer (Schulz et al., J. Endocrinol, and a claudin. 2006, 191, 121-128; Thomas et al., Endocr Rev. 2003, 24, 0343. In an embodiment of the conjugate of the invention 571-599), Mesothelioma (Alifano et al., Biochimie, 2009): the immunoglobulin superfamily receptor to which the fur 0336 group J. Pancreatic cancer (Ehlers et al., Ann Surg, ther targeting moiety of the conjugate of the invention is 2000, 231, 838-848: Reubi et al., Gut, 1998, 42, 546-550), capable of binding, is selected from the group comprising a Small cell lung cancer (Moody, Panminerva Med, 2006, 48, cytokine receptor, a growth factor receptor, and an Ig 19-26; Oceo-Garcia et al., Lung Cancer, 2001, 33, 1-9), binding receptor. Non-small cell lung cancer (Alifano et al., Clin Cancer Res, 0344. In an embodiment of the conjugate of the invention 2010, 16, 4401-4410; Moody et al., Life Sci, 2014, 100, the extracellular matrix protein to which the further targeting 25-34), Prostate cancer (Amorino et al. Oncogene, 2007, moiety of the conjugate of the invention is capable of 26, 745-756; Taylor et al., Prostate, 2012, 72, 523-532: binding, is selected from the group comprising a proteogly Valerie et al., Cancer Res, 2011, 71, 6817-6826; Swift et al., cans, a hyaluronic acid, a collagen, an elastin, a fibronectin, Cancer Res, 2010, 70,347-356), Colorectal cancer (Chao et a laminin, a fibrillin and a nidogen. al., J Surg Res, 2005, 129, 313-321; Gui et al., Peptides, 0345. In an embodiment of the conjugate of the invention 2008, 29, 1609-1615; Bossard et al., Peptides, 2007, 28, the transporter to which the further targeting moiety of the 2030-2035), Breast cancer (Dupouyet al., PLoS One, 2009, conjugate of the invention is capable of binding, is selected 4, e4223; Souaze et al., Cancer Res, 2006, 66, 6243-6249), from the group comprising an ATP-binding cassette trans Ewing's sarcoma (Reubi et al., Int J Cancer, 1999, 82, porter family, an F-type ATPase, a V-type ATPase, a P-type 213-218); ATPase, a member of the major facilitator superfamily 0337 group K: Pancreatic cancer (Ehlers et al., Ann Surg, (MFS) of transporters, and a member of the SLC superfam 2000, 231, 838-848: Reubi et al., Gut, 1998, 42, 546-550), ily of solute carriers. Prostate cancer (Amorino et al., Oncogene, 2007, 26, 745 0346. In an embodiment of the conjugate of the invention 756; Taylor et al., Prostate, 2012, 72, 523-532; Valerie et al., the target to which the further targeting moiety of the US 2017/01 19913 A1 May 4, 2017

conjugate of the invention is capable of binding, is selected Cancer Res, 2010, 16, 3548-3561), Transferrin receptor from group B as defined herein. (Daniels et al., Biochim Biophys Acta, 2012, 1820, 291-317), 0347 In an embodiment of the conjugate of the invention Prostate specific membrane antigen (PSMA) (Chang et al., the target to which the further targeting moiety of the Cancer Res, 1999, Ren et al., Med Oncol, 2014), prostate conjugate of the invention is capable of binding, is selected stem cell antigen (PSCA) (Reiter et al., Proc Natl Acad Sci from group B as defined herein. US A, 1998, 95, 1735-1740), carcinoenbryonic antigen (CEA) (Hong et al., Biomark Insights, 2008, 3, 435-451), 0348. In an embodiment of the conjugate of the invention TEM1 (Nanda et al., Proc Natl AcadSci USA, 2006, 103, the target to which the further targeting moiety of the 3351-3356), TEM5 (Vallon et al., J Biol Chem, 2006, 281, conjugate of the invention is capable of binding, is selected 34179-34.188), TEM8 (Frankel et al., Anticancer Agents from the group comprising CCK receptors (Mailleux et al., Med Chem, 2011, 11, 983-992), EGF-R (Nicholson et al., Neurosci Lett, 1990, 117, 243-247; Reubi et al., Cancer Res, EurJ Cancer, 2001, 37 Suppl 4, S9-15), ErbB2 (English et 1997, 57, 1377-1386) (Upp et al., Cancer Res, 1989, 49, al., Mol Diagn. Ther, 2013, 17, 85-99; Gravalos et al., Ann 488-492; Jensen, Pharmacol Toxicol, 2002, 91, 333-350), Oncol, 2008, 19, 1523-1529), EphA2 (Biao-Xue et al., Curr Secretin receptors (Korner et al., Am J Pathol, 2005, 167, Cancer Drug Targets, 2011; Cai et al., Eur J. Nucl Med Mol 959-968), Neurotensin receptors (Ehlers et al., Ann Surg, Imaging, 2007), Claudin-67-18(Sahin et al., Clin Cancer 2000, 231, 838-848; Reubi et al., Gut, 1998; Reubi et al., Int Res, 2008, 14, 7624-7634; Morin, Cancer Res, 2005, 65, J Cancer, 1999, 82, 213-218), NPY receptors (Reubi et al., 9603-9606: Kominsky, Expert Rev Mol Med, 2006, 8, 1-11), Cancer Res, 2001, 61, 4636-4641; Magni et al., Ann Oncol, CD52 (Rawstron et al., Haematologica, 2006, 91, 1577 2001, 12 Suppl 2, S27-29), ED-B fibronectin (Menrad et al., 1578; Piccaluga et al., Haematologica, 2007, 92,566-567), Expert Opin Ther Targets, 2005, 9, 491-500), ED-A HLA-DR10 (Epstein et al., Cancer Res, 1987, 47, 830-840: fibronectin (Xiang et al., PLoS One, 2012, 7, e35378), Balhorn et al., Clin Cancer Res, 2007, 13, 5621s-5628s), Somatostatin receptors (de Herder et al., Endocr Relat EGP-1 (epithelial glycoprotein-1) (Muhlmann et al., J. Clin Cancer, 2003, 10, 451–458: Reubi et al., Int J Cancer, 1999, Pathol, 2009, 62, 152-158; Cubas et al., Biochim Biophys 81, 376-386; Reubi et al., J. Clin Endocrinol Metab, 2000, Acta, 2009, 1796, 309-314), CEACAM5 (carcinoembryonic 85, 3882-3891), Bombesin receptors (Reubi et al., Clin antigen-related cell adhesion molecule 5) (Beauchemin et Cancer Res, 2002, 8, 1139-1146; Fathi et al., J Cell Biochem al., Cancer Metastasis Rev. 2013, 32, 643-671), E-Cadherin Suppl. 1996, 24, 237-246), Tenascin (Kusagawa et al., Br J (Kowalski et al., Breast Cancer Res, 2003, 5, R217-222; Cancer, 1998, 77, 98-102; Brack et al., Clin Cancer Res, Chan, World J Gastroenterol, 2006, 12, 199-203), CXCR4 2006), Integrin avb6 (Bandyopadhyay et al., Curr Drug (Furusato et al., Pathol Int, 2010, 60, 497-505), LRRC15 Targets, 2009, Hausner et al., Cancer Res, 2007), Integrin (Schuetz et al., Cancer Res, 2006, 66, 5278-5286; O'Prey et a5b1 (Roman et al., Am JRespir Cell Mol Biol, 2010, 43, al., J Virol, 2008, 82, 5933-5939), MMPs (Mitra et al., 684-691), Integrin avb3 (Kumar, Curr Drug Targets, 2003, JEnviron Pathol Toxicol Oncol, 2003, 22, 93-100: Davidson 4, 123-131; Danhier et al., Mol Pharm, 2012, 9, 2961-2973), et al., Arkh Patol, 2002, 64, 47-53), TFPI (Sierko et al., Gastric Mucin (Singh et al., Cancer Biol Ther; 2007, 6, Thromb Haemost, 2010, 103, 198-204), secreted form of 481-486), Glypican 3 (Baumhoer et al., Am J Clin Pathol, Clusterin SOLU (Trougakos et al., Int J Biochem Cell Biol, 2008, 129,899-906), Hepsin (Klezovitchet al., Cancer Cell, 2002, 34, 1430-1448: RiZZi et al., Endocr Relat Cancer, 2004, 6, 185-195), Robol (Wang et al., Cancer Cell, 2003, 2010, 17, R1-17), Siglec-15 (Takamiya et al., Glycobiology, 4, 19-29), Robo4 (Grone et al., Oncol Rep, 2006, 15, 2013, 23, 178-187), CAAG-1, HMW-MAA (high molecular 1437-1443), CD3, CD19 (Raufi et al., Cancer Manag Res, weight melanoma-associated antigen) (Kageshita et al., Pig 2013, 5, 225-233), CD20 (Davis et al., Clin Cancer Res, ment Cell Res, 1992, Suppl 2, 132-135; Buraggi, Nuklear 1999, 5, 611-615; Kosmas et al., Leukemia, 2002, 16, medizin, 1986, 25, 220-224), TAG-72 (Qi et al., J Surg 2004-2015), CD22 (Tu et al., JExp. Ther. Oncol, 2011, 9, Oncol, 1995, 59, 3-9: Muxi et al., Nucl Med Commun, 1999, 241-248), CD25 (Rechet al., Ann N YAcadSci, 2009, 1174, 20, 123-130), hsp70 (Murphy, Carcinogenesis, 2013, 34, 99-106), CD30 (Mechtersheimer et al., Cancer, 1990, 66, 1181-1188: Guzhova et al., Int J Hyperthermia, 2013, 29, 1732-1737: Engert, Haematologica, 2013, 98, 1165-1168), 399-408), Foetal antigen-2 (Hakkinen, Transplant Rev. CD33 (Linenberger, Leukemia, 2005, 19, 176-182), CD40 1974, 20, 61-76; Cheung et al., World J Surg. Oncol, 2010, (Vonderheide et al., Clin Cancer Res, 2013, 19, 1035-1043), 8, 38), collagen XXIII (Banyard et al., J Biol Chem, 2003, CD44 (splice variants, e.g.V6), CD77 (glycosphingolipid 278, 20989-20994: Banyard et al., Clin Cancer Res, 2007, Gb3) (Distler et al., PLoS One, 2009, 4, e6813), CD96 13, 2634-2642), nucleolin (Joo et al., Glycobiology, 2005, (Hosen et al., Proc Natl AcadSci USA, 2007, 104, 11008 15, 1-9: Destouches et al., PLoS One, 2008, 3, e2518), 11013), CD123 (Jin et al., Cell Stem Cell, 2009, 5, 31-42), TENB2 (Glynne-Jones et al., Int J Cancer, 2001, 94, 178 MCT1 (Sonveaux et al., PLoS One, 2012, 7, e33418), MCT4 184), tissue factor receptor (Schaffner et al., Semin Thromb (Gotanda et al., Anticancer Res, 2013, 33, 2941-2947), Hemost, 2008, 34, 147-153), ASC2 Aminosiuretransporter EMMPRIN (CD147) (Nabeshima et al., Pathol Int, 2006, (Shimizu et al., BrJ Cancer, 2014, 110, 2030-2039), FAP 56, 359-367), PKN3 (protein kinase N3) (Unsal-Kacmazet alpha (Lee et al., BMC Cancer, 2011, 11, 245), Folic Acid al., Mol Oncol, 2012, 6, 284-298; Aleku et al., Cancer Res, Receptor (Serpe et al., Pharmgenomics Pers Med, 2014, 7, 2008, 68, 9788-9798), Mesothelin (Ho et al., Clin Cancer Res, 2007, 13, 1571-1575), EpCAM (epithelial cell adhesion 31-42: Walters et al., Gynecol Oncol, 2013, 131, 493-498), molecule) (Munz et al., Cancer Res, 2009, 69, 5627-5629) CA19.9 (Haglund et al., Br J Cancer, 1991, 63, 386-389), (=HEA, human epithelial antigena), Vascular cell adhesion Angiopoietin-f-2 receptor (Holopainen et al., Cancer Res, molecule-1 (VCAM-1) (Chen et al., Clin Cancer Res, 2012, 2009, 69, 4656-4664; Martin et al., Histol Histopathol, 18, 5520-5525), Endoglin (EDG) (Fonsatti et al., Cardio 2008, 23, 773-780), GIP. vasc Res, 2010, 86, 12-19), gp A33 (Rageul et al., Int J 0349. In an embodiment of the conjugate of the invention Cancer, 2009, 125, 2802-2809), VEGF-R (Smith et al., Clin the target to which the further targeting moiety of the US 2017/01 19913 A1 May 4, 2017 62 conjugate of the invention is capable of binding, is selected receptor 3, Vasoactive intestinal peptide receptor, Vasoactive from the group comprising Alpha(V)beta(3) integrin, Alpha intestinal polypeptide receptor 2 (VPAC2). (5)beta(1), Alpha(V)beta(6) integrin, Amino acid transporter 0350. In an embodiment of the conjugate of the invention ASC, Amino acid transporter L, Aminopeptidase N (ANP. the target to which the further targeting moiety of the conjugate of the invention is capable of binding, is selected CD13), Angiopoietin-1 receptor, Atrial natriuretic peptide from the group comprising Alpha(5)beta(1). Alpha(V)beta receptor 1, Atrial natriuretic peptide receptor 2, A-type (3) integrin, Alpha(V)beta(6) integrin, Angiopoietin-1 recep amino acid transporter, Avidin, Bcr-Abl tyrosine kinase, tor, Bombesin receptor, CA 125 antigen, CA19.9, Carbonic Bombesin receptor, Bombesin receptor subtype-3, CA 125 anhydrase IX, Carcinoembryonic antigen, CCK-1 receptor, antigen, CA19.9, Cadherin 2, Calcitonin receptor, Carbonic CD137 antigen, CD20, CD30, CD40, CEACAM cell adhe anhydrase IX, Carcinoembryonic antigen, CCK-1 receptor, sion molecule, Chemokine receptor 4 (CXCR4), Cholecys CD105 (Endoglin, EDG), CD137 antigen, CD19, CD20, tokinin receptor subtype 2 (CCK-2), Colony stimulating CD21, CD22, CD25, CD27, CD3, CD30, CD33, CD37, factor-1 receptor (CSF-1R), Corticotropin-releasing factor CD40, CD44 (splice variants, e.g.V6), CD44 receptor, receptor 1 (CRFR1), Corticotropin-releasing factor receptor 2 (CRFR2), CTLA4, E-Cadherin, ED-A fibronectin, ED-B CD52, CEACAM cell adhesion molecule, Cell surface fibronectin, EGF HER2 receptor, EGFR (HER1), EMM nucleolin, Chemokine receptor 4 (CXCR4), Cholecystoki PRIN (CD147), EpCAM (epithelial cell adhesion molecule), nin receptor subtype 2 (CCK-2), Cholecystokinin type A EphA2 receptor, EphrinB4 receptor, Epidermal growth fac (CCK-A) receptor, Claudin 4 receptor, Claudin-6, collagen tor receptor 3, E-selectin, FGF receptor. Folate receptor, XXIII, Colony stimulating factor-1 receptor (CSF-1R), Cor Gastrin releasing peptide (GRP) receptor, Glucagon like ticotropin-releasing factor receptor 1 (CRFR1), Corticotro peptide 1 receptor, GLUT transporter system, Glycoprotein pin-releasing factor receptor 2 (CRFR2), CTLA4, Disialo IIb/IIIa receptor (GPIb/IIIa receptor), Glypican 3, Gonado gangliosides, DKK2 protein, DPPIV, E-Cadherin, ED-A tropin releasing hormone receptor, Integrins CVB5, Intercel fibronectin, ED-B fibronectin, EGF HER2 receptor, EGFR lular adhesion molecule 1 (ICAM-1), L1-CAM antigen, Luteinizing hormone releasing hormone receptor, Matrix (HER1), EGFR Tyrosine kinase, EGFR2, EGP-1 (epithelial metalloproteinases (membrane type-1), Melancortin-1 glycoprotein-1), EMMPRIN (CD147), Endothelin A (ETA) receptor (MC1R), Mesenchymal-epithelial transition factor receptor, Endothelin B receptor, EpCAM (epithelial cell (c-Met), MIF, MUC1, Mucin MUC2, neuropeptide Y recep adhesion molecule), EphA2 receptor, EphrinB4 receptor, tor 1 (NPY1-R), neuropeptide Y receptor 2 (NPY2-R), Epidermal growth factor receptor 3, E-selectin, FGF recep Neuropeptide Y receptor type 4 (NPY4-R), Neurotensin tor, Fibroblast activation protein-alpha (FAPa), Folate recep receptor, Neurotensin receptor 1 (NTSR1), Neurotensin tor, Gastrin releasing peptide (GRP) receptor, Gastrin/cho receptor 2 (NTSR2), PDGFR, Prolactin receptor, Prostate lecystokinin-2 (CCK-2, CCK-B) receptor, Glucagon like specific antigen, Prostate stem cell antigen (PSCA), Pros peptide 1 receptor, Glucose transporter, GLUT transporter tate-specific membrane antigen (PSMA), RANKL. Robol, system, Glutamate transporters, Glutamine transporter, Gly Robo4, somatostatin receptor, Substance P receptor (NK coprotein IIb/IIIa receptor (GPIb/IIIa receptor), Glypican 3, 1R), Substance-K receptor (NK-2R), Tenascin-C, Transfer Gonadotropin releasing hormone receptor, gpA33, GPR54 rin receptor (TfR), Tumor necrosis factor-related apoptosis receptor, Hepsin, HLA-DR antigen, Integrins CVB5. Inter inducing ligand receptor 1 (TRAIL-R1), Tumor necrosis cellular adhesion molecule 1 (ICAM-1), L1-CAM antigen, factor-related apoptosis-inducing ligand receptor 2 Lactoferrin receptor, L-Amino acid transporter (LAT), (TRAILR2), Vascular cell adhesion molecule 1 (VCAM-1), Luteinizing hormone releasing hormone receptor, Matrix Vascular endothelial growth factor receptor (VEGFR), Vas metalloproteinase-12, Matrix metalloproteinase-9, Matrix cular endothelial growth factor receptor 2 (VEGFR2), Vas metalloproteinases (membrane type-1), Melancortin-1 cular endothelial growth factor receptor 3, Vasoactive intes receptor (MC1R), Mesenchymal-epithelial transition factor tinal peptide receptor, Vasoactive intestinal polypeptide (c-Met), MIF, MUC1, Mucin MUC2, Neurokinin 1 (NK1) receptor 2 (VPAC2). receptor, neuropeptide Y receptor 1 (NPY1-R), neuropeptide 0351. In an embodiment of the conjugate of the invention Y receptor 2 (NPY2-R), Neuropeptide Y receptor type 4 the target to which the further targeting moiety of the (NPY4-R), Neurotensin receptor, Neurotensin receptor 1 conjugate of the invention is capable of binding, is selected (NTSR1), Neurotensin receptor 2 (NTSR2), PDGFR, Pro from the group comprising Amino acid transporter L. lactin receptor, Prostate specific antigen, Prostate stem cell Angiopoietin-1 receptor, Atrial natriuretic peptide receptor antigen (PSCA), Prostate-specific membrane antigen 1, Atrial natriuretic peptide receptor 2, A-type amino acid (PSMA), RANKL, Robol, Robo4, somatostatin receptor, transporter, Avidin, Bcr-Abl tyrosine kinase, Bombesin Somatostatin receptor 1 (SSTR1). Somatostatin receptor 2 receptor, Bombesin receptor subtype-3. Cadherin 2, Calci (SSTR2), Somatostatin receptor 3 (SSTR3). Somatostatin tonin receptor, CCK-1 receptor, CD20, CD21, CD27, CD30, receptor Sub-type 4. Somatostatin receptor type 5, Substance CD37, Chemokine receptor 4 (CXCR4), Cholecystokinin P receptor (NK-1R), Substance-K receptor (NK-2R), TAG receptor subtype 2 (CCK-2), Cholecystokinin type A (CCK 72, Tenascin-C, Tissue factor, Transferrin receptor (TfR), A) receptor, Claudin 4 receptor, Colony stimulating factor-1 Tumor endothelial marker 1 (TEM1), Tumor necrosis factor receptor (CSF-1R), DKK2 protein, E-Cadherin, EGF HER2 receptor, Tumor necrosis factor-related apoptosis-inducing receptor, EGFR (HER1), EGFR Tyrosine kinase, EGFR2, ligand receptor 1 (TRAIL-R1), Tumor necrosis factor-re Endothelin A (ETA) receptor, Endothelin B receptor, lated apoptosis-inducing ligand receptor 2 (TRAILR2), Uro EpCAM (epithelial cell adhesion molecule), EphA2 recep kinase plasminogen activator receptor, Urokinase-type plas tor, EphrinB4 receptor, FGF receptor, Gastrin releasing minogen activator receptor (uPAR), Vascular cell adhesion peptide (GRP) receptor, Gastrin/cholecystokinin-2 (CCK-2, molecule 1 (VCAM-1), Vascular endothelial growth factor CCK-B) receptor, Gonadotropin releasing hormone recep receptor (VEGFR), Vascular endothelial growth factor tor, GPR54 receptor, Lactoferrin receptor, Luteinizing hor receptor 2 (VEGFR2), Vascular endothelial growth factor mone releasing hormone receptor, Matrix metalloprotein US 2017/01 19913 A1 May 4, 2017

ase-12, Melancortin-1 receptor (MC1R), neuropeptide Y receptor (Korner et al., J Nucl Med, 2007, 48, 736-743), receptor 1 (NPY1-R), neuropeptide Y receptor 2 (NPY2-R), Gonadotropin releasing hormone receptor (Grundker et al., Neurotensin receptor, somatostatin receptor, Substance P Mol Cancer Ther, 2005, 4, 225-231), Melanocyte-stimulat receptor (NK-1R), Tumor necrosis factor receptor, Uroki ing hormone receptor (Cheng et al., J Nucl Med, 2007, 48, nase plasminogen activator receptor, Vascular endothelial 987-994), Neuromedin-B receptor (NMBR) (Park et al., growth factor receptor (VEGFR), Vasoactive intestinal pep Cancer Lett, 2011, 312, 117-127), Neurokinin-3 receptor tide receptor. (NK-3R) (Rameshwar et al., Blood, 1995, 86, 482-490), 0352. In an embodiment of the conjugate of the invention neuropeptide Y receptor 1 (NPY1-R) (Reubi et al., Cancer the target to which the further targeting moiety of the Res, 2001, 61, 4636-4641; Magni et al., Ann Oncol, 2001, 12 conjugate of the invention is capable of binding, is selected Suppl 2, S27-29), neuropeptide Y receptor 2 (NPY2-R) from the group comprising Alpha(V)beta(3) integrin, Alpha (Medeiros et al., Int J Cancer, 2012, 131, 276-286: Korner (V)beta(6) integrin, Amino acid transporter ASC, Amino acid et al., Peptides, 2007, 28, 419-425), Neuropeptide Y recep transporter L, Aminopeptidase N (ANP, CD13), Angiopoi tor type 4 (NPY4-R) (Cox et al., BrJ Pharmacol, 2001, 132, etin-1 receptor, Atrial natriuretic peptide receptor 1, Atrial 345-353), Neurotensin receptor 1 (NTSR1) (Ehlers et al., natriuretic peptide receptor 2, Bombesin receptor, Bombesin Ann Surg, 2000, 231, 838-848; Reubi et al., Gut, 1998), receptor subtype-3, CA 125 antigen, CA19.9, Cadherin 2, Neurotensin receptor 2 (NTSR2) (Reubi et al., Int J Cancer, Calcitonin receptor, Carbonic anhydrase IX, Carcinoembry 1999, 82. 213-218), Oxytocin receptor (Bussolati et al., Am onic antigen, CCK-1 receptor, CD105 (Endoglin, EDG), J Pathol, 1996, 148, 1895-1903), Pituitary adenylate CD19, CD20, CD22, CD25, CD3, CD30, CD33, CD40, cyclase-activating polypeptide type I receptor (Reubi et al., CD44 (splice variants, e.g.V6), CD44 receptor, CD52, Cancer Res, 2000, 60,3105-3112), Somatostatin receptor 1 CEACAM cell adhesion molecule, Cell surface nucleolin, (SSTR1) (Fujita et al., Life Sci, 1994, 55, 1797-1806), Cholecystokinin receptor subtype 2 (CCK-2), Claudin-6, Somatostatin receptor 2 (SSTR2) (Reubi et al., J. Clin collagen XXIII, Corticotropin-releasing factor receptor 1 Endocrinol Metab, 2000, 85, 3882-3891), Somatostatin (CRFR1), Corticotropin-releasing factor receptor 2 receptor 3 (SSTR3) (Reubi et al., Int J Cancer, 1999, 81, (CRFR2), Disialogangliosides, DPPIV, E-Cadherin, ED-A 376-386). Somatostatin receptor sub-type 4 (Plockinger et fibronectin, ED-B fibronectin, EGF HER2 receptor, EGP-1 al., Eur J Endocrinol, 2012, 166, 223-234). Somatostatin (epithelial glycoprotein-1), EMMPRIN (CD147), Eph A2 receptor type 5 (de Herder et al., Endocr Relat Cancer, 2003, receptor, Fibroblast activation protein-alpha (FAP2), Gastrin 10, 451–458), Sortilin (NTSR3) (Hemmati et al., Avicenna J releasing peptide (GRP) receptor, Glucose transporter, Glu Med Biotechnol, 2009, 1, 125-131), Substance P receptor tamate transporters, Glutamine transporter, gpA33, GPR54 (NK-1R) (Hennig et al., Int J Cancer, 1995, 61, 786-792), receptor, Hepsin, HLA-DR antigen, L-Amino acid trans Substance-K receptor (NK-2R) (Bigioni et al., Anticancer porter (LAT), Lactoferrin receptor, Matrix metalloprotein Drugs, 2005, 16, 1083-1089), Vasoactive intestinal peptide ase-9, MUC1, Neurokinin 1 (NK1) receptor, neuropeptide Y receptor (VPAC1) (Virgolini et al., N Engl.J Med 1994, 331, receptor 1 (NPY1-R), neuropeptide Y receptor 2 (NPY2-R), 1116-1121), Vasoactive intestinal polypeptide receptor 2 Neuropeptide Y receptor type 4 (NPY4-R), Neurotensin (VPAC2) (Reubi et al., Cancer Res, 2000, 60, 3105-3112), receptor, Neurotensin receptor 1 (NTSR1), Neurotensin BB4 (Reubi et al., Clin Cancer Res, 2002, 8, 1139-1146). receptor 2 (NTSR2), Prostate stem cell antigen (PSCA), 0354. In an embodiment of the conjugate of the invention Prostate-specific membrane antigen (PSMA), Robol, Soma the target to which the further targeting moiety of the tostatin receptor 1 (SSTR1). Somatostatin receptor 2 conjugate of the invention is capable of binding, is selected (SSTR2), Somatostatin receptor 3 (SSTR3). Somatostatin from the group comprising Alpha(V)beta(3) integrin (Ku receptor sub-type 4. Somatostatin receptor type 5, TAG 72, mar, Curr Drug Targets, 2003, 4, 123-131; Danhier et al., Tenascin-C, Tumor necrosis factor receptor, Urokinase-type Mol Pharm, 2012, 9, 2961-2973), Alpha(v)beta(6) integrin plasminogen activator receptor (uPAR), Tumor endothelial (Bandyopadhyay et al., Curr Drug Targets, 2009, Hausner et marker 1 (TEM1), Tissue factor and Transferrin receptor al., Cancer Res, 2007), Amino acid transporter L. (Haase et (TfR). al., JNucl Med, 2007, 48, 2063-2071; Imai et al., Anticancer 0353. In an embodiment of the conjugate of the invention Res, 2010, 30, 4819-4828), Atrial natriuretic peptide recep the target to which the further targeting moiety of the tor 1 (Wang et al., Mol Cancer, 2011, 10, 56; Kong et al., conjugate of the invention is capable of binding, is selected Cancer Res, 2008, 68, 249-256), Atrial natriuretic peptide from the group comprising Atrial natriuretic peptide receptor receptor 2 (Zhao et al., World J Surg Oncol, 2014, 12, 154), 1 (Wang et al., Mol Cancer, 2011, 10, 56; Kong et al., Bombesin receptor subtype-3 (Reubi et al., Clin Cancer Res, Cancer Res, 2008, 68, 249-256), Atrial natriuretic peptide 2002, 8, 1139-1146; Moody et al., Peptides, 2011, 32, receptor 2 (Zhao et al., World J Surg Oncol, 2014, 12, 154), 1677-1684), CA 125 antigen (Devan et al., Asian Pac J Bombesin receptor subtype-3 (Reubi et al., Clin Cancer Res, Cancer Prey, 2013, 14, 4545-4548: Seelenmeyer et al., J 2002, 8, 1139-1146; Moody et al., Peptides, 2011, 32, CellSci, 2003, 116, 1305-1318), CA19.9 (Haglund et al., Br 1677-1684), Calcitonin receptor (Wang et al., Breast Cancer J Cancer, 1991, 63, 386-389), Cadherin 2 (Nakajima et al., Res Treat, 2004, 83, 109-117), Corticotropin-releasing fac Clin Cancer Res, 2004, 10, 4125-4133), Calcitonin receptor tor receptor 1 (CRFR1) (Wang et al., Biochem Biophy's Res (Wang et al., Breast Cancer Res Treat, 2004, 83, 109-117), Commun, 2007, 362,785-788), Corticotropin-releasing fac Carbonic anhydrase IX (McDonald et al. Oncotarget, 2012, tor receptor 2 (CRFR2) (Wang et al., Biochem Biophy's Res 3, 84-97), Carcinoembryonic antigen (Hong et al., Biomark Commun, 2007, 362,785-788), Endothelin A (ETA) receptor Insights, 2008, 3, 435-451), CD40 (Vonderheide et al., Clin (Bagnato et al., J Transl Med, 2004, 2, 16), Endothelin B Cancer Res, 2013, 19, 1035-1043), CEACAM cell adhesion receptor (Kandalaft et al., Clin Cancer Res, 2009, 15, molecule (Beauchemin et al., Cancer Metastasis Rev. 2013, 4521-4528), Gastrin releasing peptide (GRP) receptor (Sun 32, 643-671), Chemokine receptor 4 (CXCR4) (Furusato et et al., Prostate, 2000, 42, 295-303), Glucagon like peptide 1 al., Pathol Int, 2010, 60, 497-505), Colony stimulating US 2017/01 19913 A1 May 4, 2017 64 factor-1 receptor (CSF-1R) (Kacinski, Ann Med, 1995, 27. 2007), Gastrin releasing peptide (GRP) receptor (Carroll et 79-85), Corticotropin-releasing factor receptor 1 (CRFR1) al., Peptides, 1999, 20, 229-237; Saurinet al., EurJ Cancer, (Wang et al., Biochem Biophy's Res Commun, 2007, 362, 1999, 35, 125-132), neuropeptide Y receptor 1 (NPY1-R) 785-788), Corticotropin-releasing factor receptor 2 (Reubi et al., Cancer Res, 2001, 61, 4636-4641; Magniet al., (CRFR2) (Wang et al., Biochem Biophy's Res Commun, Ann Oncol, 2001, 12 Suppl 2, S27-29), neuropeptide Y 2007, 362, 785-788), ED-A fibronectin (Xiang et al., PLoS receptor 2 (NPY2-R) (Medeiros et al., Int J Cancer, 2012, One, 2012, 7, e35378), ED-B fibronectin (Menrad et al., 131, 276-286: Korner et al., Peptides, 2007, 28, 419-425), Expert Opin Ther Targets, 2005, 9,491-500), EGFR (HER1) Neurotensin receptor (Ehlers et al., Ann Surg, 2000, 231, (Nicholson et al., Eur J Cancer, 2001, 37 Suppl 4, S9-15), 838-848; Reubi et al., Gut, 1998). EMMPRIN (CD147) (Nabeshima et al., Pathol Int, 2006, 0356. In an embodiment of the conjugate of the invention 56, 359-367), EpCAM (epithelial cell adhesion molecule) the target to which the further targeting moiety of the (Munz et al., Cancer Res, 2009, 69, 5627-5629), EphrinB4 conjugate of the invention is capable of binding, is selected receptor (Li et al., Mol Pharm, 2013, 10, 329-336), FGF from the group comprising Alphavbeta6 integrin (Bandyo receptor (Katoh et al., Med Res Rev. 2014, 34, 280-300), padhyay et al., Curr Drug Targets, 2009, 10,645-652; Bates, Gonadotropin releasing hormone receptor (Grundker et al., Future Oncol, 2005, 1,821-828; Eberlein et al., Oncogene, Mol Cancer Ther; 2005, 4, 225-231), GPR54 receptor (Cho 2013, 32, 4406-4416: Hausner et al., Cancer Res, 2007, 67, et al., Cancer Metastasis Rev. 2012, 31, 585-591), Lacto 7833-7840: Hecht et al., Appl Immunohistochem Mol Mor ferrin receptor (Wrba et al., Verh Dtsch Ges Pathol, 1986, phol, 2008, 16, 543-547: Kogelberg et al., PLoS One, 2013, 70, 247-250), Luteinizing hormone releasing hormone 8, e73260: Liet al., Bioorg Med Chem, 2011, 19, 5480-5489: receptor (Buchholz et al., Int J Oncol, 2009, 35, 789-796), Liu et al., JNucl Med, 2014: Schittenhelm et al., Int J Clin Melancortin-1 receptor (MC1R) (Cheng et al., J Nucl Med, Eyp Pathol, 2013, 6, 2719-2732; Vogetseder et al., Int J 2007, 48,987-994), MUC1 (Singh et al., Cancer Biol. Ther Cancer, 2013, 133, 2362-2371), Bradykinin Bi receptor 2007, 6,481-486), Neuropeptide Y receptor type 4 (NPY4 (Chee et al., Biol Chem, 2008, 389, 1225-1233: Esseghir et R) (Cox et al., Br J Pharmacol, 2001, 132, 345-353), al., J Pathol, 2006, 210, 420-430; Figueroa et al., Expert Neurotensin receptor 1 (NTSR1) (Ehlers et al., Ann Surg, Opin Ther Targets, 2012, 16, 299-312: Molina et al., Breast 2000, 231, 838-848; Reubi et al., Gut, 1998), Neurotensin Cancer Res Treat, 2009, 118, 499-510; Moodley et al., Biol receptor 2 (NTSR2) (Reubi et al., Int J Cancer, 1999, 82, Chem, 2005, 386, 375-382: Sgnaolin et al., Invest New 213-218), Prostate stem cell antigen (PSCA) (Reiter et al., Drugs, 2012: Taub et al., Cancer Res, 2003, 63, 2037-2041), Proc Natl Acad Sci USA, 1998, 95, 1735-1740), Prostate EphA2 (Biao-Xue et al., Curr Cancer Drug Targets, 2011; specific membrane antigen (PSMA) (Chang et al., Cancer Cai et al., Eur J. Nucl Med Mol Imaging, 2007, 34, 2024 Res, 1999, Ren et al., Med Oncol, 2014), Robol (Wang et al., 2036; Castano et al. Histol Histopathol, 2008, 23, 1011 Cancer Cell, 2003, 4, 19-29), somatostatin receptor (Reubi 1023; Herath et al., Int J Cancer, 2010, 126, 2003-2011; et al., IntJ Cancer, 1999, 81,376-386), Substance Preceptor Jackson et al., Cancer Res, 2008, 68,9367-9374; Kinch et (NK-1R) (Hennig et al., IntJ Cancer, 0.1995, 61,786-792), al., Clin Exp Metastasis, 2003, 20, 59-68; Pasquale, Nat Rev Tenascin-C (Kusagawa et al., Br. J Cancer, 1998, 77,98-102; Cancer, 2010, 10, 165-180; Tandon et al., Expert Opin Ther Brack et al., Clin Cancer Res, 2006), Transferrin receptor Targets, 2011, 15, 31-51; Wang et al., J Med Chem, 2012: (TfR) (Daniels et al., Biochim Biophys Acta, 2012, 1820, Wykosky et al., Mol Cancer Res, 2008, 6, 1795-1806), 291-317), Tumor necrosis factor receptor (Szlosarek et al., Tenascin C (Kusagawa et al., Bru Cancer, 1998, 77, 98-102; Mol Cancer Ther; 2006, 5, 382-390), Vascular endothelial Bracket al., Clin Cancer Res, 2006, 12,3200-3208; Brunner growth factor receptor (VEGFR) (Smith et al., Clin Cancer et al., J. Clin Pathol, 2004, 57,927-931; Hancox et al., Breast Res, 2010, 16, 3548-3561), Vasoactive intestinal peptide Cancer Res, 2009, 11, R24; Juuti et al., J. Clin Pathol, 2004, receptor (Reubi, J Nucl Med 1995, 36, 1846-1853). 57, 1151-1155; Leins et al., Cancer, 2003, 98, 2430-2439; 0355. In an embodiment of the conjugate of the invention Parekh et al., Lung Cancer, 2005, 47, 17-29; Silacci et al., the target to which the further targeting moiety of the Protein Eng Des Sel, 2006, 19, 471-478; Tsunoda et al., Am conjugate of the invention is capable of binding, is selected JPathol, 2003, 162, 1857-1867). from the group comprising Angiopoietin-1 receptor (Tie-2) 0357. In an embodiment of the conjugate of the invention (Holopainen et al., Cancer Res, 2009, 69, 4656-4664: Mar the further targeting moiety is preferably a targeting moiety tin et al., Histol Histopathol, 2008, 23, 773-780), Bombesin having an affinity to the target molecule to which the further receptor (Reubi et al., Clin Cancer Res, 2002, 8, 1139-1146; targeting moiety is capable of binding, of <100 pM, of <1 Fathi et al., J Cell Biochem Suppl. 1996, 24, 237-246), nM, of <10 nM, of <100 nM, of <1 uM or of <10 uM. It is CCK-1 receptor (Mailleux et al., Neurosci Lett, 1990, 117, within the present invention that such affinity of the further 243-247; Reubi et al., Cancer Res, 1997, 57, 1377-1386), targeting moiety is shown by any embodiment of Such CD20 (Davis et al., Clin Cancer Res, 1999, 5, 611-615; further targeting moiety. Specifically, such affinity of the Kosmas et al., Leukemia, 2002, 16, 2004-2015), CD30 further targeting moiety can also be realized in those (Mechtersheimer et al., Cancer, 1990, 66, 1732-1737; embodiments of the conjugate of the invention where the Engert, Haematologica, 2013, 98, 1165-1168), Cholecysto further targeting moiety is preferably selected from the kinin receptor subtype 2 (CCK-2) (Uppet al., Cancer Res, group comprising an antibody, an antigen-binding antibody 1989, 49, 488-492; Jensen, Pharmacol Toxicol, 2002, 91, fragments, camelid heavy chain IgG (hcIgG), a cartilaginous 333-350), E-Cadherin (Kowalski et al., Breast Cancer Res, fish (e.g. shark) IgNAR antibody, a protein scaffold, a 2003, 5, R217-222; Chan, World J Gastroenterol, 2006, 12, target-binding peptide, a peptide nucleic acid (PNA), a 199-203), EGF HER2 receptor (English et al., Mol Diagn target-binding polypeptide or protein, a target binding Ther, 2013, 17, 85-99; Gravalos et al., Ann Oncol, 2008, 19, nucleic acid molecule, a carbohydrate, a lipid and a target 1523-1529), EphA2 receptor (Biao-Xue et al., Curr Cancer binding small molecule. Methods for determining the affin Drug Targets, 2011; Cai et al., Eurj Nucl Med Mol Imaging, ity of a compound Such as the further targeting moiety to a US 2017/01 19913 A1 May 4, 2017

or the target are known to the one skilled in the art and, for ized in those embodiments of the conjugate of the invention example described in (Schier et al., Hum Antibodies where the further targeting moiety is preferably selected Hybridomas, 1996, 7, 97-105) from the group comprising an antibody, an antigen-binding 0358. In an embodiment of the conjugate of the invention antibody fragments, camelid heavy chain IgG (hcIgG), a the further targeting moiety is preferably a targeting moiety cartilaginous fish (e.g. shark) IgNAR antibody, a protein having a stability of 100%, of at least 80%, of at least 50%, scaffold, a target-binding peptide, a peptide nucleic acid of at least 30% or of at least 10% after 24 h, 12 h, 8 h, 4 h, (PNA), a target-binding polypeptide or protein, a target 2 h, 1 h or 30 min in plasma, serum, a homogenate of a tissue binding nucleic acid molecule, a carbohydrate, a lipid and a of any origin, an enzyme cocktail, a solution of an isolated target-binding Small molecule. Methods for determining the enzyme, a protease cocktail or a solution of an isolated selectivity factor of a compound Such as the further targeting protease. Preferably, the further targeting moiety has a moiety to a or the target are known to the one skilled in the stability of 100% after 24 hours at 37° C. under the above art and, for example described in (Neubauer et al., J Med given reaction conditions, preferably if the stability is tested Chem, 2014, 57, 3410-3417). in plasma, serum or a homogenate of a tissue, more prefer 0361. It is within the present invention that the first ably a tissue which contains or expresses the target targeted targeting moiety TM1 and the second targeting moiety TM2 by the further targeting moiety. It is, however, also within are linked to or connected with each other by a linkage. Such the present invention that the further targeting moiety has a linkage can be direct such that both TM1 and TM2 are stability of at least 10% after 30 minutes at 37° C. under the directly linked to each other such as realized in embodiment above given reaction conditions, preferably if the stability is (4) of the conjugate of the invention disclosed above, i.e. tested in plasma, serum or a homogenate of a tissue, more (TM1-TM2), or by one or moieties being introduced preferably a tissue which contains or expresses the target between said first targeting moiety TM1 and said second targeted by the further targeting moiety. It is within the targeting moiety TM2. Such or more moieties being the first present invention that such stability of the further targeting adaptor moiety AD1, the linker moiety LM and the second moiety is shown by any embodiment of Such further target adaptor moiety AD2, or any combination thereof, preferably ing moiety. More specifically, such stability of the further any combination thereof as disclosed herein. Such linkage targeting moiety can also be realized in those embodiments results in the first targeting moiety TM1 and the second of the conjugate of the invention where the further targeting targeting moiety TM2 being separated from each other. Such moiety is preferably selected from the group comprising an separation can be expressed by the number of covalent antibody, an antigen-binding antibody fragments, camelid linkages realized between the first targeting moiety TM1 and heavy chain IgG (hcIgG), a cartilaginous fish (e.g. shark) the second targeting moiety TM2. In preferred embodiment IgNAR antibody, a protein scaffold, a target-binding peptide, the covalent linkages are provided by the first adaptor a peptide nucleic acid (PNA), a target-binding polypeptide moiety AD1, the linker moiety LM and the second adaptor or protein, a target binding nucleic acid molecule, a carbo moiety AD2, or any combination thereof. In an embodiment hydrate, a lipid and a target-binding Small molecule. the number of covalent bonds between the first targeting 0359. In an embodiment of the conjugate of the invention moiety TM1 and the second targeting moiety TM2 is 1. In the further targeting moiety is preferably a targeting moiety an alternative embodiment the number of covalent bonds having a selectivity factor of equal to ore more than 10,000; between the first targeting moiety TM1 and the second of equal to or more than 1000; of equal to or more than 100: targeting moiety TM2 is about from 4 to 1000, preferably of equal to or more than 50; of equal to or more than 10; of about from 5 to 150, and more preferably about from 6 to 40. equal to or more than 5 or of equal to or more than 2 to an anti-target. The Selectivity factor is the quotient of target Adapter Moieties dissociation constant and anti-target dissociation constant. The dissociation constant is commonly used to describe the 0362. In an embodiment of the conjugate of the invention affinity between a ligand (L) (Such as a drug) and a protein the conjugate comprises, in terms of an adapter moiety, a (P) i.e. how tightly a ligand binds to a particular protein. The first adapter moiety AD1 only. In another embodiment of the formation of a ligand-protein complex (C) can be described conjugate of the invention the conjugate comprises, in terms by a two-state process of an adapter moiety, a second adapter moiety AD2 only. In C PL another embodiment of the conjugate of the invention the conjugate comprises, in terms of an adapter moiety, a third 0360 The corresponding dissociation constant is defined adapter moiety AD3 only. In another embodiment of the aS conjugate of the invention the conjugate comprises, in terms of an adapter moiety, only a first adapter moiety AD1 and a second adapter moiety AD2. In another embodiment of the conjugate of the invention the conjugate comprises, in terms of an adapter moiety, only a first adapter moiety AD1 and a third adapter moiety AD3. In another embodiment of the where P. Land IC represent molar concentrations of the conjugate of the invention the conjugate comprises, in terms protein, ligand and complex, respectively. The anti-target of an adapter moiety, only a first adapter moiety AD2 and a with regard to the selectivity factor is preferably one which third adapter moiety AD3. In another embodiment of the must not or should not be targeted by the further targeting conjugate of the invention the conjugate comprises, in terms moiety. It is within the present invention that such selectivity of an adapter moiety, a first adapter moiety AD1, a second of the further targeting moiety is shown by any embodiment adapter moiety AD2 and a third adapter moiety AD3. of Such further targeting moiety. More specifically, Such 0363 The following is, in principle, applicable to each selectivity of the further targeting moiety can also be real and any of the adapter moieties which can be realized in the US 2017/01 19913 A1 May 4, 2017 66 various embodiments of the conjugate of the invention, i.e. 0370 Preferably, linkages which are established by the first adapter moiety, the second adapter moiety and the means of an adaptor moiety are selected from the group third adapter moiety. comprising an amide linkage, a urea linkage, a thioether 0364 Adapter moieties mediate the linkage between two linkage, an alkylamine linkage, a triazole linkage, an oxime different moieties. The main purpose is to selectively gen linkage, a hydraZone linkage, a hydrazide linkage, an ether erate a linkage between these two moieties which usually linkage, a carbamate linkage, an amine linkage, a disulfide have not complementary reactive groups for a selective linkage, a pyrazine linkage and a dihydropyrazine. Further linkage available. Accordingly, an adapter moiety is present more, any of the linkages Summarized in Table 4 herein, can in a conjugate of the invention in cases where two moieties be realized by means of an adapter moiety, preferably the of the conjugate of the invention do not provide reactive first adapter moiety. groups, more specifically, two addressable groups, i.e. one 0371. A generic formula of a preferred embodiment of an on each of the two moieties, which are not complementary, adapter moiety is as follows: preferably which do not allow the formation of a linkage RG3-R8-RG4 (10) between said two different moieties. Because of this, in a preferred embodiment an adaptor moiety provides for two 0372 wherein RG3 is a reactive group as described reactive groups, whereby a first of said two reactive groups herein, preferably a reactive group as indicated in Table is Suitable for generating a linkage between a first of the two 4 or selected from the group comprising amino, car moieties, and whereby a second of said two reactive groups boxylic acid, activated carboxylic acid, chloro, bromo, is Suitable for generating a linkage between a second of the iodo, Sulfhydryl, hydroxyl, Sulfonic acid, activated Sul two moieties. In a preferred embodiment, the two reactive fonic acid, Sulfonic acid esters like mesylate or tosylate, groups provided by the adapter moiety are different. In an Michael acceptors, strained alkenes like trans alternative embodiment the two reactive groups provided by cyclooctene, isocyanate, isothiocyanate, aldehyde, the adapter moiety are the same. ketone, aminooxy, hydrazide, hydrazine, azide, alkyne and tetrazine; 0365. In accordance with the function of an adapter 0373 wherein RG4 is a reactive group as described moiety in a conjugate of the invention, the backbone of Such herein, preferably a reactive group as indicated in Table adaptor moiety can, in principle, be quite diverse as long as 4 or selected from the group comprising amino, car such backbone of the adaptor moiety does not interfere with boxylic acid, activated carboxylic acid, chloro, bromo, the synthesis and use, respectively, of the conjugate of the iodo, Sulfhydryl, hydroxyl, Sulfonic acid, activated Sul invention. fonic acid, Sulfonic acid esters like mesylate or tosylate, 0366 Adapter moieties are in some embodiments bifunc Michael acceptors, strained alkenes like trans tional moieties which are known in the art. See, e.g., cyclooctene, isocyanate, isothiocyanate, aldehyde, Bioconjugate Techniques, G. T. Hermanson (Academic ketone, aminooxy, hydrazide, hydrazine, azide, alkyne Press, San Diego, Calif., 1996), which is incorporated by and tetrazine; and reference in its entirety. 0374 wherein R8 is selected 0367 Also in accordance with the function of an adapter selected from —(C-Co.)alkylidene-, -(C-Cs)carbocy moiety in a conjugate of the invention, the reactive group(s) clo-, -O-(C-Cs)alkyl-, -arylene-, -(C-C)alkylidene borne or provided by the adaptor moiety are of importance. arylene-, -arylene-(C-Co.)alkylidene-, -(C-Co.)alky It will be appreciated by a person skilled in the art that lidene-(C-C)carbocyclo, -(C-C)carbocyclo-(C-Co) depending on the structural class and origin of the targeting alkylidene-, -(C-Cs)heterocyclo-, (C-C)alkylidene moiety different types of reactive groups are provided by the (C-Cs)heterocyclo-, —(C-Cs)heterocyclo-(C-C) targeting molecule. Depending on the type of reactive group alkylidene-, -(CH2CH2O), , and —(CH2CH2O), provided by the targeting moeity, the adaptor moiety pro CH2—, vides a reactive group which is complementary to Such and r is any integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. reactive group provided by the targeting moiety. If, for 0375. In an embodiment R8 is —(C-C)alkylidene-, example, the targeting moiety is a protein, such as an —(C-Co.)alkylidene-(C-C)carbocyclo. —(C-Cs)hetero antibody or antibody fragment, the preferred reactive groups cyclo-, -(CH2CH2O), , and —(CH2CH2O), CH . for forming a linkage with another moiety and an adapter 0376. In a preferred embodiment of the conjugate of the moiety in particular, are sulfhydryl groups and amino invention R8 of the adapter moiety is —(CH), and n is groups. Sulfhydryl groups can be generated by reduction of any integer from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, preferably an intramolecular disulfide bond of a targeting moiety. Alternatively, Sulfhydryl groups can be generated by reac n is 5. tion of an amino group of a lysine moiety of a targeting 0377. In a preferred embodiment of the conjugate of the moiety using 2-iminothiolane (Traut's reagent) or another invention R8 of the adapter moiety is —(CH, CH, O) Sulfhydryl generating reagent. In a preferred embodiment —CH2— with r being an integer from 1, 2, 3, 4, 5, 6, 7, 8, thereof, the adapter moiety forms a thioether linkage with a 9 and 10, preferably r is 2. 0378. Inserted into a conjugate of the invention an adap Sulfur atom of the targeting moiety. tor moiety as preferably used in the conjugate of the inven 0368. In the following various design principles and tion is one which is indicated in the following formulae, reaction principles of an adapter moiety Suitable for use in whereby it is understood that to the extent the adapter moiety a conjugate of the invention will be outlined in the follow is represented in the formulae as being inserted between ing. linking moiety LM and targeting moiety TM2 thus being a 0369 Preferred linkages established between two moi second adapter moiety, this is made for purpose of illustra eties by means of an adapter moiety are the linkages tion only and the adapter moiety as such is the structure indicated in Table 3 herein. contained in square brackets. The very same structure US 2017/01 19913 A1 May 4, 2017 67 depicted as a second adapter moiety can, in accordance with and—RC= (of oxime and hydrazone), and R' is selected the instant invention, be equally used as a first targeting from the group consisting of hydrogen and (C-C)alkyl; moiety: and wherein the second targeting moiety provides a sulfhydryl group; (34) O O (38) (TM2); R8-N S TM1-AD1-LM) Lin-R8- TM2) O TM1-AD1-LM H (35) O O wherein Lin1 is selected from the group consisting of (TM2); CO. , S: , – NR' CO NR' CS R8-N NRO , O—, CH2—, SO. , -succinimide-, TM1-AD1-LM) H CH CO. NR' , —C=C (in case of for example triazole), —N O —N N —N N CO . —N=N N (in case of for example triazole), —HC— (36) and—RC= (of oxime and hydrazone), and R' is selected from the group consisting of hydrogen and (C-C)alkyl: O and (TM2); wherein the second targeting moiety provides a nucleophilic Lin-R-N group like an amino group; TM1-AD1-LM

O (39) O wherein Lin1 is selected from the group consisting of Lin-R CO , S NR' CO NR' , CS TM1-AD1 LM TM2) NRO , O—, CH2—, SO. , -succinimide-, CH CO. NR' , -C=C- (in case of, for example triazole), —N O —N N— —N N CO . wherein Lin1 is selected from the group consisting of —N—N N (in case of for example triazole), —HC— CO , S NR' CO NR' , CS and —RC= (of oxime and hydrazone); NRO , O—, CH , SO. , -succinimide-, wherein CH CO. NR' , -C=C- (in case of, for example 0379 “-succinimide-” means triazole), —N O —N N —N N CO . —N=N N (in case of for example triazole), —HC— and—RC= (of oxime and hydrazone), and R' is selected (9) from the group consisting of hydrogen and (C-C)alkyl: and wherein the second targeting moiety provides a nucleophilic group like an amino or hydroxyl group;

vil (40) Lin-R N=TM2) and R' is selected from the group consisting of hydrogen in-to-ust No1 | and (C-C)alkyl, wherein Lin1 is selected from the group consisting of (37) CO. , S: , – NR' CO NR' CS NRO , O—, CH2—, SO. , -succinimide-, TM1-AD1 LM uLin'-R-S-HTM2) CH CO. NR' , —C=C (in case of for example triazole), —N O —N N —N N CO . wherein Lin1 is selected from the group consisting of —N=N N (in case of for example triazole), —HC— CO , S NR' CO NR' CS and—RC= (of oxime and hydrazone), and R' is selected NRO , O—, CH2—, SO. , -succinimide-, from the group consisting of hydrogen and (C-C)alkyl: CH CO. NR' , -C=C- (in case of, for example and triazole), —N O —N N— —N N CO . wherein the second targeting moiety provides a ketone or —N—N N (in case of for example triazole), —HC— aldehyde group; US 2017/01 19913 A1 May 4, 2017 68

carboxylic acid, activated carboxylic acid, Sulfonic acid, (41) activated Sulfonic acid, isocyanates and isothiocyanates, Lin'-R line wherein the reactive group is preferably provided by an in-toi-aut N adapter0381. moiety.It will be appreciated by a person skilled in the art that adapter moiety as subject to formulae (34) to (37) and the linkages indicated therein are preferably the result of, on wherein Lin1 is selected from the group consisting of the one hand of a sulfhydryl group, preferably provided by CQ s S NR' CO NR' , CS a targeting moiety, and, on the other hand, of a reactive NR' , O—, CH2—, SO. , -Succinimide-, group selected from the group comprising Michael acceptor, CH CO. NR' , —C=C (in case of, for example halogen and Sulfhydryl, wherein the reactive group is pref triazole), —N O —N N— —N N CO . erably provided by an adapter moiety. —N—N N (in case of for example triazole), —HC— 0382. It will be appreciated by a person skilled in the art and—RC= (of oxime and hydrazone), and R' is selected that adapter moiety as subject to formulae (40) to (42) and from the group consisting of hydrogen and (C-C)alkyl; the linkages indicated therein are preferably the result of, on and the one hand of a carbohydrate, preferably provided by a wherein the second targeting moiety provides a ketone or targeting moiety, wherein the carbohydrate is preferably aldehyde group; and mildly oxidized using a reagent Such as, for example, sodium periodate and the resulting ( CHO) unit of the oxidized carbohydrate can be condensed with a with reactive group selected from the group comprising hydrazide, ami (42) nooxy, primary or secondary amino or hydrazine, such as H those described by Kaneko, T. et al. Bioconjugate Chem Lin'-R N-N==TM2) 1991, 2, 133-141, wherein the group is preferably provided TM1-AD1-LM b y an adapter moiety. O 0383. In a further embodiment of the conjugate of the invention an adapter moiety is one of wherein Lin1 is selected from the group consisting of CO - S -, - NR' , CO NR' CS (44) NRO , O—, CH , SO. , -Succinimide-, O O CH CO. NR' , —C=C (in case of, for example triazole), —N O —N N— —N N CO . N —N—N N (in case of for example triazole), —HC— H and—RC= (of oxime and hydrazone), and R' is selected from the group consisting of hydrogen and (C-C)alkyl; O (45) and wherein the second targeting moiety provides a ketone or aldehyde group; and N ; and O O TM2) (43) (46) \ O Y TM1-AD1-LM Lin-R8 NM 1\-1 - A O wherein Lin1 is selected from the group consisting of O CO , S NR' CO NR' , CS NRO , O—, CH , SO. , -succinimide-, 0384. If, in an embodiment a linkage between a moiety A CH CO. NR' , -C=C- (in case of, for example containing a primary amino group (A-NH2) and a moiety B triazole), —N O —N N— —N N CO . containing a sulfhydryl group (B-SH) is to be established, in —N—N N (in case of for example triazole), —HC— an embodiment an adapter moiety is utilized which is able and—RC= (of oxime and hydrazone), and R' is selected to form a first linkage with the amino group of moiety A and from the group consisting of hydrogen and (C-C)alkyl; a second linkage with the sulfhydryl of moiety B. Selected and synthetic precursors for the adapter moieties for this appli wherein the second targeting moiety provides an azide cation are in either commercially available and also referred group. to as cross-linkers, or can be prepared by a person skilled in (0380. It will be appreciated by a person skilled in the art the art by routine measure. that adapter moiety as subject to formulae (38) and (39) and the linkages indicated therein are preferably the result of, on the one hand of a primary or secondary amino group, H (47) preferably provided by a targeting moiety, and, on the other A-N-Adapter-HS-B hand, of a reactive group selected from the group comprising US 2017/01 19913 A1 May 4, 2017 69

-continued with m being any integer of 0, 1, 2 and 3, preferably the integer is X;

(50) RG-Adapter-RG O

O A-N S-B 0385. In this example the first linkage to the amino group N of moiety A is preferably selected from the group of amide, O urea, thiourea, alkylamine and Sulfonamide and the corre sponding third reactive group RG as provided by the adapter moiety is selected from the group of carboxylic acid, (51) activated carboxylic acid, Sulfonic acid, activated Sulfonic O acid, aldehyde, ketone, isocyanate and isothiocyanate. The O S-B; second linkage to the Sulfhydryl group of moiety B is A --N --> O 1n-N preferably selected from the group of thioether and disulfide H and the corresponding fourth reactive group RG' as pro O vided by the adapter moiety is selected from the group of halogen, Michael acceptors such as maleimide or vinyl (52) sulfone and activated mixed disulfides like 2-pyridine dis O O ulfide. O S-B; 0386 In an embodiment of the conjugate of the invention AHN 1N1 N-1NN an adapter moiety realizing the above principles and which H mediates the linkage of an amino containing moiety and a O Sulfhydryl containing moiety is selected from the group comprising (53) O

(48) SHB A-N H

(54) O S-B; and A-N S H with n being any integer of 1, 2, 3, 4, 5, 6, 7, 8, and 9. preferably the integer is 2 or 3: (55) O

(49) A-N H S S-B;

m-and p-substituted wherein the adapter moiety is depicted in the square brackets of the above indicated formulae In an embodiment of the conjugate of the invention an adapter moiety realizing the US 2017/01 19913 A1 May 4, 2017 70 above principles and which mediates the linkage of an amino containing moiety and a amino containing moiety (56) forms linkages to these moieties which are independently selected from the group comprising amide, urea, thiourea, alkylamine and Sulfonamide and the corresponding reactive groups as provided by the adapter moiety are independently selected from the group of carboxylic acid, activated car boxylic acid, Sulfonic acid, activated Sulfonic acid, alde hyde, ketone, isocyanate and isothiocyanate. The preferred type of adapter moieties in one embodiment are dicarboxylic acids, or activated forms thereof. 0387 In an embodiment of the conjugate of the invention an adapter moiety realizing the above principles and which mediates the linkage of an amino containing moiety and a carboxylic acid containing moiety forms linkages to these moieties wherein the first linkage to the amino group is selected from the group comprising amide, urea, thiourea, alkylamine and Sulfonamide and the corresponding reactive group as provided by the adapter moiety is independently selected from the group of carboxylic acid, activated car boxylic acid, Sulfonic acid, activated Sulfonic acid, alde 0393. The preparation of (56) is described in Example hyde, ketone, isocyanate and isothiocyanate. The second 5A. This compound is well suited to form amide, urea or linkage to the carboxylic acid group is an amide linkage and thiourea linkages to other moieties especially for the addi the corresponding reactive group as provided by the adapter tion of an adapter moiety. One example for this is the moiety is a primary or secondary amino group. The pre attachment of a maleimide containing adapter moiety is ferred type of adapter moieties in one embodiment are described in example 5B: amino acids, or activated forms thereof. 0388 According to the present invention the conjugate of the invention comprises as a first targeting moiety TM1 (57) and/or as a second targeting moiety TM2 a compound of formula (2); in connection with Such compound of formula (2) the point of attachment to any other moiety contained in the conjugate of the invention is R and thus provide as a reactive group a primary or secondary amino group as point of attachment. NH OH 0389) As described in more detail below and in the example part the compounds of the invention are conve ( \, niently prepared by either liquid phase or Solid phase synthesis methods. 0390. It is well understood that the synthesis of interme diates which contain said compound of formula (2) as a f o --> targeting moiety together with some other moieties as con tained in the conjugate of the invention in activated form for further conjugation are of specific value by their own right. O -- In an specific embodiment preactivated moieties can be assembled directly before use or even after or during in vivo application. 0394. This adapter moiety enables the conjugation of 0391. In the following targeting moieties, either alone or Sulfhydryl containing moieties as shown in example 19. linked to an adapter moiety, are described which are realized Compound (57) is also well suited for the conjugation of in embodiments of the conjugate of the invention. proteins or modified oligonucleotides. 0392 A representative example of a targeting moiety 0395. More chemical possibilities open up if one synthe based on the compound of formula (2) is the one of formula sizes a tEu protected form of the amino acid (56) which is (56): described in example 3: US 2017/01 19913 A1 May 4, 2017 71

(58) (59)

O

Sk OH

O

O ~~~~ O

0397. The intermediate (59) was used in many examples. It performs very well for forming linkage to amino contain ing moieties bound to the solid phase resin. 0398. If, in an embodiment of the conjugate of the 0396 This targeting moiety is utilized for manifold pur invention a larger structure is or is to be conjugated as a poses. First of all the amide linkage of this can be formed to targeting moiety to a targeting moiety of formula (2) it is a carboxylic acid group of moiety in solution (example 8 and often desirable to have a larger linker moiety separating the two targeting moieties, because this should ensure that their 9) without the need for isolated activated carboxylic groups. individual function is not impaired. Two respective Secondly it is simpler modified with adapter an moiety as examples of intermediates are described in more detail in shown in example 4: example 6 and 7:

(60)

OH

O US 2017/01 19913 A1 May 4, 2017 72

-continued (61)

OH

's-1 N O N1N1,N1N1 NN-guards NH O ) / \ H CONH O

0399. As disclosed herein, the conjugate of the invention wherein may, in an embodiment, consist of a first targeting moiety, a DX is a building block moiety formed of “a” building linker moiety and a second targeting moiety. Such embodi blocks X, ment is indicated in formula (28) and is described in more detail in example 24: Y is a branching moiety or is absent, IZ, is a building block moiety formed of “b' building blocks Z, and (28) wherein “a” and “b' are individually and independently any integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 under the proviso that a--b is 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or

0. In an embodiment “a” and “bare individually any integer from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In a preferred embodiment “a” and “b' are individually any integer from OH 1, 2, 3, 4 and 5. 0403. In accordance with the present invention in the conjugate of the invention building block moiety X, may be absent or be present in the form of a single building block X or be present in the form of a polymer, wherein the polymer consists of a number of building blocks X, wherein the number of building blocks X forming such polymer is “a”, i.e. any integer from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, O 14, 15, 16, 17, 18, 19 and 20. non-rr-r 04.04. In accordance with the present invention in the conjugate of the invention building block moiety Z, may 0400. The linkage of the targeting moiety Biotin, target be absent or be present in the form of a single building block ing avidin or streptavidin, to the targeting moiety (4) is Z or be present in the form of a polymer, wherein the mediated by a single amino acid Ttds as linker moiety polymer consists of a number of building blocks Z, wherein without the use of any adapter moieties. the number of building blocks Z forming such polymer is “b', i.e. any integer from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, Linker Moiety 14, 15, 16, 17, 18, 19 and 20. 04.01. It is within the present invention that the conjugate 0405. In accordance with the present invention in the of the invention comprises a linker moiety. It is, however, conjugate of the invention branching moiety Y is either also within the present invention that the conjugate of the present or is absent. invention does not comprise a linker moiety. 0406 Building block moiety X, if present, is linked to 0402. In an embodiment the linker moiety LM of the both of its neighbours by a linkage, wherein the linkage is conjugate of the invention is of the following general selected from the group comprising an amide linkage, a urea formula: linkage, a carbamate linkage, an ester linkage, an ether linkage, a thioether linkage and a disulfide linkage. One of US 2017/01 19913 A1 May 4, 2017

said two neighbors is either the first adaptor moiety AD1 or, and wherein if the conjugate of the invention does not comprise a first r is any integer from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; adaptor moiety AD1, the first targeting moiety TM1. The S is any integer from 0, 1, 2, 3 and 4; and other of said two neighbors is branching moiety Y. if such t is any integer from 0, 1, 2, 3 and 4. branching moiety Y is present in the conjugate of the 0411. In an embodiment the building block X is selected invention; is building block moiety Z, if such building from the group comprising an amino acid, a dicarboxylic block moiety Z, is present and branching moiety Y is acid and a diamine. In an embodiment the amino acid is an absent, is the second adapter moiety AD2, if Such second amino acid selected from the group comprising natural and adapter moiety AD2 is present and both the branching non-natural amino acids. In an embodiment an amino acid is moiety Y and the building block moiety Z, are absent; and one selected from the group comprising B-amino acids, is the second targeting moiety TM2, if the branching moiety y-amino acids, Ö-amino acids, e-amino acids and (D-amino Y, the building block moiety Z, and the second adaptor acids. In a further embodiment an amino acid is a cyclic moiety AD2 is absent. amino acid or a linear amino acid. It will be appreciated by 0407 Building block moiety XI preferably comprises at a person skilled in the art that in case of an amino acid with least two reactive groups. In a preferred embodiment each of Stereogenic centers all stereoisomeic forms may be used in the at least two reactive groups is independently and indi the building block X. vidually selected from the group comprising a primary 0412. In an embodiment the building block X is a amino amino group, a secondary amino group, a carboxylic acid acid, wherein the amino acid is selected from a group group, an activated carboxylic acid Such as acid chloride, an comprising amino acids which differ as to the spacing of the acid bromide, a Succinimide ester, a pentafluorophenol ester, amino group from the carboxylic group. This kind of amino a nitrophenol ester, a benzotriazole ester, an azabenotriaz acid can be generically represented as follows: oleester, a thioester, a symmetrical anhydride, an unsym metrical anhydride, chloro, bromo, iodo, a sulfhydryl group and a hydroxyl group. (62) 0408 Building block X preferably also comprises at least O two groups. In a preferred embodiment each of the at least HN two reactive groups is independently and individually 1-10 OH selected from the group comprising a primary amino group, a secondary amino group, a carboxylic acid group, an 0413. It is within the present invention that such amino activated carboxylic acid such as acid chloride, an acid acid is not further substituted. It is, however, also within the bromide, a Succinimide ester, a pentafluorophenol ester, a present invention that such amino acid is further Substituted; nitrophenol ester, a benzotriazole ester, an azabenotriazol preferably such substitution is CO. NH and/or Ac-NH-. eester, a thioester, a symmetrical anhydride, an unsymmetri 0414 Representative of this kind of amino acid which cal anhydride. If two or more building blocks X are cova can be used as a building block X are glycine (Gly), lently linked to each other the linkage between such two or B-alanine, Y-aminobutyric acid (GABA), aminopentanoic more building blockS X is selected from the group compris acid, aminohexanoic acid and homologs with up to 10 CH ing an amide linkage, a urea linkage, a carbamate linkage, an groups. ester linkage, an ether linkage, a thioether linkage and a 0415. In a further embodiment the amino acid is an disulfide linkage. Preferably, the linkage is an amide linkage. aromatic amino acid; preferably the amino acid is one the 04.09. In an embodiment the building block X is of rigidity and orientation of which can be modified. This kind general formula of amino acid can be generically represented as follows: --Lin'-R-Lin- (8) wherein, 0410 Lin, if present, and Lin, if present, are each (63) individually and independently selected from the group comprising CO , NRO , S—, CO NR' , —CS NR' , —O-, -succinimide- and CH CO. NR' : wherein R' is selected from the group consisting of hydro gen and (C-C)alkyl; NH2 and the nitrogen of all nitrogen containing fragments is 0-4 linked to R: and wherein R is selected from selected from —(C-Clio) and the ortho and para alkylidene-, -(C-C)carbocyclo-, -arylene-, -(C-Co) Substituted isomers alkylidene-arylene-, -arylene-(C-C)alkylidene-, -(C- Co)alkylidene-arylene-(C-C)alkylidene-, -(C-Co) 0416. It will be acknowledged by a person skilled in the alkylidene-(C-C)carbocyclo-, -(C-C)carbocyclo-(C- art that the two substitutions indicated in the above generic Co)alkylidene-, -(C-Co.)alkylidene-(C-C)carbocyclo formula in meta position can also be arranged in either para (C-C)alkylidene-, -(CCs)heterocyclo-, (C-C) position or in ortho position. Accordingly, in an embodiment alkylidene-(C-Cs)heterocyclo-, -(C-Cs)heterocyclo-(C- the aromatic amino acid can be one where the two Substi Co)alkylidene-, -(C-Co.)alkylidene-(C-Cs)heterocyclo tutents as indicated in the above generic formula in meta (C-Co.)alkylidene-, -(CH2CH2O), , and —(CH) - position are arranged either in para position or in ortho (CH2CH2O), (CH) ; position. US 2017/01 19913 A1 May 4, 2017 74

0417 Representative of this kind of amino acid which 0424 wherein the length of both chains of C atoms can are preferably used as a building block X are B-amin attaching the NH group to the phenyl group is indi omethyl-benzoic acid, 4-aminomethyl-benzoic acid, anthra vidually and independently 1, 2, 3 or 4 C atoms; and nilic acid, 3-amino benzoic acid and 4-amino benzoic acid. wherein it will be acknowledged by a person skilled in 0418. In a further embodiment, the amino acid is an amino acid which contains, preferably as a backbone, a the art that the two substitutions indicated in the above polyether. Preferably such polyether is polyethylene glycol generic formula in meta position can also be arranged and consists of up to 20 monomer units. Preferably, an in either para position or in ortho position; therefore, in amino acid comprising Such polyether shows an increase in an embodiment the diamine can be one where the two hydrophilicity compared to an amino acid not comprising Substitutents as indicated in the above generic formula such polyether. If incorporated into a building block X and, in meta position are arranged either in para position or ultimately, into a building block moiety X and a linker in ortho position; moiety LM, respectively, such building block moiety Xa and linker moiety LM, respectively, typically shown an 0425 a compound of the following formula increase in hydrophilicity, too. A preferred embodiment of this kind of amino acid is depicted in the following, wherein it will be acknowledged that such amino acid may comprise (68) 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 ethylene oxide moieties: HN N11 No1n- 0-9-N 1-3NH2. (64) O 0426 wherein the length of both chains of C atoms "N-h-'-- bearing the NH2 group attached to each of the two terminal O atoms of the ethylene oxide backbone 0419. A preferred amino acid is Ttds (N-(3-2-[2-(3- contained in the diamin is individually and indepen Amino-propoxy)-ethoxy-ethoxy)-propyl)-succinamic dently 2, 3 or 4 C atoms; and wherein the ethylene acid) the formula of which is as follows: oxide backbone will comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of ethylene oxide monomers. 0427. In a preferred embodiment the diamine is a sub (65) stituted diamine, preferably of the following general for O mula: HN1-1-o1a1 O n-no-n-r OH (69) HN O 1-6 NH2 Ttds O NH2 0420. In an embodiment the building block X is a diamine. Such diamine is preferably one selected form the group comprising 0428 wherein such substituted diamine comprises 1, 0421 a compound of the following formula 2, 3, 4, 5 or 6 CH groups, preferably 4 CH2 groups. As used herein, the abbreviation for this kind of substituted diamine having 4 of said CH2 groups, if present in (66) S-configuration, is e-Lys-NH2, and the residue in its linked form is abbreviated -(e-Lys-NH)—, wherein "Nan NH2 the hyphen on the left side of the abbreviation sym bolizes the attachment to the C-amino group and the 0422 wherein the diamine may comprise a length of 1, hyphen at the right side the attachment to the e-amino 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms: group of this residue. 0423 a compound of the following formula 0429. In an embodiment the building block X is a dicar boxylic acid. Such dicarboxylic acid is preferably one (67) selected from the group comprising: NH2 0430 a compound of the following formula

(70) O O

and the ortho and para --- substituted isomers US 2017/01 19913 A1 May 4, 2017

0431 wherein n is any integer from 1, 2, 3, 4, 5, 6, 7, comprising aminothiols which differ as to the spacing of the 8, 9 and 10; amino group from the Sulfhydryl group: 0432 a compound of the following formula (74) SH (71) HN1,N1

0440 wherein the integer may be any in the range of 1, 2, 3, 4, 5, 6, 7, 8 or 9. 0441 Representative of this kind of aminothiols which can be used as a building block X are 2-amino-ethanethiol, B-amino-propane-1-thiol, 4-amino-butane-1-thiol, 5-amino pentane-1-thiol and 6-amino-hexan-1-thiol. and the ortho and para 0442. In a preferred embodiment the aminothiol is a substituted isomers substituted aminothiol, preferably of the following general formula: 0433 wherein m and n are individually and indepen dently any integer from 1, 2, 3, and 4; and wherein it (75) will be acknowledged by a person skilled in the art that CONH the two substitutions indicated in the above generic formula in meta position can also be arranged in either HN pi para position or in ortho position; therefore, in an --- embodiment the dicarboxylic acid can be one where the two Substitutents as indicated in the above generic wherein the integer may be any in the range of 1, 2, 3, 4, 5 formula in meta position are arranged either in para or 6, preferably n=1 and n=2. As used herein, the abbrevia position or in ortho position; tion for this kind of substituted aminothiols with n=1, if 0434 a compound of the following formula present in S-configuration, is -Cys-NH2, and the residue in its linked form is abbreviated -(P-Cys-NH)—, wherein the hyphen on the left side of the abbreviation symbolizes the (72) attachment to the C-amino group and the hyphen at the right O side the attachment to the P3-thiol group of this residue. 0443) In an embodiment the building block X is a thiol O group containing carboxylic acid wherein the thiol group --~-h- |-in containing carboxylic is selected from a group comprising O thiol group containing carboxylic acids which differ as to the spacing of the carboxylic group from the Sulfhydryl group: 0435 wherein the integers m and o may individually and independently be any in the range of 0 to 4; and (76) wherein the integer n may be in the range of 1 to 10. HS OH 0436 Representative of this kind of dicarboxylic acids which can be used as a building block X are dicarboxylic S acids which are preferably related to suitable commercially O available cyclic anhydrides. Such dicarboxylic acids com prise glutaric acid, Succinic acid, phthalic acid, 1.2-cyclo 0444 wherein the integer may be any in the range of hexanedicarboxylic acid and maleic acid. 1, 2, 3, 4, 5, 6, 7, 8 or 9. 0437. In a preferred embodiment the dicarboxylic acid is 0445 Representative of this kind of thiol group contain a substituted dicarboxylic acid, preferably of the following ing carboxylic acids which can be used as a building block general formula: X are mercaptoacetic acid, 3-mercaptopropionic acid, 4-mercaptobutanoic acid, 5-mercaptopentanoic acid and 6-mercaptohexanoic acid. (73) 0446. In a preferred embodiment the thiol group contain ing carboxylic acid is a Substituted aminothiol, preferably of OH the following general formula:

AcHN O (77) NHAC 0438 wherein the integer n of such substituted dicar HS OH boxylic acids may be any in a range of 0 to 6, preferably n=1 and n=2. 0439. In an embodiment the building block X is an aminothiol wherein the aminothiol is selected from a group US 2017/01 19913 A1 May 4, 2017 76

0447 wherein the integer may be any in the range of first adapter moiety AD1 are absent. The other of said two 1, 2, 3, 4, 5 or 6, preferably n=1 and n=2. neighbors is building block moiety Z, if Such building 0448. In an embodiment of the conjugate of the invention block moiety Z, is present, is the second adapter moiety the building block moiety X, is a peptide, whereby such AD2, if such adaptor moiety AD2 is present and building peptide is formed by a plurality of building blocks X, block moiety Z, is absent; or is the second targeting moiety preferably building blocks X as defined herein. In this TM2 if such second targeting moiety TM2 is present and embodiment the linkages linking the building blocks, is an both building block moiety Z, and the second adapter amide linkage. It is within the present invention that the moiety AD2 are absent. building blocks X forming the building block moiety XI 0455 Preferably, the branching moiety provides a point are the same or are different. Accordingly, the peptide of attachment to the conjugate of the invention. Such point forming the building block moiety DX may be a homopo of attachment allows that a further linkage is established lymer or a heteropolymer. between the conjugate of the invention of formula (1) and a 0449 In a further embodiment of the conjugate of the further moiety. In an embodiment the further moiety is a invention the building block moiety X, is a polymer, third adapter moiety AD3 or an Effector moiety EM. In an wherein the monomers forming the polymer are linked to embodiment the further linkage between the conjugate of the each other by an ether linkage. In this embodiment the invention of formula (1) and a further moiety is selected building blockS X are compounds having preferably at least from the group comprising an amide linkage, a urea linkage, two reactive groups, wherein at least one of the at least two a thioruea linkage and an amine linkage. A preferred further reactive groups is selected from the group comprising a linkage between the conjugate of the invention of formula hydroxyl group and a halogen group. (1) and a further moiety is an amide linkage. 0450. In a further embodiment of the conjugate of the 0456. In an embodiment the structure of branching moi invention the building block moiety X, is a polymer, ety Y is based on the structure of building block X in its wherein the monomers, i.e. the building blockS X forming various embodiments as disclosed herein, whereby branch the polymer are linked to each other by an ether linkage and ing moiety Y comprises at least one further reactive group. an amide linkage under the proviso that the polymer com In an embodiment the branching moiety comprises at least prises at least three of the building blocks X thus providing three reactive groups. Preferably, the at least one further at least two linkages. reactive group is one which allows the formation of com 0451 What has been disclosed herein as to building prising an amide linkage, a urea linkage, a thioruea linkage block moiety X equally applies to building block moiety and an amine linkage, preferably under the proviso that the Z, and is incorporated insofar herein by reference. further moiety provides a corresponding complementary 0452 Irrespective of the above it will be appreciated that reactive group. More preferably the at least one further the building moiety Z, if present is linked to both of its reactive group is selected from the group comprising an neighbours by a linkage, wherein the linkage is selected amino group and a carboxyl group. from the group comprising an amide linkage, a urea linkage, 0457. In an embodiment the branching moiety Y com a carbamate linkage, an ester linkage, an ether linkage, a prises a fully acyclic structure in addition to the at least three thioether linkage and a disulfide linkage. One of said two reactive groups. In another embodiment the branching moi neighbors is either the second adaptor moiety AD2 or, if the ety Y comprises a cyclic structure in addition to the at least conjugate of the invention does not comprise a second three reactive groups. In a still further embodiment the adaptor moiety AD2, the second targeting moiety TM1. The branching moiety Y comprises an aromatic structure in other of said two neighbors is branching moiety Y. if such addition to the at least three reactive groups. branching moiety Y is present in the conjugate of the 0458 In an embodiment the branching moiety Y is an invention; is building block moiety X, if such building amino acid, wherein the amino acid comprises an additional block moiety X, is present and branching moiety Y is amino group. Preferably, the amino acid is selected from the absent; is the first adapter moiety AD1, if such first adapter group comprising an O-amino acid, a f-amino acid, a moiety AD1 is present and both the branching moiety Y and y-amino acid and a cyclic amino acid; more preferably the the building block moiety X are absent; and is the first amino acid is selected from the group comprising an targeting moiety TM1, if the branching moiety Y, the build C.-amino acid, a B-amino acid and a cyclic amino acid. A ing block moiety X, and the first adaptor moiety AD1 is particularly preferred branching moiety Y is an amino acid absent. selected from the group comprising 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, lysine, homolysine and Branching Moiety Y ornithine. 0453. In an embodiment the conjugate of the invention 0459. In an embodiment the branching moiety Y is an comprises a branching moiety Y. amino acid, wherein the amino acid comprises an additional 0454 Branching moiety Y. if present, is linked to both of carboxyl group. Preferably, the amino acid is selected from its neighbours by a linkage, wherein the linkage is selected the group comprising an O-amino acid, a B-amino acid, a from the group comprising an amide linkage, a urea linkage, y-amino acid, a cyclic amino acid; more preferably the a carbamate linkage, an ester linkage, an ether linkage, a amino acid is selected from the group comprising an thioether linkage and a disulfide linkage. A preferred linkage C.-amino acid, a B-amino acid and a cyclic amino acid. A is an amide linkage. One of said neighbors is building block particularly preferred branching moiety Y is an amino acid moiety X, if such building block moiety X, is present, is selected from the group comprising aspartatic acid, glutamic the first adapter moiety AD1, if such adaptor moiety AD1 is acid, 2-aminoadipic acid, and C.-aminoSuberic acid. present and building block moiety X, is absent; or is the 0460. In a preferred embodiment the branching moiety Y first targeting moiety TM1 of Such first targeting moiety is selected from the group comprising the following com TM1 is present and both building block moiety XI, and the pounds US 2017/01 19913 A1 May 4, 2017 77

0461. In an embodiment the branching moiety Y is an 0467. In an embodiment the branching moiety Y is a imino acid, wherein the imino acid comprises an additional cyclic imino acid, wherein the imino acid comprises an amino group. This kind of amino acid can be generically additional amino group. This kind of amino acid can be represented as follows generically represented as follows

(78) O (81) H N 0-4 HN1N1, -- HO OH 14 04 0462 Preferably, the imino acid is selected from the N group comprising an O.-imino acid, a B-imino acid, a Y-imino acid and a cyclic imino acid; more preferably the imino acid is selected from the group comprising an O.-imino acid, a 0468 Preferably, the imino acid is selected from the B-imino acid and a cyclic imino acid. A particularly pre group comprising an O-limino acid, a B-imino acid, a Y-imino ferred branching moiety Y is an imino acid selected from the group comprising iminoacetic acid, N-carboxymethyl-3- acid and a cyclic imino acid; more preferably the imino acid alanine, 3 (2-carboxyethylamino)propanoic acid, 4.4-bis(N. is selected from the group comprising an O.-imino acid, a N-dibutyric acid). B-imino acid and a cyclic imino acid. A particularly pre 0463. In an embodiment the branching moiety Y is an ferred branching moiety Y is an imino acid selected from the imino acid, wherein the imino acid comprises an additional group comprising 2,3-dicarboxypyrrolidine, and pyrroli carboxyl group. This kind of amino acid can be generically dine-2,4-dicarboxylate. represented as follows 0469 In a further embodiment the branching moiety Y is an aromatic amino acid wherein the amino acid comprises (79) O O an additional amino group; preferably within this amino acid H the rigidity and orientation can be modified. This kind of amino acid can be generically represented as follows HO--- I-5 I-5 OH

0464 Preferably, the imino acid is selected from the (82) group comprising an O.-imino acid, a B-imino acid, a Y-imino acid and a cyclic imino acid; more preferably the imino acid is selected from the group comprising an O.-imino acid, a B-imino acid and a cyclic imino acid. A particularly pre ferred branching moiety Y is an imino acid selected from the group comprising N-(2-Aminoethyl)glycine, N-(5-amino pentyl)-glycine. HN NH2 0-4 0-4 0465. In an embodiment the branching moiety Y is a cyclic imino acid, wherein the imino acid comprises an including all Substitution pattern at aryl additional amino group. This kind of amino acid can be generically represented as follows 0470. It will be acknowledged by a person skilled in the art that the two substitutions indicated in the above generic (80) O formula in meta position can also be arranged in either para 0-4 position or in ortho position. Accordingly, in an embodiment HN the aromatic amino acid can be one where the two Substi OH tutents as indicated in the above generic formula in meta 1-4( )0-4 N position are arranged either in para position or in ortho H position. A particularly preferred branching moiety Y is an aromatic amino acid selected form the group comprising 0466 Preferably, the imino acid is selected from the 3,5-diaminobenzoic acid and 3,5-bis-aminomethyl-benzoic group comprising an O.-imino acid, a B-imino acid, a Y-imino acid. acid and a cyclic imino acid; more preferably the imino acid is selected from the group comprising an O.-imino acid, a 0471. In a further embodiment the branching moiety Y is B-imino acid and a cyclic imino acid. A particularly pre an aromatic amino acid wherein the amino acid comprises ferred branching moiety Y is an imino acid selected from the an additional carboxy group; preferably within this amino group comprising 4-amino-3-pyrrolidinecarboxylic acid, acid the rigidity and orientation can be modified. This kind B-amino-proline and 4-amino-proline. of amino acid can be generically represented as follows US 2017/01 19913 A1 May 4, 2017 78

0476. In an embodiment the reactive group of the branch (83) ing moiety Y involved in forming the AD3 linkage is selected from the group comprising amino, carboxylic acid, activated carboxylic acid, chloro, bromo, iodo, Sulfhydryl, OH hydroxyl, Sulfonic acid, activated Sulfonic acid, Sulfonic acid esters like mesylate or tosylate, Michael acceptors, strained alkenes like trans cyclooctene, isocyanate, isothio cyanate, aldehyde, ketone, aminooxy, hydrazide, hydrazine, azide, alkyne and tetrazine. HO 0-4 0-4 0477. In an embodiment the reactive group of the second targeting moiety TM2 involved in forming the AD3 linkage including all Substitution pattern at aryl is selected from the group comprising amino, carboxylic acid, activated carboxylic acid, chloro, bromo, iodo, Sulf 0472. It will be acknowledged by a person skilled in the hydryl, hydroxyl, Sulfonic acid, activated Sulfonic acid, art that the two substitutions indicated in the above generic Sulfonic acid esters like mesylate or tosylate, Michael accep formula in meta position can also be arranged in either para tors, strained alkenes like trans cyclooctene, isocyanate, position or in orthoposition. Accordingly, in an embodiment isothiocyanate, aldehyde, ketone, aminooxy, hydrazide, the aromatic amino acid can be one where the two Substi hydrazine, azide, alkyne and tetrazine. tutents as indicated in the above generic formula in meta 0478. In an embodiment the third adapter moiety AD3 is position are arranged either in para position or in ortho one which is shown in the square brackets of formula (84): position. A particularly preferred branching moiety Y is an Y-Lin-R-Lin EM (84) aromatic amino acid is 5-aminoisophthalic acid. wherein 0473. In an embodiment the branching moiety Y is a Y and EM and Rare as defined herein; triamine. Preferably, the triamine is selected from the group Lin' is selected from the group comprising —CO , comprising 1,3,5-triaZinane, propane-1,2,3-triamine, 1.3.5- NR' CO NR' CS NR' CH and triaminobenzene, diethylenetriamine, 3.3'diaminopropylam a direct bond; ine and bis(hexamethylene)triamine. wherein R' is selected from the group consisting of hydro 0474. In an embodiment the branching moiety Y is a gen and (C-C)alkyl; tricarboxylic acid. Preferably, the tricarboxylic acid is and selected from the group comprising 1,3,5-benzenetricarbox Lin is selected from the group comprising—CO-, -S , ylic acid, 1,2,3-benzenetricarboxylic acid and 1,2,4-benze NRO , CO NR' , CS NR' , O—, netricarboxylic acid, 1,3,5-benzenetriacetic acid and citric —CH2—, -SO. , -succinimide-, -CH-CO-NR' , acid. —C=C- (in case of for example triazole), =N-O-, Third Adapter Moiety AD3 In an embodiment of the con —N N —N N CO —N=N N (in case of jugate of the invention the conjugate comprises a third for example triazole), —HC– and RC= (of oxime and adapter moiety AD3. Preferably, the third adapter moiety hydraZone); AD3 mediates the linkage, or establishes a linkage, between wherein R' is selected from the group consisting of hydro the branching moeity Y and the effector moiety. Alterna gen and (C-C)alkyl. tively, the third adapter moiety AD3 mediates the linkage, or 0479. Depending on the structural class and origin of the establishes a linkage, between the second targeting moiety effector moiety EM different types of reactive groups are TM2 and the effector moiety EM. The linkage is also typically preferred. If the effector moiety is a protein, the referred to herein as the AD3 linkage. In an embodiment the preferred reactive groups are sulfhydryl and amino. AD3 linkage is one selected from the group comprising an 0480. In a further embodiment the same principles and amide linkage, a Sulfonamide linkage, a urea linkage, a preferred structures as for the first and second adapter thiourea linkage, a thioether linkage, an ether linkage, a moiety apply to the third adapter moiety AD3. carbamate linkage, an amine linkage, a triazole linkage, an 0481. In a still further embodiment the third adapter Oxime linkage, a hydrazone linkage, a disulfide linkage, a moiety AD3 comprises an additional building block moiety pyrazine linkage and a dihydro-pyrazine linkage. Preferably, IW as disclosed herein. This building block moiety may the AD3 linkage is a linkage selected from the group provide for optimal spacing of the two entities or may comprising an amide linkage, a urea linkage, a thiourea further supply a labile linkage that allows the two entities to linkage and an amine linkage. be separated from each other. Labile linkages include hydro 0475. In order to establish the AD3 linkage the third ly Zable groups, photocleavable groups, acid-labile moieties, adapter moiety AD3 comprises a first reactive group and the base-labile moieties and enzyme cleavable groups. branching moiety Y comprises a reactive group, wherein the 0482 In an embodiment this building block moiety W. reactive group of the branching moiety Y is complementary is an amino acid or a peptide consisting of 2 to 10 amino to the first reactive group of the third adapter moiety AD3 acids, whereby the amino acids are independently selected which allows the formation of an AD3 linkage. Alterna from the group of natural and non-natural amino acids. tively, in order to establish the AD3 linkage the third adapter Amino acids as used in the building block moiety W and moiety AD3 comprises a first reactive group and the second thus in the embodiment of the third adapter moiety AD3 targeting moiety TM2 comprises a reactive group, wherein include, but are not limited, to C-amino acids and amino the reactive group of the second targeting moiety TM2 is acids where the amino and the carboxylic group are spaced complementary to the first reactive group of the third adapter further apart Such as p?3-amino acids, y-amino acids, moiety AD3. Ö-amino acids, e-amino acids and ()-amino acids. In any US 2017/01 19913 A1 May 4, 2017 79 case the amino acids may be cyclic or linear. In the case of words, an Effector moiety can be an effector which is already amino acids with stereogenic centers all stereoisomeric complexed by or covalently bound to the conjugate of the forms may be used. An illustrative example of this adapter invention, whereby such complexing or binding is realized, moiety is shown within the square brackets of formula (85): in a preferred embodiment by a structure of Acceptor Effector. Alternatively, the conjugate of the invention is Y-W-R9-Lin5 -EM (85) capable of reacting readily with an Effector. Accordingly, in wherein Y. EM, R9 and Lin are as defined herein, and embodiments of the invention the Effector moiety is an IW is an amino acid or peptide consisting of up to 10 Effector, an Acceptor or -Acceptor-Effector. amino acids, which are independently selected from the 0493. In a further embodiment, the covalent linkage group comprising natural amino acids, non-natural amino between the third adapter moiety AD3 and the Acceptor is acids, C.-amino acids and amino acids where the amino and selected from the group comprising amide (also referred to the carboxylic group are spaced further apart Such as as amide linkage), alkylamine (also referred to as alkylamine B-amino acids, y-amino acids, Ö-amino acids, e-amino acids linkage), urea (also referred to as urea linkage), ether (also and (D-amino acids. and c is an integer from 1.2, 3, 4, 5, 6, referred to as ether linkage), thioether (also referred to as 7, 8, 9 and 10, and thioether linkage), thiourea (also referred to as thiourea the linkage to branching moiety Y is amide. linkage) and carbamate (also referred to as carbamate link 0483. In some embodiments the moiety W of the age). conjugates of the invention can be enzymatically cleaved by 0494. Acceptor as preferably used herein is a moiety one or more enzymes, including a tumor-associated pro which is used or present in the conjugate of the invention tease, to liberate the effector moiety (-EM). and which mediates the linking of an Effector to the conju 0484 The building block moiety IW comprises illus gate of the invention, preferably the conjugate of the inven trative enzymatically cleavable sequences as shown below: tion of formula (1). 0485 a) Dipeptides: -Phe-Lys-, -Ala-Lys-, -Val-Lys-, 0495. In a further embodiment the Acceptor comprises a -Val-Cit-, -Phe-Cit-, -Ile-Cit-, -Leu-Cit-, -Trp-Cit-, functional group which is capable of forming a covalent -Phe-Ala-, and -Phe-Arg-; and linkage to either the third adapter moiety AD3, if present, or 0486 b) Tripeptides: -Phe-Phe-Lys-, -Val-Phe-Lys-, to the branching moiety Y, if present, without destroying the and -Gly-Phe-Lys-; and Acceptor's function, i.e. the binding or complexing of the 0487 c) Tetrapeptides: -Gly-Phe-Leu-Gly (SEQ ID Effector. Such functional group is preferably selected from NO: 22), and -Ala-Leu-Ala-Leu- (SEQ ID NO. 23). the group comprising comprising amino, carboxylic acid, 0488. The moiety IW in the present invention can be activated carboxylic acid, chloro, bromo, iodo, sulfhydryl, designed and optimized in their selectivity for enzymatic hydroxyl, Sulfonic acid esters like mesylate or tosylate, cleavage by particular enzymes, for example, a tumor Michael acceptors, isocyanate, isothiocyanate, aldehyde and associated protease. In one embodiment, W is that whose ketone. cleavage is catalyzed by cathepsin B, C and D, or a plasmin 0496. It is within the present invention that the Effector is protease. either directly linked to the third adapter moiety AD3 or to 0489. In one embodiment, WI is a dipeptide, tripeptide the branching moiety Y, or linked to either the third adapter or pentapeptide. moiety AD3 or to the branching moiety Y by means of the Acceptor if Such Acceptor is present. Such Acceptor is, 0490. In a further embodiment a preferred moiety IW among others, a chelator. In one embodiment thereof, the comprises a Gly at the C-terminal end. compound of the invention is bearing a metal, preferably a 0491. In still another embodiment a preferred moiety radioactive transition metal which is chelated by the chela IW comprises a Gly-Gly Dipeptide at the C-terminal end. tor. In another embodiment, the compound of the invention is bearing the chelator with no metal chelated by the Effector Moiety EM chelator. 0492. As disclosed herein in more detail, an Effector 0497. The following Table 10 summarizes illustrative moiety is a moiety which comprises or is capable of com examples of a conjugate of the invention. It is within the prising an Effector, whereby the Effector is preferably present invention that each any any of the moieties indicated selected from the group consisting of a diagnostically active in said table may be, individually and independently, com agent, a therapeutically active agent, an agent which is bined with each any of the other moieties indicated in said Suitable as both a diagnostically active agent and a thera table. Insofar, any permutation arising from Such combining peutically active agent, and a combination of a diagnosti constitutes an embodiment of the conjugate of the invention cally active agent and a therapeutically active agent. In other which is disclosed herein in an individualized form. TABL E 1 O Compound/ SEQ ID NO : TM1) AD1 Xa Y AD3 EM) Zb AD2 TM2)

(12) /4 12O6 Glutar TtcS Lys DOTA TtcS GABA 12O6

(13) /5 12O6 Glutar Lys DOTA GABA 12O6

(14) ?e 12O6 Glutar Ahx Lys DOTA (e-Lys- Glutar 12O6

US 2017/01 19913 A1 May 4, 2017

TABLE 1 O - continued Compound/ SEO ID NO: TM1) AD1 Xa Y AD3 EM) Zb AD2 TM2)

(27) /19 12O6 Glutar TtcS Lys DOTA TtcS GABA Orn-R-Oic PG-Amf-S- nal-Ile-OH

(28) Biotin TtcS 12O6 * AD3-EM - (e-Lys-NH2) - DOTA) is linked at the C-terminus of TM2 H Compound (25) comprises a conjugate of the invention and is equipped with a second TM1-moiety (1206-Glutar-Ttds)

0498 Possible forms of chelating interaction which allow used to eject an orbital electron by interaction with the the practicing of the present invention between a chelator excited nucleus in a process called internal conversion. and an Effector, which is preferably a transition metal, are 0503. In a preferred embodiment of the present invention, known to the person skilled in the art and respective the radionuclide can be used for stable labeling of the examples, structures and applications are, for example, compound of the invention. described in Wadas et al. (Wadas et al., Chem. Rev., 2010, 0504. In a preferred embodiment of the present invention, 110, 2858-2902) and literature cited therein. the radionuclide has a half-life that allows for diagnostic or 0499. In another embodiment Acceptor is or comprises an therapeutic medical use. Specifically, the half-life is between aromate, preferably an electron rich aromate such as indoles 30 min and 7 days. More specifically, the half-life is between or benzenes optionally substituted by oxygen, nitrogen 2 hand 3 days. Sulfur atoms. 0505. In a preferred embodiment of the present invention, the radionuclide has a decay energy and radiation range that 0500. In one embodiment thereof, the compound of the invention is bearing a halogen, preferably a radioactive allows for diagnostic or therapeutic medical use. halogen which is Substituting said aromatic moiety. In 0506. In a preferred embodiment of the present invention, another embodiment, the compound of the invention is the radionuclide is industrially produced for medical use. bearing the aromatic moiety with no halogen bound to this Specifically, the radionuclide is available in GMP quality. aromatic moiety. 0507. In a preferred embodiment of the present invention, the daughter nuclide(s) after radioactive decay of the radio 0501. It will be acknowledged by a person skilled in the nuclide are compatible with the diagnostic or therapeutic art that the specific effector which is or which is to be medical use. attached to the compound of the invention, is selected taking 0508 Specifically, the daughter nuclide(s) remain chemi into consideration the disease to be treated and the disease cally bound or complexed to the compound of the invention to be diagnosed, respectively, and the particularities of the and are not toxic. Furthermore, the daughter nuclides are patient and patient group, respectively, to be treated and to either stable or further decay in a way that does not interfere be diagnosed, respectively. with or even Support the diagnostic or therapeutic medical 0502. In an embodiment the Effector is a radioactive US nuclide which is also referred to as radionuclide. Radioac 0509. In an embodiment of the present invention, the tive decay is the process by which an atomic nucleus of an radionuclide which is preferably a metal and more prefer unstable atom loses energy by emitting ionizing particles ably a transition metal, is suitable for being complexed with (ionizing radiation). There are different types of radioactive a metal chelator and leading to radioactive metal chelator for decay. A decay, or loss of energy, results when an atom with imaging. It will, however, be acknowledged by a person one type of nucleus, called the parent radionuclide, trans skilled in the art that the radionuclide may also be directly forms to an atom with a nucleus in a different state, or to a bound to the compound of the invention. Preferably, the different nucleus containing different numbers of protons radioactive isotope is selected from the group comprising and neutrons. Either of these products is named the daughter 18F lion, 113In, 114. In 99mTc, 7Ga, 52Fe, Fe, Ga, nuclide. In some decays the parent and daughter are different In, 7Ru, 208Pb, 62Cu, Cu, 67Cu, 51Cr Mn, 52"Mn, chemical elements, and thus the decay process results in 55Co, 57Co, 58Co., 7°As, 7Se, 157Gd, 120I. 123, 1241, 125I, nuclear transmutation (creation of an atom of a new ele 13 II, 75 Br, 7°Br, 77Br, 89Zr, 82Rb, Sr. 86Y. 94mTc, 169Yb, ment). For example the radioactive decay can be alpha '7Hg, 'Tl, and Br. More preferably, the radioactive decay, beta decay, and gamma decay. Alpha decay occurs metal is selected from the group comprising '"Tc, ''Ga, when the nucleus ejects an alpha particle (helium nucleus). Ga, '''In, Zr and 'I. Even more preferably the radio This is the most common process of emitting nucleons, but active metal is '''In and Zr. It will however, also be in rarer types of decays, nuclei can eject protons, or specific acknowledged by a person skilled in the art that the use of nuclei of other elements (in the process called cluster decay). said radioactive metals is not limited to imaging purposes, Beta decay occurs when the nucleus emits an electron but encompasses their use in diagnosis, therapy and therag (P-decay) or positron (B'-decay) and a type of neutrino, in nostics. a process that changes a proton to a neutron or the other way 0510. In an embodiment of the present invention, the around. By contrast, there exist radioactive decay processes radionuclide which is preferably a metal and more prefer that do not result in transmutation. The energy of an excited ably a transition metal is Suitable for complexing with a nucleus may be emitted as a gamma ray in gamma decay, or metal chelator and leading to radioactive metal chelator for US 2017/01 19913 A1 May 4, 2017

radiotherapy. It will, however, be acknowledged by a person bisamino bisthiol (BAT) based chelators as disclosed in U.S. skilled in the art that the radionuclide may also be directly Pat. No. 5,720,934; Desferrioxamin (DFO) as disclosed bound to the compound of the invention. Preferably, the (Doulias et al., Free Radic. Biol. Med., 2003, 35, 719-728), radioactive isotope is selected from the group comprising whereby all of the references are included herein by refer p, 33P. 7Sc, sCo., Fe, 64CU, 7Cu, 7Ga, Ga, 7Se, ence in their entirety. 77As, 80m Br. 89Sr. 897r, 90Y. 99M, 103 mRh 105Rh, 109Pd, 0516. The diagnostic and/or therapeutic use of some of 109 Pt. '''Ag, In, 19Sb, 12'Sn, 127Te, 125I. 123, 129I. 13 II, the above chelators is described in the prior art. For example, 142 Pr. 14.Pr 14°Pm, 15Pm, 152Dy, 'Sim, 15°Gd, 161Tb, 2-hydrazino nicotinamide (HYNIC) has been widely used in 1.6l Ho, 166Ho, 166Dy, 169Er, 169Yb. 175Yb. 172Tm, 177Lu, the presence of a coligand for incorporation of "Tc and 177Sn, 18.Re, 188Re, 18°Re, 188Rd, 189mOS, 192Ir, 194Ir, '''Re (Schwartz et al., Bioconi. Chem., 1991, 2, 333 198Au, 199Au, 21 At 211 Pb, 212Pb, 211 Bi, 212Bi, 213Bi, 215Po, 336; Babich et al., J. Nucl. Med., 1993, 34, 1964-1970; 217At 2Rn, 22 Fr. 223Ra 225Ac, 227Th, 255Fm. More Babich et al., Nucl. Med. Biol., 1995, 22, 25-30): DTPA is preferably, the radioactive isotope is selected from the group used in Octreoscan R) which is marketed by Covidien, for comprising '''In, 77Lu, Zr, Ga, Ga, Cu, Cu and complexing 'In and several modifications are described in 'Y. More preferably, the radioactive metal is selected from the literature (Brechbiel et al., Bioconi. Chem., 1991, 2, the group comprising 'In, 'Y and '77Lu. It will however, 187-194; Li et al., Nucl Med. Biol., 2001, 28, 145-154); also be acknowledged by a person skilled in the art that the DOTA type chelators for radiotherapy applications are use of said radioactive metals is not limited to imaging described by Tweedle et al. (U.S. Pat. No. 4,885.363); other purposes, but encompasses their use in diagnosis, therapy polyaza macrocycles for chelating trivalent isotopes metals and theragnostics. are described by Maecke et al., Bioconi. Chem., 2002, 13, 0511. In a further embodiment, the effector is a radioac 530-541; and Na-chelators such as a "Tc Na-chelator tive halogen Such as iodine and bromine isotopes which can have been used for peptide labeling in the case of minigas be used, when attached to the compound of the invention, for trin for targeting CCK-2 receptors (Nocket al., J. Nucl Med., therapy, diagnosis and/or theragnostics. In a preferred 2005, 46, 1727-1736). embodiment the radioactive halogen is bonded directly to the compound of the invention. 0517. In a preferred embodiment of the present invention, 0512 Preferred radionuclides used for diagnosis such as the metal chelator is a metal chelator for trivalent metals or Ga, '''In and Zr, and preferred radionuclides used for for pentavalent metals and their close analogs. Many metal therapy such as 'Y. Sm and ''Lu, are trivalent cations chelators of this type are disclosed by WO2009/109332A1. from the class of elements known as the lanthanides. Typical 0518. In an embodiment the metal chelator for trivalent radioactive metals in this class include the isotopes metals is selected from the group comprising DOTA, NOTA, 'Yttrium, '''Indium, ''Promethium, 'Samarium, DTPA, TETA, EDTA, NODAGA, NODASA, TRITA, Dysprosium, 'Holmium, ''Ytterbium, and '77Lute CDTA, BAT, DFO and HYNIC based chelators and their tium. All of these metals and others in the lanthanide series close analogs, wherein have very similar chemistries, in that they remain in the +3 DOTA stands for 1,4,7,10-tetrazacyclododecane-1,4,7,10 oxidation state and prefer to chelate to ligands that bear hard donor atoms such as oxygen/nitrogen donor atoms. tetraacetic acid, 0513. As is evident from the above, a radionuclide is, in NOTA stands for 14,7-triazacyclononanetriacetic acid, principle, useful in the treatment and/or diagnosis of a DTPA stands for diethylenetriaminepentaacetic acid, disease when conjugated to the compound of the invention. 0514. In an embodiment of the compound of the inven TETA stands for 14,8,11-tetraazacyclododecane-1,4,8,11 tion the compound of the invention comprises a chelator. tetraacetic acid, Preferably, the chelator is part of the Acceptor of the EDTA stands for ethylenediamine-N,N'-tetraacetic acid, compound of the invention, whereby the chelator is either directly or indirectly such as by a linker attached to the NODAGA stands for 1,4,7-triazacyclononane-N-glutaric compound of the invention. A preferred chelator is a metal acid-N',N'-diacetic acid, chelator, whereby the metal chelator preferably comprises at NODASA stands for 1,4,7-triazacyclononane-1-succinic least one radioactive metal. The at least one radioactive acid-4,7-diacetic acid, metal is preferably useful in or suitable for diagnostic and/or TRITA stands for 1,4,7,10 tetraazacyclotridecane-1,4,7,10 therapeutic use and is more preferably useful in or suitable for imaging and/or radiotherapy. tetraacetic acid, 0515 Chelators in principle useful in and/or suitable for CDTA stands for trans-1,2-diaminocyclohexane-N,N,N',N'- the practicing of the instant invention including diagnosis tetraacetic acid, and/or therapy of a disease, are known to the person skilled DFO stands for the Desferal or Desferrioxamine type group in the art. A wide variety of respective chelators is available of chelators, the chemical name of the non-limiting example and has been reviewed, e.g. by Banerjee et al. (Banerjee et is N-5-({3-5-(Acetyl-hydroxy-amino)-pentylcarbamoyl al., Nucl. Med. Biol., 2005, 32, 1-20, and references therein, propionyl-hydroxy-amino)-pentyl)-N'-(5-amino-pentyl)- Wadas et al., Chem. Rev., 2010, 110, 2858-2902 and refer N'-hydroxy-succinamide, ences therein) included herein by reference. Such chelators BAT stands for the Bisamino-bisthiol group of chelators, the include, but are not limited to linear, macrocyclic, tetrapyri chemical name of the non limiting example is 1-2-(2- dine and NS, NS and Na chelators as disclosed in U.S. mercapto-2-methyl-propylamino)-ethylamino-2-methyl Pat. No. 5,367,080 A, U.S. Pat. No. 5,364,613 A, U.S. Pat. propane-2-thiol, No. 5,021,556 A, U.S. Pat. No. 5,075,099 A, U.S. Pat. No. 5,886,142 A: HYNIC, DTPA, EDTA, DOTA, TETA, HYNIC stands for 6-Hydrazino-nicotinic acid, US 2017/01 19913 A1 May 4, 2017 83 and with the chemical structures thereof being as follows: Hoc- / V/ cott CO2H CN ND ( HOC-1 \-4\-coil HOC N-COH m = n = 1 DOTA = n = 2 TETA 1, n = 2 TRITA

-CO2H

HOC-2 N 2 / \-coil N N CO2H Hoc-/ HO.C-1N / HO.C-1 N N-1 N CO2H EDTA CO2H CO2H NODASA NODAGA O O HO H

VN N 1n 1\1\ N N H O OH O

N O 1 CDTA HO NH2 DFO NH HN HO N NH. N O N / fi SH HS HYNIC BAT

0519 In a preferred embodiment the metal chelator is 0522. In a more preferred embodiment the metal chelator selected from the group comprising DOTA-, NOTA-, for trivalent metals is selected from the group comprising DTPA-, TETA-DFO and HYNIC based chelators and their DTPA (diethylenetriaminepentaacetic acid) and polyaza close analogs. polycarboxylate macrocycles such as DOTA (1,4,7,10-tet 0520 Compounds of the invention which are complexes razacyclododecane-1,4,7,10-tetraacetic acid) and the close of a metal with a chelator a clearly and precisely termed by analogs thereof. the following short notation: 0523. In one preferred embodiment the metal chelator for 0521. In “Metal-(YY) the optional atomic mass Zr is DFO, DTPA, DOTA or EDTA. number of specific isotopes (XXX) in SuperScript is followed 0524. It will be acknowledged by the persons skilled in directly by the atomic symbol of metal (Metal), separated by the art that the chelator, in principle, may be used regardless an hyphen from number of the formula of the parent whether the compound of the invention is used in or suitable uncomplexed compound (YY) in parentheses; Lu-(12), for for diagnosis or therapy. Such principles are, among others, instance, means Lutethium complexed to a chelator of the outlined in international patent application WO 2009/ compound of formula (12) and 'In-(12), for instance, 109332 A1. means '''Indium complexed to a chelator of the compound 0525. In a further embodiment the conjugate of the of formula (12). invention is conjugated to a therapeutically active or thera US 2017/01 19913 A1 May 4, 2017

peutically effective agent which is also referred to herein as 20, R113-125; Vesely, Anticancer Res, 2012, 32, 2515 therapeutic effector moiety. Therapeutic effector moieties 2521), immunotoxins (Choudhary et al., Drug Discov Today, may be anti-proliferative, antimigration, antiangiogenic, 2011, 16, 495-503; Madhumathi et al., Curr Opin Microbiol, cytostatic, cytotoxic, antithrombotic, anti-inflammatory, 2012, 15, 300-309; Pastan et al., Curr Opin Investig Drugs, antiphlogistic, anticoagulative, antibacterial, antiviral and/or 2002, 3, 1089-1091), kinase inhibitors (Akin et al., JBUON, antimycotic agents, wherein antiproliferative, antimigration, 2014, 19, 42-46; Eigentler et al., Expert Opin Pharmacother, antiangiogenic, cytostatic and/or cytotoxic Substances as 2013, 14, 2195-2201; Sun, Cancer Lett, 2013, 340, 1-8), well as nucleic acids, Small molecules, amino acids, pep microtubule inhibitors (Higa et al., Expert Rev Anticancer tides, proteins, carbohydrates, lipids, glycoproteins, glycans Ther; 2008, 8, 671-681; Mareel et al., Int Rev. Cytol, 1984, or lipoproteins having antiproliferative, antimigration, anti 90, 125-168; Rothermel et al., Semin Oncol, 2003, 30, angiogenic, cytostatic and/or cytotoxic properties are pre 51-55) and topoisomerase inhibitors (Minagawa et al., Hum ferred. Cell, 2001, 14, 237-243; Munster et al., Expert Opin Investig 0526 Furthermore, such substances may also be radio Drugs, 2011, 20, 1565-1574: Takagi et al., Leuk Lymphoma, sensitizers or sensitizers or amplifiers of other combined 2001, 42, 577-586: Walczak et al., supra), compounds conventional cancer treatment methods or contain Such containing platinum (Bonanno et al., Anticancer Res, 2014, sensitizers. 34, 493-501; Poveda et al., Cancer Treat Rev. 2014, 40, 0527. In an embodiment of the conjugate of the invention 366-375; Puisset et al., Anticancer Res, 2014, 34, 465-470), the therapeutically active agent is a cytotoxic and/or cyto retinoids (Garattini et al., Cancer Treat Rev. 2014, 40, Static agent. 739-749; Pasquali et al., Curr Pharm Des, 2006, 12, 1923 1929: Tang et al., Annu Rev Pathol, 2011, 6, 345-364), 0528. A cytotoxin or cytotoxic agent includes any agent taxanes (Binder, Clin J Oncol Nurs, 2013, 17 Suppl. 9-14: that is detrimental to (e.g., kills) cells. A cytostatic agent Fauzee, Asian Pac J Cancer Prey, 2011, 12,837-851; Schutz includes any agent that inhibits or Suppresses cellular growth et al., Crit Rev. Oncol Hematol, 2014), toxins (Ansiaux et al., and multiplication. As cytotoxic and/or cytostatic com Expert Opin Investig Drugs, 2007, 16, 209-218: Bergan et pounds, i.e. chemical compounds having cytotoxic and/or al., Toxicon, 2012, 60, 1085-1107; Li et al., Toxins (Basel), cytostatic properties the following may be used: alkaloids 2010, 2, 2645-2662), auristatins (Gerber et al., Blood, 2009, (Moudi et al., IntJ Prev Med, 2013, 4, 1231-1235; Walczak 113, 4352-4361; Li et al., Mol Cancer Ther; 2013, 12, et al., J. An Acad Orthop Surg, 2013, 21, 480–491), alky 1255-1265; Oflazoglu et al., Clin Cancer Res, 2008, 14, lating agents (Begleiter. Front Biosci, 2000, 5, E153-171; 6171-6180) and other cytostatics such as, for example, Rockwell et al., Cancer Metastasis Rev. 1993, 12, 165-176: asparaginase (Covini et al., Recent Pat Anticancer Drug Spiro et al., Forum (Genova), 2000, 10,274-285; Walczak et Discov, 2012, 7, 4-13; Rizzari et al., Curr Opin Oncol, 2013, al., Supra), angiogenesis inhibitors (Cesca et al. Front 25 Suppl 1, S1-9; Verma et al., Crit Rev. Biotechnol, 2007, Oncol, 2013, 3, 259; Wang et al., Mar Drugs, 2013, 11, 27, 45-62), tretinoin (Gillis et al., Drugs, 1995, 50,897-923; 903-933; Zaki et al., Curr Top Med Chem, 2012, 12, 32-49), Makishima et al., Leuk Lymphoma, 1997, 26, 43-48: Wong, antibiotics having cytostatic properties (Abraham et al., Cancer Pract, 1996, 4, 220-223), podophyllotoxins Drug Saf 1996, 15, 406-429; Gewirtz, Biochem Pharmacol, (DIncalci et al., Cancer Chemother Biol Response Modif 1999, 57, 727-741; Oki, Biotechnol Bioeng, 1980, 22 Suppl 1992, 13, 75-82; Gordaliza et al., Curr Pharm Des, 2000, 6, 1, 83-97; Walczak et al., supra), anthracyclins (Shah, Recent 1811-1839; Hartmann et al., Drug Saf 2006, 29, 209-230), Pat Anticancer Drug Discov, 2009, 4, 241-245; Gewirtz et taxanes and miltefosine(R) (Clive et al., Cancer Chemother al. Supra; Walczak et al., Supra), antifolates (Purcell et al., Pharmacol, 1999, 44 Suppl. S29-30; Clive et al., Lancet, Curr Oncol Rep, 2003, 5, 114-125; Rollins et al., Clin Ther 1997, 349, 621-622; Terwogt et al., Br J Cancer, 1999, 79, 2005, 27, 1343-1382: Wright et al., Expert Opin Ther Pat, 1158-1161), immunomodulators (Rogalski et al., JEur Acad 2011, 21, 1293-1308), anti-mitotic toxins (Antignani et al., Dermatol Venereol, 1999, 13, 83-90; Thotathil et al., Expert Toxins (Basel), 2013, 5, 1486-1502; Engedal et al., Microb Opin Investig Drugs, 2007, 16, 1391-1403; Villa et al., J Biotechnol, 2011, 4, 32–46; Potala et al., Drug Discov Today, Drugs Dermatol, 2004, 3, 533-539), monoclonal antibodies 2008, 13, 807-815), mitotic inhibitors (Casaluce et al., (Glassman et al., Cancer Biol Med, 2014, 11, 20-33; Vac Expert Opin Emerg Drugs, 2013, 18, 97-107; Gabrielli et al., chelli et al. Oncoimmunology, 2014, 3, e27048; Jarboe et Adv. Cancer Res, 2012, 116, 1-37; Jiang et al., Mini Rev Med al., Methods Mol Biol, 2014, 1060, 61-77), signal transduc Chem, 2006, 6, 885-895), antimetabolites (Budde et al., ers (molecules for signal transduction) (Koptyra et al., Int J Curr Treat Options Oncol, 2005, 6, 83-93; Peters et al., Biochem Cell Biol, 2011, 43, 1417-1421; Masciocchi et al., Pharmacol Ther, 2000, 87, 227-253: Tiwari, J Cancer Res Future Med Chem, 2011, 3, 567-597; Catlett-Falcone et al., Ther, 2012, 8, 510-519; Walczak et al., supra), anti-prolif Curr Opin Oncol, 1999, 11, 490-496) and cytokines erative substances (Mader, Curr Opin Drug Discov Devel, (Kontermann, Arch Biochem Biophys, 2012, 526, 194-205; 2005, 8, 613-618: Rajak et al., Curr Med Chem, 2013, 20, Matsuo et al., Curr Pharm Des, 2012, 18, 2416-2419). 1887-1903, Stadler, Invest New Drugs, 2002, 20, 201-208), Cytotoxic and/or cyStatic agents may belong to only one or corticosteroids (Dietrich et al., Expert Rev Clin Pharmacol, 2011, 4, 233-242; Wooldridge et al., Oncology (Williston more of these categories. Park), 2001, 15, 225-234; discussion 234-226), duocarmy 0529. In an embodiment of the conjugate of the invention cins (Ghosh et al., Curr Top Med Chem, 2009, 9, 1494-1524; the therapeutically active agent is an alkaloid. Tietze et al., Anticancer Agents Med Chem, 2009, 9, 304 0530 Examples for alkaloids include but are not limited 325), HDAC inhibitors (Khan et al., Immunol Cell Biol, to emetime, lidocaine, procaine, and tetracaine. 2012, 90, 85-94; Sharma et al., BJUInt, 2013, 111,537-542: 0531. In an embodiment of the conjugate of the invention West et al., J. Clin Invest, 2014, 124, 30-39; Gabrielli et al., the therapeutically active agent is an alkylating agent. Supra; Rajak et al., Supra), hormones (Siegfried et al., Semin 0532. Examples for alkylating agents include but are not Oncol, 2014, 41, 5-16; Vesely, Endocr Relat Cancer, 2013, limited to Bendamustine, Ifosfamide, L-Sarcolysin, Phenyl