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Antibodies Against T Cell Immunoglobulin Domain And (19) TZZ__¥Z_T (11) EP 1 613 750 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 15/12 (2006.01) C07K 14/47 (2006.01) 14.10.2015 Bulletin 2015/42 C07K 16/18 (2006.01) A61P 35/00 (2006.01) (21) Application number: 04757910.7 (86) International application number: PCT/US2004/008502 (22) Date of filing: 19.03.2004 (87) International publication number: WO 2004/084823 (07.10.2004 Gazette 2004/41) (54) ANTIBODIES AGAINST T CELL IMMUNOGLOBULIN DOMAIN AND MUCIN DOMAIN 1 (TIM-1) ANTIGEN AND USES THEREOF ANTIKÖRPER GEGEN DAS T- ZELLEN-IMMUNGLOBULINDOMÄNE- UND MUCINDOMÄNE- 1 (TIM- 1) ANTIGEN UND VERWENDUNGEN DAVON ANTICORPS CONTRE L’ANTIGENE DE LYMPHOCYTES T, DU DOMAINE D’IMMUNOGLOBULINE ET DU DOMAINE 1 DE MUCINE (TIM-1) ET LEURS UTILISATIONS (84) Designated Contracting States: • MESRI, Mehdi AT BE BG CH CY CZ DE DK EE ES FI FR GB GR North Potomac, MD 20878 (US) HU IE IT LI LU MC NL PL PT RO SE SI SK TR (74) Representative: Giles, Ashley Simon et al (30) Priority: 19.03.2003 US 456652 P Haseltine Lake LLP Lincoln House, 5th Floor (43) Date of publication of application: 300 High Holborn 11.01.2006 Bulletin 2006/02 London WC1V 7JH (GB) (73) Proprietor: Amgen Fremont Inc. (56) References cited: Fremont, CA 94555 (US) WO-A-02/098920 WO-A-03/002722 WO-A-03/080856 WO-A-2005/001092 (72) Inventors: WO-A1-97/44460 US-B1- 6 664 385 • LANDES, Gregory, M. Livermore, CA 94550 (US) • FEIGELSTOCK D ET AL: "The human homolog of • CHEN, Francine HAVcr-1 codes for a hepatitis A virus cellular San Francisco, CA 94116 (US) receptor" JOURNAL OF VIROLOGY, THE • BEZABEH, Binyam AMERICAN SOCIETY FOR MICROBIOLOGY, US, Oakland, CA 94610 (US) vol. 72, no. 8, 1 August 1998 (1998-08-01), pages • FOLTZ, Ian 6621-6628, XP002959127 ISSN: 0022-538X Vancouver, British Columbia V6J 4S3 (CA) • MCINTIRE J J ET AL: "Identification of Tapr (an • TSE, Kam Fei airway hyperreactivity regulatory locus) and the Chester Springs, PA 19425 (US) linked Tim gene family" NATURE IMMUNOLOGY, • JEFFERS, Michael NATURE PUBLISHING GROUP, GB, vol. 2, no. 12, Branford, Connecticut 06405 (US) 1 December 2001 (2001-12-01), pages 1109-1116, • STARLING, Gary XP002306671 ISSN: 1529-2908 Clinton, Connecticut 06413 (US) • WINTER G. ET AL.: ’Humanized antibodies.’ • MEZES, Peter IMMUNOL.TODAY. vol. 14, 1993, pages 243 - 246, Old Lyme, Connecticut 06371 (US) XP001005438 • KHRAMTSOV, Nikolia Branford, Connecticut 06405 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 613 750 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 613 750 B1 Description Background of the Invention 5 Field of the Invention [0001] The invention disclosed herein is related to antibodies directed to the antigen T cell, immunoglobulin domain and mucin domain 1 (TIM-1) proteins and uses of such antibodies. In particular, there are provided fully human monoclonal antibodies directed to the antigen TIM-1. Nucleotide sequences encoding, and amino acid sequences comprising, heavy 10 and light chain immunoglobulin molecules, particularly sequences corresponding to contiguous heavy and light chain sequences spanning the framework regions and/or complement arity determining regions (CDRs), specifically from FR1 through FR4 or CDR1 through CDR3, are provided. Hybridomas or other cell lines expressing such immunoglobulin molecules and monoclonal antibodies are also provided. 15 Description of the Related Art [0002] A new family of genes encoding T cell, immunoglobulin domain and mucin domain (TIM) proteins (three in humans and eight in mice) have been described recently with emerging roles in immunity. Kuchroo et al., Nat Rev Immunol 3:454-462 (2003); McIntire et al., Nat Immunol 2:1109-1116 (2001). The TIM gene family members reside in 20 chromosomal regions, 5q33.2 in human and 11B1.1 in mouse, and have been linked to allergy and autoimmune diseases. Shevach, Nat Rev Immunol 2:389-400 (2002); Wills-Karp et al., Nat Immunol 4:1050-1052 (2003). [0003] One TIM family member, TIM-1, is also known as Hepatitis A virus cellular receptor (HAVcr-1) and was originally discovered as a receptor for Hepatitis A virus (HAV) (Kaplan et al, EMBO J 15(16):4282-96 (1996)). This gene was later cloned as kidney injury molecule 1 (KIM-1) (Ichimura et al., J Biol Chem 273:4135-4142 (1998); Han et al., Kidney Int 25 62:237-244 (2002)). [0004] Kaplan et al. isolated the cellular receptor for hepatitis A virus from a cDNA library from a primary African Green Monkey Kidney (AGMK) cell line expressing the receptor. See U.S. Patent No. 5,622,861. The disclosed utility of the polypeptides and nucleic acids was to diagnose infection by hepatitis A virus, to separate hepatitis A virus from impurities in a sample, to treat infection as well as to prevent infection by hepatitis A virus. Furthermore, the polypeptides could 30 be expressed in transformed cells and used to test efficacy of compounds in an anti-hepatitis A virus binding assay. [0005] The human homolog, hHAVcr-1 (aka TIM-1), was described by Feigelstock et al., J Virology 72(8): 6621-6628 (1998). The same molecules were described in PCT Publication Nos: WO 97/44460 and WO 98/53071 and U.S. Patent No. 6,664,385 as Kidney Injury-related Molecules (KIM) that were found to be upregulated in renal tissue after injury to the kidney. The molecules were described as being useful in a variety of therapeutic interventions, specifically, renal 35 disease, disorder or injury. For example, PCT Publication No. WO 02/098920 describes antibodies to KIM and describes antibodies that inhibit the shedding of KIM-1 polypeptide from KIM-1 expressing cells e.g., renal cells, or renal cancer cells. [0006] TIM-1 is a type 1’ membrane protein that contains a novel six-cysteine immunoglobulin-like domain and a mucin threonine/serine.proline-rich (T/S/P) domain. TIM-1 was originally identified in rat. TIM-1 has been found in mouse, African green monkey, and humans (Feigelstock et al., J Virol 72(8):6621-8 (1998). The African green monkey ortholog 40 is most closely related to human TIM-1 showing 77.6% amino acid identity over 358 aligned amino acids. Rat and mouse orthologs exhibit 50% (155/310) and 45.6% (126/276) amino acid identity respectively, although over shorter segments of aligned sequence than for African green monkey. Monoclonal antibodies to the Ig-like domain of TIM-1 have been shown to be protective against Hepatitis A Virus infectionin vitro. Silberstein et al., J Virol 75(2): 717-25 (2001). In addition, KIM-1 was shown to be expressed at low levels in normal kidney but its expression is increased dramatically 45 in postischemic kidney. Ichimura et al., JBiol Chem 273(7):4135-42 (1998). HA VCR-1 is also expressed at elevated levels in clear cell carcinomas and cancer cell lines derived from the same. [0007] WO 02/098920 relates to mouse monoclonal antibodies to KIM-1 (kidney injury molecule-1) which bind to polypeptides reported to be expressed in injured or diseased kidney cells. [0008] TIM-1 shows homology to the P-type "trefoil" domain suggesting that it may have similar biological activity to 50 other P-type trefoil family members. Some trefoil domain containing proteins have been shown to induce cellular scattering and invasion when used to treat kidney, colon and breast tumor cell lines. Prest et al., FASEB J16 (6):592-4 (2002). In addition, some trefoil containing proteins confer cellular resistance to anoikis, an anchorage-related apoptosis phenom- enon in epithelium. Chen et al., Biochem Biophys Res Commun 274(3): 576-82 (2000). [0009] TIM-1 maps to a region of human chromosome 5 known as Tapr in the murine sytenic region that has been 55 implicated in asthma. Tapr, a major T cell regulatory, locus, controls the development of airway hyperreactivity. Wills- Kaip, Nature Immunology 2:1095-1096 (2001); McIntire et al., Nature Immunology 2: 1109-1116 (2001). 2 EP 1 613 750 B1 Summary of the Invention [0010] Embodiments of the invention described herein are based upon the development of human monoclonal anti- bodies, or binding fragments thereof, that bind TIM-1 and affect TIM-1 function. TIM-1 is expressed at elevated levels 5 in pathologies, such as neoplasms and inflammatory diseases. Inhibition of the biological activity of TIM-1 can thus prevent inflammation and other desired effects, including TIM-1 induced cell proliferation. Embodiments of the invention are based upon the generation and identification of isolated antibodies, or binding fragments thereof, that bind specifically to TIM-1. [0011] Accordingly, the invention provides an isolated human antibody or binding fragment thereof that specifically 10 binds to T cell, immunoglobulin domain and mucin domain 1 (TIM-1), wherein said antibody or binding fragment has a heavy chain polypeptide comprising an amino acid sequence comprising three complementarity determining regions (CDRs) and a light chain polypeptide comprising three CDRs, where the three heavy chain CDRs and the three light chain CDRS are selected from: 15 (a) a heavy chain CDR1 comprising the amino acid sequence GFIFSRYGMH, a heavy chain CDR2 comprising the amino acid sequence VIWYDGSNKLYADSVK, a heavy chai n CDR3 comprising the amino acid sequence DYYDN- SRHHWGFDY, a light chain CDR1 comprising the amino acid sequence RSSRSLLDSDDGNTYLD, a light chain CDR2 comprising the amino acid sequence TLSYRAS, and a light chain CDR3 comprising the amino acid sequence MQRVEFPIT; and 20 (b) a heavy chain CDR1 comprising the amino acid sequence GGSISSDGYYWS, a heavy chain CDR2 comprising the amino acid sequence YIYYSGSTFYNPSLKS, a heavy chain CDR3 comprising the amino acid sequence ES- PHSSNWYSGFDC, a light chain CDR1 comprising the amino acid sequence RASQSIGSRLH, a light chain CDR2 comprising the amino acid sequence YASQSFS, and a light chain CDR3 comprising the amino acid sequence 25 HQSSNLPFT.
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