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Amino Acid Sequences Directed Against a Metalloproteinase from the ADAM Family and Polypeptides Comprising the Same for the Trea

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Amino Acid Sequences Directed Against a Metalloproteinase from the ADAM Family and Polypeptides Comprising the Same for the Trea (19) TZZ __T (11) EP 2 514 767 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 24.10.2012 Bulletin 2012/43 C07K 16/40 (2006.01) (21) Application number: 12164303.5 (22) Date of filing: 19.12.2007 (84) Designated Contracting States: • Saunders, Michael John Scott AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 1190 Brussels (BE) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • de Haard, Johannes Joseph Wilhelmus SI SK TR 4436 NA Oudelande (NL) (30) Priority: 19.12.2006 US 875834 P (74) Representative: HOFFMANN EITLE Patent- und Rechtsanwälte (62) Document number(s) of the earlier application(s) in Arabellastrasse 4 accordance with Art. 76 EPC: 81925 München (DE) 07857865.5 / 2 102 244 Remarks: (71) Applicant: Ablynx N.V. This application was filed on 16-04-2012 as a 9052 Ghent-Zwijnaarde (BE) divisional application to the application mentioned under INID code 62. (72) Inventors: • Blanchetot, Christophe 2806 RG Gouda (NL) (54) Amino acid sequences directed against a metalloproteinase from the ADAM family and polypeptides comprising the same for the treatment of ADAM-related diseases and disorders (57) The present invention relates to amino acid se- ular proteins and polypeptides, that comprise or essen- quences that are directed against and/or that can spe- tially consist of one or more such amino acid sequences, cifically bind to metalloproteinases from the ADAM fam- and to methods or preparing the same. ily, as well as to compounds or constructs, and in partic- EP 2 514 767 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 514 767 A1 Description [0001] The present invention relates to amino acid sequences that are directed against (as defined herein) metallo- proteinases from the ADAM family, as well as to compounds or constructs, and in particular proteins and polypeptides, 5 that comprise or essentially consist of one or more such amino acid sequences (also referred to herein as "amino acid sequences of the invention", "compounds of the invention", and "polypeptides of the invention", respectively). [0002] The invention also relates to nucleic acids encoding such amino acid sequences and polypeptides (also referred to herein as "nucleic acids of the invention" or "nucleotide sequences of the invention"); to methods for preparing such amino acid sequences and polypeptides; to host cells expressing or capable of expressing such amino acid sequences 10 or polypeptides; to compositions, and in particular to pharmaceutical compositions, that comprise such amino acid sequences, polypeptides, nucleic acids and/or host cells; and to uses of such amino acid sequences or polypeptides, nucleic acids, host cells and/or compositions, in particular for prophylactic, therapeutic or diagnostic purposes, such as the prophylactic, therapeutic or diagnostic purposes mentioned herein. [0003] Other aspects, embodiments, advantages and applications of the invention will become clear from the further 15 description herein. [0004] The ADAM metalloproteinases disintegrins form a well-known family of proteases (or proteinases) that mediates ectodomain shedding. Many of the processing events that include the release of cytokines, shedding of cell surface molecules, release of growth factors and cleavage of amyloid precursor protein (APP), are all shown to be mediated by metalloproteases. Reference is for example made to the reviews by Huovila et al., Trends Biochem Sci, (30), 7, 413-22 20 (2005); Seals and Courtneidge, Genes Dev 17, 7-30 (2003); Fox and Serrano, Toxicon 45, 969-85 (2005); Moss et al., Drug Discov Today, (6), 8, 417-426 (2001); Moss et al., Biochemistry, (43), 23, 7227-35 (2004); Handsley et al. Int J Cancer, (115), 6, 849-60 (2005); Herren, News Physiol Sci, (17), 73-6 (2002); and Hojilla et al., Br J Cancer, (89), 10, 1817-21 (2003); as well as to the further references cited therein and the further prior art cited in the present specification. Reference is for example made to Figure 1 in the review by Huovila et al., supra; Figures 2 and 3 in Allinson et al., J 25 Neurosci Res 74, 342-52 (2003); to Figures 1 and 3 in the review by Moss et al (2004), supra; to Figures 1 and 3 from the review by Seals and Courtneidge, supra; and to Figure 1 in the review by Herren, supra. [0005] The ADAM (A disintegrin And Metalloproteases) family includes proteins containing a disintegrin-like and metalloprotease-like domain). The ADAMTS contain a thrombospondin (TS) domain in addition to the other common domains (and should be considered included within the term ADAM proteinase as used in the specification and claims). 30 Together with the Snake Venom Metalloproteinases (SVMPs), ADAM and ADAM-TS form the reprolysin subfamily of metalloprotease. All family members share a common multi-domain structure minimally containing a Pro domain, a metalloprotease (-like) and a disintegrin-like domain. Some ADAM have additional domains like cystein-rich and a transmembrane and cytoplasmic domains. Reference is again made to Figure 1 in the review by Huovila et al., supra; Figures 2 and 3 in Allinson et al., J Neurosci Res 74, 342-52 (2003); to Figures 1 and 3 in the review by Moss et al 35 (2004), supra; to Figures 1 and 3 from the review by Seals and Courtneidge, supra; and to Figure 1 in the review by Herren, supra. [0006] The substrates of ADAM metalloproteinases are also well-known, and for example include CD23, TNFR1, IL1- RII, CX3CL1, TNF-alpha, TNFR1, TNFRII, and TRANCE, as well as the substrates mentioned in Table 1 of the review by Huovila et al., supra.; and Table 1 in the review by Moss et al (2004), supra. 40 [0007] Members of the ADAM family are also well-known in the art, and for example and without limitation include: - ADAM 1, ADAM2, ADAM3B, ADAM4, ADAM5, ADAM6, ADAM7, ADAM8, ADAM9, ADAM10, ADAM11, ADAM12, ADAM13, ADAM14, ADAM15, ADAM16, ADAM17, ADAM18, ADAM19, ADAM20, ADAM21, ADAM21, ADAM22, ADAM23, ADAM24, ADAM25, ADAM26, ADAM27, ADAM28, ADAM29, ADAM30, ADAM31, ADAM32, ADAM33, 45 ADAM34, ADAM35, ADAM36, ADAM37, ADAM38, ADAM39, ADAM40 - ADAMTS1, ADAMTS2, ADAMTS3, ADAMTS4, ADAMTS5, ADAMTS6, ADAMTS7, ADAMTS8, ADAMTS9, ADAMTS10, ADAMTS11, ADAMTS12, ADAMTS13, ADAMTS14, ADAMTS15, ADAMTS16, ADAMTS17, ADAMTS18, ADAMTS19, ADAMTS20 50 [0008] Reference is also made to the following websites: http://merops.sanger.ac.uk/ and http://www.uta.fi/%7Eloiika/ ADAMs/HADAMs.htm. [0009] Diseases and disorders in which ADAM metalloproteinases are involved as also well-known in the art. Reference is again made to the reviews mentioned above and the further references cited therein; and also to for example to Levy et al. , Nature 413, 488-94 (2001); Stanton et al.; Nature 434, 648-52 (2005); Glasson et al., Nature 434, 644-8 (2005), 55 Weskamp et al., Nat Immunol 7, 1293-1298 (2006); Allinson et al., J Neurosci Res 74, 342-52 (2003); and Blobel, Nat Rev Mol Cell Biol 6, 32-43 (2005); and for example include: - ADAM8: allergy, inflammation (asthma, TRAPS) 2 EP 2 514 767 A1 - ADAM9: hematological malignancies - ADAM10: chemotaxis, inflammation (asthma, rhinitis) Alzheimer - ADAM17/TACE: inflammation, IL1beta signaling, sepsis, inflammatory, arthritis, diabetes, HIV cachexia, cancer and TNF/EGF dependent diseases 5 - ADAM-TS5: aggrecanase 2 and osteoarthritis, arthritis - ADAM15: atherosclerosis - ADAM33: Asthma [0010] For example, ADAM17 is the major physiological TNFalpha converting enzyme and is therefore essential to 10 TNFalpha signaling. Therefore, inhibition of ADAM17 will be useful in any disease state where TNF antagonist has been validated, such as arthritis, diabetes, HIV cachexia, sepsis and cancer. Reference is for example made to the review articles cited above and the further references cited herein and in the present specification. Moss et al. (2001) and Moss et al. (2004). [0011] Also ADAM17 is responsible for the processing and release of TGFalpha and EGF. Indeed ADAM17-/- mice 15 are embryonic lethal with phenotype reminiscent of the TGFalpha-/- and EGFR-/- mice. "Key functions of ADAMs have emerged in ErbB signalling pathways as being sheddases for multiple ErbB ligands. As the ErbB pathway is a validated target for anti-cancer drugs, the upstream activators of ErbB ligands, their sheddases, now enter the spotlight as new drug targets in the ErbB pathway. ADAMs are involved not only in tumour cell proliferation but also in angiogenesis and metastasis. Therefore, strategies targeting ADAMs might be an important complement to existing anti-ErbB approaches." 20 (See Blobel, supra). [0012] ADAM10 and ADAM17 have been described as important sheddases for cytokines and their receptors, sug- gesting that these ADAMs are key modulator of cytokines in vivo. [0013] The gene ADAM33, was identified as an asthma susceptibility gene involved in airway remodeling. [0014] Increasing evidence point that ADAM10 (and to lesser extend ADAM17) is an alpha-secretase of the amyloid 25 precursor protein (APP). Because cleavage of APP at the alpha site is believed to preclude cleavage at the beta and gamma site (cleavage sites promoting the APP aggregation leading to Alzheimer disease), ADAM10 can be considered as a protective factor in the etiology of Alzheimer’s disease. Activation of ADAM10 might prove useful for the treatment of Alzheimer’s disease (see for review Allinson 2003 and ref therein). [0015] ADAM12 cleaves and inactivate IGFBP3, a natural inhibitor of IGF1 and 2. Because low level of IGF are 30 associated with osteoarthritis and diabetes, the balance between IGFs and IGFBPs is crucial. Interestingly, mice over- expressing ADAM12 develop more abdominal and body fat. Also ADAM12-/- mice have reduced adipocytes and partial defect in myogenesis. [0016] ADAM9 is expressed in hematological malignancies and might process the EGFR ligand HB-EGF. [0017] ADAM8 is a serological and histochemical marker for lung cancer (Ishikawa N, 2004). ADAM8 may be the 35 CD23 shedding enzyme. Soluble CD23 released from cells during allergic response stimulate IgE production.
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