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(12) United States Patent (10) Patent No.: US 8,859,509 B2 Spiegel Et Al

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(12) United States Patent (10) Patent No.: US 8,859,509 B2 Spiegel Et Al US008859509B2 (12) United States Patent (10) Patent No.: US 8,859,509 B2 Spiegel et al. (45) Date of Patent: Oct. 14, 2014 (54) CHIMERIC SMALL MOLECULES FOR THE 2007/0248988 A1 10, 2007 Cuervo et al. RECRUITMENT OF ANTIBODESTO 2008.0171040 A1 7/2008 Ebens, et al. 2008/0267865 A1 10/2008 Sandberg et al. CANCER CELLS 2010/0324008 A1* 12/2010 Low et al. ..................... 514, 184 (75) Inventors: David Spiegel, New Haven, CT (US); Ryan Murelli, Torrington, CT (US); FOREIGN PATENT DOCUMENTS Andrew Zhang, New Haven, CT (US) WO Of 74382 A1 10, 2001 WO O306.0523 A1 T 2003 (73) Assignee: Yale University, New Haven, CT (US) WO 2007002222 A2 1, 2007 WO WO 2007/O11339 * 1 2007 (*) Notice: Subject to any disclaimer, the term of this WO 2009026177 A1 2, 2009 patent is extended or adjusted under 35 WO WO 2009,026177 A1 * 2/2009 U.S.C. 154(b) by 581 days. OTHER PUBLICATIONS Jung et al. Biophysical Journal, Apr. 2008, 94, 3094-3103.* (21) Appl. No.: 12/991,926 Baird etal, Biotechnology 2003, 12739-748.* American Cancer Society, Cancer Facts and Figures 2008. Atlanta: (22) PCT Filed: May 13, 2009 American Cancer Society; 2008. Ortega, E.; Kostovetzky, M.; Larralde, C.; Natural DNP-Binding (86). PCT No.: PCT/US2009/002957 Immunoglobulins and Antibody Multispecificity; Mol. Immun. 1984, 21,883. S371 (c)(1), Lu, et al., Folate receptor-targeted immunotherapy of cancer: mecha (2), (4) Date: Apr. 12, 2011 nism and therapeutic potential; Adv. Drug Deliv. Rev. 2004, 56, 1161. Lu, et al., Folate-Targeted Dinitrophenyl Hapten Immunotherapy: (87) PCT Pub. No.: WO2009/139863 Effect of Linker Chemistry on Antitumor Activity and Allergic Poten PCT Pub. Date: Nov. 19, 2009 tial; Mol. Pharmaceut. 2007, 4,695. Carlson, et al., Selective Tumor Cell Targeting Using Low-Affinity, (65) Prior Publication Data Multivalent Interactions; ACS Chem. Bio. 2007, 2, 119. Popkov, M.; Gonzalez, B.: Sinha, S. C.; Barbas, C. F., III. Instant US 2011 FO2O1563 A1 Aug. 18, 2011 immunity through chemically programmable vaccination and cova lent self-assembly; Proc. Nat. Acad. Sci., 2009, 1. Slusher, et al, Selective inhibition of NAALADase, which converts Related U.S. Application Data NAAG to glutamate, reduces ischemic brain injury; Nature Medi (60) Provisional application No. 61/127,539, filed on May cine, 1999, 5, 1396. 13, 2008. Kozikowski, Synthesis of Urea-Based Inhibitors as Active Site Probes of Glutamate Carboxypeptidase II: Efficacy as Analgesic Agents; J. Med. Chem., 2004, 47, 1729. (51) Int. Cl. Link, et al., Presentation and Detection of Azide Functionality in A6 IK3I/702 (2006.01) Bacterial Cell Surface Proteins; J. Am. Chem. Soc., 2004, 126, A6 IK3I/675 (2006.01) 10598. A6 IK3I/66 (2006.01) Natarajan, et al., Construction of di-scFv through a tribvalent alkyne A6 IK3I/492 (2006.01) azide 1,3-dipolar cycloaddition; J. Chem. Comm., 2007, 7,695. A 6LX3L/95 (2006.01) Bouillon, et al., Microwave Assisted “Click” Chemistry for the Syn C07H 99/00 (2006.01) thesis of Multiple Labeled-Carbohydrate Oligonucleotides on Solid A6 IK 47/48 (2006.01) Support; J. Org. Chem., 2006, 71, 4700. C07K I6/44 (2006.01) Sharpless and Manetsch, In Situ click chemistry: a powerful means A61 K39/00 (2006.01) for lead discovery; Expert Opinion on Drug Discovery 2006, 1, 525-538. (52) U.S. Cl. Jackson, et al., Design and Pharmacological Activity of Phosphinic CPC ............... C07K 16/44 (2013.01); A61 K47/481 Acid Based NAALADase Inhibitors; J. Med. Chem... 2001, 44, 4170 (2013.01); A61 K 2039/505 (2013.01); A61 K 4175. 47/4833 (2013.01); A61K 47/4802.3 (2013.01); A61K47/48092 (2013.01) (Continued) USPC ............... 514/25: 514/93: 514/114: 514/359; 514/562:536/17.9: 548/119: 548/255; 562/426; Primary Examiner — Ganapathy Krishnan 564/15 (74) Attorney, Agent, or Firm — Henry D. Coleman; R. Neil (58) Field of Classification Search Sudol USPC ..................... 514/25, 359, 93,562; 536/17.9; 548/255, 119:562/15 (57) ABSTRACT See application file for complete search history. The present invention relates to chimeric chemical com pounds which are used to recruit antibodies to cancer cells, in (56) References Cited particular, prostate cancer cells or metastasized prostate can cer cells. The compounds according to the present invention U.S. PATENT DOCUMENTS comprise an antibody binding terminus (ABT) moiety 4,522,811 A 6/1985 Eppstein et al. covalently bonded to a cell binding terminus (CBT) through 6,780,884 B2 8/2004 Zisapel et al. a linker and optionally, a connector molecule. 2004/OO29778 A1 2, 2004 Isaacs et al. 2005/0256030 A1 1 1/2005 Feng 39 Claims, 13 Drawing Sheets US 8,859,509 B2 Page 2 (56) References Cited Dinitro Phenol P Amino Benzoyl Glutamate Antibody Light Chains. Immunology 1978, 34:353-862. OTHER PUBLICATIONS Niculescu-DuvaZD et al. Longfunctionalized poly(ethylene glycol)S of defined molecular weight: Synthesis and application in Solid Liu and Stahl. Two-Faced Reactivity of Alkenes: cis- versus trans phase synthesis of conjugates. Bioconjugate Chemistry 2008, Aminopalladation in Aerobic Pod-Catalyzed Intramolecular AZa 19:973-981. Wacker Reactions; J. Am. Chem. Soc.; 2007: 129; 6328-6335. Sibrian-Vazquez M et al. Synthesis and properties of cell-targeted Luo, et al., Poly(vinyl alcohol)-graft-poly(ethylene glycol) resins and Zn(II)-phthalocyanine-peptide conjugates. Bioconjugate Chemistry their use in solid-phase synthesis and Supported TEMPO catalysis; 2007, 18:410-420. Chem. Comm. 2007, 2136-2138. Shami P J et al., Antitumor Activity of JS-K O2-(2,4- Baird, et al.; Highly Effective Poly(Ethylene Glycol) Architectures Dinitrophenylo) 1-(4-Ethoxy-carbonyl)piperazine-1-ylidiazen for Specific Inhibition of Immune Receptor Activation; Biochemistry ium-1,2-diolate and related O2-Aryl Diazeniumdiolates in vitro and 2003, 42, 12739-12748. in vivo. Journal of Medicinal Chemistry 2006; 49 (14), pp. 4356 Demko, et al., Preparation of 5-Substituted 1H-Tetrazoles from 4366. Nitriles in Water; J. Org. Chem. 2001, 66, 7945-7950. Dubrovska A. Kim C. Elliot J, et al. A Chemically Induced Vaccine Kale, et al., Synthesis of soluble multivalent glycoconjugates that Strategy for Prostate Cancer. ACS Chem Biol. 2011;6:1223-1231. target the Hc region of botulinum neurotoxin A; Biorg. Med. Chem. Xia W. Low PS. Folate-Targeted Therapies for Cancer. JMed Chem, Lett. 2007, 17, 2459-2464. 2010:53:681 1-6824. Popkov M et al., Instant immunity through chemically program Shokat, KM; and Schultz, PG. Redirecting the Immune Response: mable vaccination and covalent self-assembly. Proc. Natl. Acad. Sci. Ligand-Mediated Immunogenicity. JAmChemSoc. 1991; 113:1861 USA 2009, 106:4378-4383. 1862. Hagins D Metal. A Comparison of the Amino Terminal Amino Acids Sequences of Early and Late Pools of Anti D1 Nitro Phenol and Anti * cited by examiner U.S. Patent Oct. 14, 2014 Sheet 1 of 13 US 8,859,509 B2 FIGURE 1 Q-w immune PC-ARM (3) effector -- cells -- > s/ --> = 4 \W anti- DNP anitbodies targeted cell death ternary complex prostate cancer cell U.S. Patent Oct. 14, 2014 Sheet 2 of 13 US 8,859,509 B2 FIGURE 2 U.S. Patent Oct. 14, 2014 Sheet 3 of 13 US 8,859,509 B2 FIGURE 3 PSMA-binding small molecule N=N 2a, R = H 2b, R = CHCHCN HofOH CO2H ot 1 HOC1N1,N1",H H 1)COH 2 O {-> on8 NPNN r O COH ON NO2 2 HOCN l...!N "1 NCOH U.S. Patent Oct. 14, 2014 Sheet 5 of 13 US 8,859,509 B2 FIGURES 150 10O 101 O2 o 109 10 o o Log fluorescence Log fluorescence U.S. Patent Oct. 14, 2014 Sheet 6 of 13 US 8,859,509 B2 FIGURE 6 100 XX lgG1 80 lgG3 Human lgG 2 60 O & 40 < 20 U.S. Patent Oct. 14, 2014 Sheet 7 of 13 US 8,859,509 B2 H Zz ?ON U.S. Patent US 8,859,509 B2 CO)CC U.S. Patent Oct. 14, 2014 Sheet 9 of 13 US 8,859,509 B2 U.S. Patent US 8,859,509 B2 N OOW (%19)ZI OOW •O U.S. Patent Sheet 11 of 13 US 8,859,509 B2 U.S. Patent Sheet 12 of 13 US 8,859,509 B2 2 g 2. ºONO fy a.s Nz M lle 2 o 2. IZ O 2. // al -? g 2.r S2 al 2. a. U.S. Patent Oct. 14, 2014 Sheet 13 of 13 US 8,859,509 B2 (I)nCO VBIJL [7] US 8,859,509 B2 1. 2 CHMERIC SMALL MOLECULES FOR THE more invasive procedures such as hormonal therapy or che RECRUITMENT OF ANTIBODESTO motherapy. Unfortunately, most patients eventually stop CANCER CELLS responding to hormonal therapy and the most Successful che motherapeutic, Taxotere, only prolongs the life of advanced RELATED APPLICATIONS AND GRANT 5 prostate cancer patients by 2.5 months on average. SUPPORT As another alternative therapeutic, monoclonal antibody (mAb)-based immunotherapy has proven clinically benefi The present application claims the benefit of priority of cial for cancer patients while allowing them to maintain a U.S. provisional application Ser. No. 61/127,539, entitled, good quality of life. These antibodies can either regulate “Chimeric Small Molecules for the Recruitment of Antibod 10 proliferation of cancer cells through the manipulation of Sig ies to Cancer Cells, filed May 13, 2008, the entire contents of nal transduction, or promote cytotoxicity. Two examples of which are incorporated by reference herein. FDA-approved mAb-based anticancer drugs are Herceptin This invention was supported by a grant from the National and Rituxan (Rituximab), which are currently being used for Institutes of Health, grant no.
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