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(12) United States Patent (10) Patent No.: US 7,563,450 B2 Cosman (45) Date of Patent: Jul

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(12) United States Patent (10) Patent No.: US 7,563,450 B2 Cosman (45) Date of Patent: Jul US00756345OB2 (12) United States Patent (10) Patent No.: US 7,563,450 B2 Cosman (45) Date of Patent: Jul. 21, 2009 (54) UL16 BINDING PROTEIN 4 Bauer S et al., “Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.” Science 285:727-729 (Jul 30, (75) Inventor: David J. Cosman, Seattle, WA (US) 1999). Bowie et al., “Deciphering the message in protein sequences: toler (73) Assignee: Immunex Corporation, Thousand Oaks, ance to amino acid substitutions.” Science 247: 1306-1310 (1990). CA (US) Bork P. "Powers and pitfalls in sequence analysis: the 70% hurdle.” Genome Research 10:398-400 (2000). (*) Notice: Subject to any disclaimer, the term of this Burgess et al., “Possible dissociation of the heparin-binding and patent is extended or adjusted under 35 mitogenic activities of heparin-binding (acidic fibroblast) growth factor-1 from its receptor-binding activities by site-directed U.S.C. 154(b) by 538 days. mutagenesis of a single lysine residue.” J Cell Biol 111:2129-2138 (1990). (21) Appl. No.: 10/265,811 Cerwenka A et al., “Ectopic expression of retinoic acid early induc ible-1 gene (RAE-1) permits natural killer cell-mediated rejection of (22) Filed: Oct. 4, 2002 a MHC class I-bearing tumor in vivo..” PNAS 98(20): 11521-11526 (Sep. 25, 2001). (65) Prior Publication Data Cerwenka A et al., “Retinoic acid early inducible genes define a US 2003/O195337 A1 Oct. 16, 2003 ligand family for the activating NKG2D receptor in mice.” Immunity 12:721-727 (Jun. 2000). Related U.S. Application Data Colucci Fet al., “Functional dichotomy in natural killer cell signal ing: Vavl-dependent and -independent mechanisms. J Exp Med (60) Provisional application No. 60/327.252, filed on Oct. 193(12): 1413-1424 (Jun. 18, 2001). 4, 2001. Cosman D et al., “ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through (51) Int. Cl. the NKG2D receptor.” Immunity 14:123-133 Feb. 2001. A6 IK 39/00 (2006.01) Das Het al., “MICA engagement by human Vy2V62T cells enhances A6 IK 38/00 (2006.01) their antigen-dependent affector function.” Immunity 15:83-93 Jul. A6 IK 38/16 (2006.01) 2001. C07K I4/00 (2006.01) Diefenbach A et al., “Rael and H60 ligands of the NKG2D receptor CI2N 5/00 (2006.01) stimulate tumour immunity.” Nature 413:165-171 Sep. 13, 2001. (52) U.S. Cl. ........................ 424/277.1: 514/2; 530/350; Diefenbach A et al., “Ligands for the murine NKG2D receptor: 530/402 expression by tumor cells and activation of NK cells and macroph ages.” Nature Immunol 1(2): 119-126 (Aug. 2000). (58) Field of Classification Search ........... ... None Dorfman D et al., “In vivo expression of B7-1 and B7-2 by follicular See application file for complete search history. lymphoma cells can prevent induction of T-cell anergy but is insuf (56) References Cited ficient to induce significant T-cell proliferation.” Blood 90(11):4297 4306 (Dec. 1, 1997). U.S. PATENT DOCUMENTS Gattei V et al., “CD30 ligand is frequently expressed in human hematopoietic malignancies of myeloid and lymphoid origin. Blood 6,458,350 B1 10/2002 Cosman et al. 2003, OOO4311 A1 1/2003 Baker et al. 89(6):2048-2059 (Mar. 15, 1997). 2003/0022239 A1 1/2003 Baker et al. Gilles SD et al., “Improving the efficacy of antibody-interleukin 2 fusion proteins by reducing their interaction with Fc receptors. Can FOREIGN PATENT DOCUMENTS cer Res. 59:2159-2166 (May 1, 1999). Girardi Metal., “Regulation of cutaneous malignancy by YöT cells.” WO WO99.31236 A2 6, 1999 Science 294:605-609 (Oct. 19, 2001). WO WOO1/O7611 A2 2, 2001 Holden SA et al., “Augmentation of antitumor activity of an anti WO WOO1/40466 A2 6, 2001 body-interleukin 2 immunocytokine with chemotherapeutic agents.” WO WOO1? 497 28 A2 T 2001 WO WOO1,71005 A3 9, 2001 Clin Cancer Res 7:2862-2869 (Sep. 2001). WO WO 01/83545 A1 11, 2001 Holmes MA et al., “Structural studies of allelic diversity of the MHC WO WOO2,68615 A2 9, 2002 class I homolog MIC-B, a stress-inducible ligand for the activating WO WO 03/14322 A2 2, 2003 immunoreceptor NKG2D,”J Immunol 169: 1395-1400 (2002). WO WOO3/O54152 T 2003 WO WOO3,O74.556 9, 2003 (Continued) WO WO 2004/O227O6 3, 2004 Primary Examiner G. REwoldt Assistant Examiner DiBrino Marianne OTHER PUBLICATIONS (74) Attorney, Agent, or Firm Rosemary Sweeney; Susan E. Cosman et al. Immunity. Feb. 2001. vol. 14, pp. 123-133.* Lingenfelter A Geneseq 21 Accession No. AAG68335. Feb. 28, 2002, one page. (57) ABSTRACT Kubinet al ((2001) Eur, J. Immunol. 31: 1428-37).* Kubinet al (1999) Eur, J. Immunol. 29: 3466-3477).* Smith et al ((1993) Cell 73: 1349-1360).* ULBP4, a novel member of the ULBP family has been iso Zamaietal ((2007).J. Immunology 178: 4011-4016).* lated and characterized. ULBP4 is a useful activator of Miller ((2001) Exp. Hematol. 29: 1157-1168).* Scott-Algaraetal ((2002) Current Molecular Medicine 2: 757-768).* immune effector cells, particularly of NK cells. Chalupny JN et al., “ULBP4 is a novel ligand for human NKG2D.” Biochem Biophy's Res Commun (2003) 305(1): 129-135. 18 Claims, 4 Drawing Sheets US 7,563,450 B2 Page 2 OTHER PUBLICATIONS GenBank Accession No. AAD 12613 (2001). GenBank Accession No. AAY36021 (1999). 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Radosavljevic Met al., “A cluster often novel MHC class I related Conejo-Garcia et al., “Letal, a tumor-associated NKG2D genes on human chromosome 6q24.2-q25.3.” Genomics 79(1): 114 immunoreceptor ligand, induces activation and expansion of effector 123 Jan. 2002. immune cells.” Cancer Biol. Ther: 2(4):446-451, 2003. Scott et al., “The pendred syndrome gene encodes a chloride-iodide Conejo-Garcia et al., “Ovarian carcinoma expresses the NKG2D transport protein.” Nat Gen 21:440-443 (Apr. 1999). ligand Letal and promotes the Survival and expansion of CD28 anti Steinle A et al., “Interactions of human NKG2D with its ligands tumor T cells, Cancer Res. 64:2175-2182, 2004. MICA, MICB, and homologs of the mouse RAE-1 protein family.” Diefenbach et al., “Rael and H60 ligands of the NKG2D receptor Immunogenetics 53:279-287 (2001). stimulate tumour immunity.” Nature 413: 165-171, 2001. Sun T. et al., “Histiocyte-rich B-cell lymphoma.” Human Pathology Diefenbach et al., “A novelligand for the NKG2D receptor activates 28(11): 1321-1324 (Nov. 1997). NK cells and macrophages and induces tumor immunity.” Eur: J. Sutherland CL et al., “The UL 16-binding proteins, a novel family of Immunol. 33:381-391, 2003. MHC class I-related ligands for NKG2D, activate natural killer cell NCBI Protein/GenBank Database Accession No. AAL58090, Aug. functions.” Immunol Rev 181:185-192 (2001). 13, 2004. Ugolini Sand Vivier E. “Multifaceted roles of MHC class I and MHC Rölle et al., “Effects of human cytomegalovirus infection on ligands class I-like molecules in T cell activation.” Nature Immunol2(3):198 for the activating of NKG2D receptor of NK cells: up-regulation of 200 (Mar. 2001). UL 16-binding protein (ULBP) 1 and ULBP2 is counteracted by the Whiteside T. and Herberman R., “The role of natural killer cells in viral UL16 protein.” J. Immunol. 171:902-908, 2003. immune surveillance of cancer.” Curr Opin Immunol 7:704-710 Song et al., “Soluble ULBP suppresses natural killer cell activity via (1995). down-regulating NKG2D expression.” Cell. Immunol. 239:22-30, Yamabe et al., “Induction of the 2B9 antigen/dipeptidyl peptidase 2006. IV/CD26 on human natural killer cells by IL-2, IL-12 and IL-15.” Immunology 91:151-158 (1997). * cited by examiner U.S. Patent Jul. 21, 2009 Sheet 1 of 4 US 7,563,450 B2 100 ELA 90 ULBP -- ELA. 80 ULBP2 - ELA. 7O ULBP3 + ELA ULBP4 - ELA. 6O 5 O 4 O 3.O 20 10 Effector:Target Ratio Figure 1 U.S.
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