(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`1 May 2014 (01.05.2014)
`
`WIPOI PCT
`
`\9
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`(10) International Publication Number
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`WO 2014/066532 A1
`
`Agents: REMILLARD, Jane, E. et a1; Nelson Mullins
`Riley & Scarborough LLP, One Post Office Square, Bo-
`ston, MA 02109—2127 (US).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ,
`OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA,
`SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM,
`ZW.
`
`(51)
`
`International Patent Classification:
`C07K 16/28 (2006.01)
`A61P 35/00 (2006.01)
`A61K 39/395 (2006.01)
`
`(21)
`
`International Application Number:
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`PCT/US2013/066431
`
`(74)
`
`(81)
`
`(22)
`
`International Filing Date:
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`23 October 2013 (23.10.2013)
`
`(25)
`
`(26)
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`(30)
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`(71)
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`(72)
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`Filing Language:
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`Publication Language:
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`English
`
`English
`
`Priority Data:
`61/717,304
`
`23 October 2012 (23.10.2012)
`
`US
`
`Applicants: BRISTOL-MYERS SQUIBB COMPANY
`[US/US]; Route 206 & Province Line Road, Princeton, NJ
`08543 (US). INNATE PHARMA [i/FR]; 117 Avenue
`De Luminy, F-13009 Marseille (FR).
`
`Inventors: GRAZIANO, Robert, F.; Route 206 &
`Province Line Road, Princeton, NJ 08543 (US). GUPTA,
`Ashok, K.; Route 206 & Province Line Rd., Princeton, NJ
`08543 (US). KIM, Su, Young; Route 206 & Province
`Line Rd., Princeton, NJ 08543 (US). WIGGINTON, Jon;
`Route 206 & Province Line Road, Princeton, NJ 08543
`(US). ANDRE, Pascale; 38 Rue De La Loubiere, F-13006
`Marseille (FR).
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`KM, ML, MR, NE, SN, TD, TG).
`Published:
`
`with international search report (Art. 21 (3))
`
`(54) Title: COMBINATION OF ANTI—KIR AND ANTI—CTLA—4 ANTIBODIES TO TREAT CANCER
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`(57) Abstract: Provided are methods for clinical treatment of cancer (e. g., solid tumors or hematological malignancies) using an an—
`ti-KIR antibody in combination with an anti-CTLA-4 antibody.
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`WO 2014/066532
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`PCT/USZOl3/066431
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`COMBINATION OF ANTI-KIR AND ANTI-CTLA-4 ANTIBODIES
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`TO TREAT CANCER
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`BACKGROUND
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`Natural killer (NK) cells constitute 15% of peripheral blood lymphocytes and
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`play an important role in the ability of the innate immune system to fight off viral
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`infections and also cancer (Purdy AK et al. (2009) Cancer Biol Ther 8:13—22). NK
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`cells bind to target cells through multiple receptors, including natural cytotoxicity
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`receptors (NCR), the Fc receptor CD16, NKG2D, and others. Binding of ligand to
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`receptor initiates tyrosine phosphorylation and recruitment of accessory signaling
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`molecules. This cascade results in activation of the NK cell, release of preformed
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`granules containing perforin and granzymes into the target cell, and apoptosis. The
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`concurrent release of cytokines and chemokines results in a micro—environmental
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`milieu that recruits other immune cells.
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`NK cells have the capability of binding every cell in the body (Murphy W] et al.
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`(2012) Biol Blood Marrow Transplant 18:82-87). However, binding of normal cells
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`does not result in cytotoxic activity because of the ability of NK cells to
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`simultaneously utilize a different set of receptors to bind major histocompatibility
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`complex (MHC) class I molecules. Binding of human leukocyte antigen (HLA) E to
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`the NKG2A/CD94 heterodimeric receptor, or of HLA—A, B and C molecules to
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`inhibitory killer Ig—like receptors (1(le), results in tyrosine phosphorylation,
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`recruitment of the signaling adaptors SHP—l or SHP—2, and downstream signaling.
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`The end result is a dominant signal that suppresses normal activation signals. Thus,
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`KIR/HLA interaction can impact NK cell responsiveness and also the development of
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`the total number of mature responsive NK cells, known as licensing.
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`There are seven inhibitory KIRs and seven activating KIRs, which is one
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`factor that results in diversity of KIR inheritance and expression. KIR is also
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`expressed on natural killer T (NKT) cells and a small subset of T cells (Uhrberg M et
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`al. (2001) J Immunol 166:3923—3932). Thus, mechanistically, blockade of inhibitory
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`KIR could induce anti—tumor effects by allowing for activation of NK cell and
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`Evidence in support of NK cell involvement in the anti—tumor response comes
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`from the hematopoietic stem cell transplant (HSCT) setting. Given the diversity in
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`both KIR and HLA, it is not surprising that KIR on donor NK cells may not interact
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`with host HLA, referred to as KIR mismatch. The finding that AML patients
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`transplanted with KIR mismatched donor NK cells had lower relapse rates (3% versus
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`47%, p <0.01) and reduced risk of relapse (relative risk 0.48, 95% CI 0.29—0.78) gave
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`scientific support for the role of NK cells in the anti—tumor response (Ruggeri L et
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`al. (2007) Blood 110:433—440).
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`In melanoma, certain KIR and HLA combinations may provide a more
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`immunosuppressive environment, since certain combinations are seen more
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`frequently in metastatic patients compared to non—metastatic patients (Naumova E et
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`al. (2005) Cancer Immunol Immunother 54: 172— 178). KIR mismatch has been shown
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`to be a favorable prognostic marker for high risk neuroblastoma patients undergoing
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`autologous HSCT (Delgado DC et al. (2010) Cancer Res 70:9554—9561).
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`Experimental support for the important role of NK cells in solid tumors comes from
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`murine studies in which mice lacking T cells could still eradicate large solid tumors
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`following NK cell activation by the addition of IL—15 (Liu RB et al. (2012) Cancer
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`Res 72: 1964— 1974).
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`Full activation of naive T cells requires stimulation of the antigen receptor by
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`peptide—maj or histocompatibility complexes and by co—stimulatory signals. These
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`signals are provided by the engagement of CD28, which is constitutively expressed on
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`T cell surfaces, with CD80 (B7.1) and CD86 (B7.2) molecules, which are present on
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`antigen presenting cells (APCs). Cytotoxic T lymphocyte antigen 4 (CTLA—4;
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`CD152) is an activation—induced T cell surface molecule that also binds to CD80 and
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`CD86, but with greater avidity than CD28. CTLA—4 ligation down—regulates T cell
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`responses, which results in abrogation of the effects provided by T cell activation.
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`The blockade of CTLA—4 interaction with CD80/86 results in increased T cell
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`activation. Ipilimumab (Yervoy®) is a fully human IgGlK monoclonal antibody
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`targeting CTLA—4 that inhibits the negative downstream signaling that occurs when
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`CTLA-4 engages its ligands, CD80 and CD86, on APCs. As a result, activated T
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`cells are able to maintain their CD28 mediated signaling resulting in IL-2 secretion
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`and proliferation of CD8 T cells in response to an antigen.
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`Ipilimumab is currently approved for the treatment of metastatic melanoma,
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`for which it has shown an overall survival advantage (Hodi FS et al. (2010) N Engl J
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`Med 363:711—723). Administration of 4 doses of ipilimumab alone or in combination
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`with a gpl 00 peptide vaccine improved survival by 4 months compared with the
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`administration of gp100 vaccine alone in subjects with metastatic melanoma who had
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`progressed after chemotherapy or IL—2 therapy.
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`Patients with metastatic or refractory tumors have very poor prognosis
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`(Rosenberg SA et al. (2011) Cancer immanorherapy in Cancer: Principles & Practice
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`of Oncology (Eds. DeVita VT, Lawrence TS and Rosenberg SA) 332—344 (Lippincott
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`Williams & Wilkins, Philadelphia PA)). Despite advances in multimodal therapy,
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`increases in overall survival in this patient population have been limited.
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`Accordingly, it is an object of the present invention to provide improved methods for
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`treating subjects with such tumors (e. g., advanced solid tumors).
`
`SUMMARY
`
`Provided herein are methods for treating cancer, e.g., advanced solid tumors or
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`hematological malignancies, in a human patient, comprising administering to the patient a
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`combination of an anti—KIR antibody and an anti—CTLA—4 antibody, wherein the
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`combination is administered (or is for administration) according to a particular clinical
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`dosage regimen (i.e., at a particular dose amount and according to a specific dosing
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`schedule).
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`In one embodiment, the human patient suffers from non—small cell lung cancer
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`(NSCLC), castrate resistant prostate cancer (CRPC) or melanoma.
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`An exemplary anti—KIR antibody is lirilumab (also known as EMS—986015 or
`
`IPH2012) comprising the heavy and light chains having the sequences shown in SEQ ID
`
`NOs:l and 2, respectively, or antigen binding fragments and variants thereof.
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`In other
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`embodiments, the antibody comprises the heavy and light chain complementarity
`
`determining regions (CDRs) or variable regions (VRs) of lirilumab. Accordingly, in one
`
`embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy
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`chain variable (VH) region of lirilumab having the sequence shown in SEQ ID NO:3, and
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`the CDR1, CDR2 and CDR3 domains of the light chain variable (VL) region of lirilumab
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`having the sequence shown in SEQ ID NO:5. In another embodiment, the antibody
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`comprises CDR1, CDR2 and CDR3 heavy chain sequences set forth in SEQ ID NOs:7, 8,
`
`and 9, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in
`
`SEQ ID NOs: 10, 11, and 12, respectively. In another embodiment, the antibody
`
`comprises VH and/or VL regions having the amino acid sequences set forth in SEQ ID
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`N023 and/or SEQ ID NO:5, respectively. In another embodiment, the antibody comprises
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`the VH and/or VL regions encoded by the nucleic acid sequences set forth in SEQ ID
`
`NO:4 and/or SEQ ID NO:6, respectively. In another embodiment, the antibody competes
`
`for binding with, and/or binds to the same epitope on KIR as, the above—mentioned
`
`antibodies. In another embodiment, the antibody has at least about 90% variable region
`
`amino acid sequence identity with the above—mentioned antibodies (e. g., at least about
`
`90%, 95% or 99% variable region identity with SEQ ID NO:3 or SEQ ID NO:5).
`
`An exemplary anti—CTLA—4 antibody is ipilimumab (also known as lODl, MDX—
`
`OlO, MDX— 101, and Yervoy®) comprising heavy and light chains having the sequences
`
`shown in SEQ ID NOs: l7 and 18, respectively, or antigen binding fragments and variants
`
`thereof (see, e. g., WOOl/ 14424). In other embodiments, the antibody comprises the
`
`heavy and light chain CDRs or VRs of ipilimumab. Accordingly, in one embodiment, the
`
`antibody comprises the CDRl, CDR2, and CDR3 domains of the VH region of
`
`ipilimumab having the sequence shown in SEQ ID NO: 19, and the CDRl, CDR2 and
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`CDR3 domains of the VL region of ipilimumab having the sequence shown in SEQ ID
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`NO:20. In another embodiment, the antibody comprises the heavy chain CDRl, CDR2
`
`and CDR3 domains having the sequences set forth in SEQ lD NOsz2l, 22, and 23,
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`respectively, and the CDRl, CDR2 and CDR3 domains having the sequences set forth in
`
`SEQ ID NOs: 24, 25, and 26, respectively. In another embodiment, the antibody
`
`comprises VH and/or VL regions having the amino acid sequences set forth in SEQ ID
`
`NO: 19 and/or SEQ ID NO:20, respectively. In another embodiment, the antibody
`
`competes for binding with and/or binds to the same epitope on CTLA-4 as the above—
`
`mentioned antibodies. In another embodiment, the antibody has at least about 90%
`
`variable region amino acid sequence identity with the above—mentioned antibodies (e. g., at
`
`least about 90%, 95%, or 99% variable region identity with SEQ ID NO: 19 or SEQ ID
`
`NO:20).
`
`Accordingly, in one aspect, methods of treating solid tumors (e.g., advanced
`
`solid tumors) in a human patient are provided, the methods the method comprising:
`
`administering to the patient, an effective amount of each of:
`
`(a) an anti-KIR antibody comprising the CDRl, CDR2 and CDR3 domains in
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`a heavy chain variable region having the sequence set forth in SEQ ID NO:3, and the
`
`CDRl, CDR2 and CDR3 domains in a light chain variable region having the sequence
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`set forth in SEQ ID NO:5, and
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`(b) an anti—CTLA—4 antibody comprising the CDR1, CDR2 and CDR3
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`domains in a heavy chain variable region having the sequence set forth in SEQ ID
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`NO: 19, and the CDR1, CDR2 and CDR3 domains in a light chain variable region
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`having the sequence set forth in SEQ ID NO:20,
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`wherein the anti—KIR antibody and anti-CTLA-4 antibody are first
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`administered in combination (A) every 3 weeks for a total of 4 doses over 12 weeks
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`during an induction phase, followed by (B) every 12 weeks for 4 doses starting at
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`week 24 during a maintenance phase, and
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`wherein the anti—KIR antibody is administered at a dose of 0.1—20 mg/kg body
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`weight and the anti—CTLA—4 antibody is administered at a dose of 0.1—20 mg/kg body
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`weight during both the induction and maintenance phases.
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`In certain embodiments, each dose of the anti—KIR antibody is administered at
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`0.1, 0.3, 1, 3, 5 or 10 mg/kg. In preferred embodiments, each dose of the anti—KIR
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`antibody is administered at 0.3, 1 or 3 mg/kg.
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`In other embodiments, each dose of the anti—CTLA—4 antibody is administered
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`at 0.1, 0.3, 1, 3, 5 or 10 mg/kg body weight. In preferred embodiments, each dose of
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`the anti—CTLA—4 antibody is administered at 1, 3 or 10 mg/kg. In more preferred
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`embodiments, the anti—CTLA—4 antibody is administered at a dose of 3 mg/kg.
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`In one embodiment, the anti—KIR antibody and anti—CTLA—4 antibody are
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`administered at the following doses during either the induction or maintenance phase:
`
`(a)
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`(b)
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`(c)
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`(d)
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`(e)
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`(f)
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`0.1 mg/kg anti—KIR antibody and 3 mg/kg of anti—CTLA—4 antibody;
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`0.3 mg/kg anti-KIR antibody and 3 mg/kg of anti-CTLA-4 antibody;
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`1 mg/kg anti-KIR antibody and 3 mg/kg of anti-CTLA-4 antibody;
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`3 mg/kg anti—KIR antibody and 3 mg/kg of anti—CTLA—4 antibody;
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`3 mg/kg anti—KIR antibody and 10 mg/kg of anti—CTLA—4 antibody; or
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`10 mg/kg anti—KIR antibody and 10 mg/kg of anti—CTLA—4 antibody.
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`Accordingly, in certain embodiments, the doses of the anti—KIR and/or anti—
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`CTLA—4 antibody are calculated in mg of antibody per kg body weight of patient
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`(mg/kg). However, in other embodiments, the dose of the anti-KIR and/or anti-PD—1
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`antibody is a flat—fixed dose that is fixed irrespective of the weight of the patient. For
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`example, the anti—KIR and/or anti—CTLA—4 antibody may be administered at a fixed
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`dose of 5, 20, 75, 200, 400, 750 or 1500 mg, without regard to the patient’s weight.
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`In certain embodiments, the administered dose of the anti—CTLA—4 antibody may be
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`U1
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`fixed at 200 or 750 mg, while the anti—KIR antibody is administered at a fixed dose of
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`5, 20, 75, 200, 400 or 750 mg.
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`In another embodiment, dosage regimens are adjusted
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`to provide the optimum desired response (e.g., an effective response).
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`In other embodiments, the anti—KIR and/or anti—CTLA—4 antibodies are
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`administered on (1) day 1, week 1, (2) day 22, week 4, (3) day 43, week 7, and (4)
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`day 64, week 10 of the induction phase. In another embodiment, the induction phase
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`ends on day 84 of week 12. In another embodiment, the anti—KIR and anti—CTLA—4
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`antibodies are administered on day l of week 24, day l of week 36, day l of week 48,
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`and day 1 of week 60 of the maintenance phase.
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`In one embodiment, the anti—PD—l antibody and anti—CTLA—4 antibody are
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`administered as a first ("front") line of treatment (e.g., the initial or first treatment). In
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`another embodiment, the anti—PD—l antibody and anti—CTLA—4 antibody are
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`administered as a second line of treatment (e. g., after initial treatment with the same
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`or a different therapeutic, including after relapse and/or where the first treatment has
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`failed).
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`The anti—KIR and anti—CTLA—4 antibodies described herein can be
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`administered to a subject by any suitable means. In one embodiment, the antibodies
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`are formulated for intravenous administration.
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`ln another embodiment, the antibodies
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`are administered simultaneously (e. g., in a single formulation or concurrently as
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`separate formulations). Alternatively, in another embodiment, the antibodies are
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`administered sequentially (e.g., as separate formulations).
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`The efficacy of the treatment methods provided herein can be assessed using
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`any suitable means. In one embodiment, the treatment produces at least one
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`therapeutic effect selected from the group consisting of reduction in size of a tumor,
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`reduction in number of metastasic lesions over time, complete response, partial
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`response, and stable disease.
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`Also provided are kits that include a pharmaceutical composition containing
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`an anti—KIR antibody, such as lirilumab, and an anti—CTLA—4 antibody, such as
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`ipilimumab, and a pharmaceutically—acceptable carrier, in a therapeutically effective
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`amount adapted for use in the methods described herein. In one embodiment, the kit
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`comprises:
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`(a) a dose of an anti—KIR antibody comprising the CDRl, CDR2 and CDR3
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`domains in a heavy chain variable region having the sequence set forth in SEQ ID
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`NO:3, and the CDRl, CDR2 and CDR3 domains in a light chain variable region
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`having the sequence set forth in SEQ ID NO:5;
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`(b) a dose of an anti—CTLA—4 antibody comprising the CDRl, CDR2 and
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`CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ
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`ID NO: 19, and the CDR1, CDR2 and CDR3 domains in a light chain variable region
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`having the sequence set forth in SEQ ID NO:20,
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`(c) instructions for using the anti—KIR antibody and anti—CTLA—4 antibody in
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`the methods of the invention.
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`In another aspect, an anti—KIR antibody is provided, the anti—KIR antibody
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`comprising the CDRl, CDR2 and CDR3 domains in a heavy chain variable region
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`having the sequence set forth in SEQ ID NO:3, and the CDRl, CDR2 and CDR3
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`domains in a light chain variable region having the sequence set forth in SEQ ID
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`NO:5, for co-administration with an anti-CTLA—4 antibody comprising the CDR1,
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`CDR2 and CDR3 domains in a heavy chain variable region having the sequence set
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`forth in SEQ ID NO: 19, and the CDRl, CDR2 and CDR3 domains in a light chain
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`variable region having the sequence set forth in SEQ ID NO:20,
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`wherein the anti—KIR antibody and anti—CTLA—4 antibody are first
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`administered in combination (A) every 3 weeks for a total of 4 doses over 12 weeks
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`during an induction phase, followed by (B) every 12 weeks for 4 doses starting at
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`week 24 during a maintenance phase, and
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`wherein the anti—KIR antibody is administered at a dose of 0.1, 0.3, 1, or 3
`
`mg/kg and the anti-CTLA-4 antibody is administered at a dose of 3 or 10 mg/kg
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`during both phases.
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`In another aspect of the invention, the anti—CTLA—4 antibody in any of the
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`aforementioned embodiments is replaced by, or combined with, an immunoregulatory
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`checkpoint inhibitor, for example an inhibitor of the PD—l pathway such as an anti—
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`PD—l , anti—PD—Ll or anti—PD—L2 antibody. Exemplary anti—PD—l antibodies are
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`described in WO 2006/121168, WO 2008/156712, WO 2012/145493, WO
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`2009/014708 and WO 2009/114335, the teachings of which are hereby incorporated
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`into this application by reference. Exemplary anti-PD—Ll antibodies are described in
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`WO 2007/005874, WO 2010/077634 and WO 2011/066389, and exemplary anti-PD—
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`L2 antibodies are described in WO 2004/007679, the teachings of all of which are
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`hereby incorporated by reference; Accordingly, the invention also features methods,
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`compositions and kits for treating cancer in human patients using the above—described
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`clinically effective dosages of an anti—KIR antibody combined with the above—
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`described clinically effective dosages of an anti—CTLA—4 antibody, wherein the
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`dosage of the anti—CTLA—4 antibody is replaced by the same dosage of an anti—PD—l,
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`anti—PD—Ll or anti—PD—L2 antibody.
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`BRIEF DESCRIPTION OF THE DRAWINGS
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`Figure 1 shows the anti—tumor efficacy of anti—KIR and anti—CTLA—4 antibodies in a
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`murine acute myeloid leukemia (AML) model.
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`Figure 2 is a schematic illustrating dosing during the induction phase for dose
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`escalation and cohort expansion.
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`Figure 3 is a schematic illustrating dosing during the maintenance phase for dose
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`escalation and cohort expansion.
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`I. Definitions
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`DETAILED DESCRIPTION
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`As used herein, the term "subject" or "patient" is a human cancer patient (e. g.,
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`a patient having an advanced solid tumor, such as an advanced refractory solid
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`tumor).
`
`As used herein, "cancer" is a term used for diseases in which abnormal cells
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`divide without control and are able to invade other tissues. Cancers include solid
`
`tumors and hematological tumors.
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`Solid tumors are neoplasms (new growth of cells) or lesions (damage of
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`anatomic structures or disturbance of physiological functions) formed by an abnormal
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`growth of body tissue cells other than blood, bone marrow or lymphatic cells. A solid
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`tumor consists of an abnormal mass of cells, which may stem from different tissue
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`types such as liver, colon, breast, or lung, and which initially grows in the organ of its
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`cellular origin. However, solid tumors may spread to other organs through metastatic
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`tumor growth in advanced stages of the disease.
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`Hematological tumors are cancer types affecting the blood, bone marrow, and
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`lymph nodes. Hematological tumors can derive from either of the two major blood
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`cell lineages, i.e., myeloid and lymphoid cell lines. The myeloid cell line normally
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`produces granulocytes, erythrocytes, thrombocytes, macrophages, and mast cells,
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`whereas the lymphoid cell line produces B, T, NK and plasma cells. Lymphomas
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`(e.g., Hodgkin's Lymphoma), lymphocytic leukemias, and myeloma are derived from
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`the lymphoid line, while acute and chronic myelogenous leukemia (AML, CML),
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`myelodysplastic syndromes and myeloproliferative diseases are myeloid in origin.
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`As used herein, an "advanced" cancer is a cancer that has migrated from its
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`original site to other areas of the body. In some cases, it is locally advanced in a vital
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`organ, but has not reached distant sites. In other cases, the cancer may have
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`metastasized or spread throughout the body through the lymph system or bloodstream.
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`As used herein, a "refractory cancer" (also known as a "resistant" cancer) is a
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`cancer that does not respond to treatment (e. g., the cancer may be resistant at the
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`beginning of treatment or it becomes resistant during treatment). In one embodiment,
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`the cancer is a refractory cancer that does not respond to anti—KIR therapy, anti—
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`CTLA-4 therapy, or standard therapy.As used herein, a "non—responder" is a subject
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`who does not respond to treatment. A "responder" is a subject who responds to
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`treatment (e. g., demonstrates some beneficial effect in response to treatment, such as
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`amelioration of at least one symptom of a disease or disorder).
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`As used herein, "effective treatment" refers to treatment producing a beneficial
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`effect, e.g., amelioration of at least one symptom of a disease or disorder. A
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`beneficial effect can take the form of an improvement over baseline, i.e., an
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`improvement over a measurement or observation made prior to initiation of therapy
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`according to the method. A beneficial effect can also take the form of arresting,
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`slowing, retarding, or stabilizing of a deleterious progression of a marker of solid
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`tumor. Effective treatment may refer to alleviation of at least one symptom of a solid
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`tumor. Such effective treatment may, e. g., reduce patient pain, reduce the size and/or
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`number of lesions, may reduce or prevent metastasis of a tumor, and/or may slow
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`tumor growth.
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`The term “effective amount” refers to an amount of an agent that provides the
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`desired biological, therapeutic, and/or prophylactic result. That result can be
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`reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or
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`more of the signs, symptoms, or causes of a disease, or any other desired alteration of
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`a biological system. In reference to solid tumors, an effective amount comprises an
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`amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the
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`tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell
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`proliferation. In some embodiments, an effective amount is an amount sufficient to
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`delay tumor development. In some embodiments, an effective amount is an amount
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`sufficient to prevent or delay tumor recurrence. An effective amount can be
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`administered in one or more administrations. The effective amount of the drug or
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`composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii)
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`inhibit, retard, slow to some extent and may stop cancer cell infiltration into
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`peripheral organs; (iv) inhibit (i.e., slow to some extent and may stop tumor
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`metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or
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`recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms
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`associated with the cancer. In one example, an “effective amount” is the amount of
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`anti—KIR antibody and the amount of anti—CTLA—4 antibody, in combination,
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`clinically proven to effect a significant decrease in cancer or slowing of progression
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`of cancer, such as an advanced solid tumor.
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`As used herein, the terms "fixed dose", "flat dose" and "flat—fixed dose" are
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`used interchangeably and refer to a dose that is administered to a patient without
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`regard for the weight or body surface area (BSA) of the patient. The fixed or flat dose
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`is therefore not provided as a mg/kg dose, but rather as an absolute amount of the
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`agent (e. g., the anti—KIR antibody and/or anti—CTLA—4 antibody).
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`As used herein, a "body surface area (BSA)—based dose" refers to a dose (e.g.,
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`of the anti—KIR antibody and/or anti—CTLA—4 antibody) that is adjusted to the body—
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`surface area (BSA) of the individual patient. A BSA—based dose may be provided as
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`mg/kg body weight. Various calculations have been published to arrive at the BSA
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`without direct measurement, the most widely used of which is the Du Bois formula
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`(see Du Bois D and Du Bois EF (1916) Arch Internal Med 17 (6):863—71;
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`Verbraecken J et al. (2006) Metabolism 7 Clinical and Experimental 55 (4):515724).
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`Other exemplary BSA formulas include the Mosteller formula (Mosteller RD (1987)
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`NEngl JMed 317: 1098), the Haycock formula (Haycock GB et al. (1978) JPediatr
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`93:62—66), the Gehan and George formula (Gehan EA and George SL (1970) Cancer
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`Chemother Rep 54:225—235), the Boyd formula (Current JD (1998) The Internet
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`Journal ofAnesthesiology 2 (2); and Boyd, E (1935) University of Minnesota. The
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`Institute of Child Welfare, Monograph Series, No. x. London: Oxford University
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`Press), the Fujimoto formula (Fujimoto S et al. ( 1968) Nippon Eiseigaka Zasshi
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`5:443—50), the Takahira formula (Fujimoto S et al. (1968) Nippon Eiseigaku Zasshi
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`5:443—50), and the Schlich formula (Schlich E et al. (2010) Erna'hrangs Umschaa
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`57:178—183).
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`The term "antibody” describes polypeptides comprising at least one antibody
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`derived antigen binding site (e.g., VH/VL region or Fv, or CDR). Antibodies include
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`known forms of antibodies. For example, the antibody can be a human antibody, a
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`humanized antibody, a bispecific antibody, or a chimeric antibody. The antibody also
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`can be a Fab, Fab’2, ScFv, SMIP, Affibody®, nanobody, or a domain antibody. The
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`antibody also can be of any of the following isotypes: IgGl, IgG2, IgG3, IgG4, lgM,
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`IgAl, lgA2, IgAsec, IgD, and IgE. The antibody may be a naturally occurring
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`antibody or may be an antibody that has been altered (e. g., by mutation, deletion,
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`substitution, conjugation to a non—antibody moiety). For example, an antibody may
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`include one or more variant amino acids (compared to a naturally occurring antibody)
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`which changes a property (e. g., a functional property) of the antibody. For example,
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`numerous such alterations are known in the art which affect, e. g., half—life, effector
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`function, and/or immune responses to the antibody in a patient. The term antibody
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`also includes artificial polypeptide constructs which comprise at least one antibody—
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`derived antigen binding site.
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`As used herein, the terms “induction” and “induction phase” are used
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`interchangeably and refer to the first phase of treatment in the clinical trial. For
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`example, during induction, subjects may receive intravenous doses of an anti—KIR
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`antibody (e. g., lirilumab) in combination with an anti—CLTA—4 antibody (e. g.,
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`ipilimumab) every 3 weeks for a total of 4 doses.
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`As used herein, the terms “maintenance” and “maintenance phase” are used
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`interchangeably and refer to the second phase of treatment in the clinical trial. For
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`example, during maintenance, subjects may receive an anti—KIR antibody (e.g.,
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`lirilumab) in combination with an anti—CLTA—4 antibody (e. g., ipilimumab) therapy
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`every 12 weeks for an additional 4 doses starting at week 24. In certain embodiments,
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`treatment is continued as long as clinical benefit is observed or until unmanageable
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`toxicity or disease progression occurs.
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`As used herein, a “Killer Ig-like Receptor”, “Killer Inhibitory Receptor”, or
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`“KIR”, refers to a protein or polypeptide encoded by a gene that is a member of the
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`KIR gene family or by a cDNA prepared from such a gene. A detailed review of the
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`KIR gene family, including the nomenclature of KIR genes and KIR gene products,
`
`and Genbank accession numbers for exemplary Kle, is “The KIR Gene Cluster” by
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`M. Carrington and P. Norman, available at the NCBI web—site called “Bookshelf”
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`(accessible via the World—Wide Web (WWW) address ncbi.nlm.nih.gov/books). The
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`sequences of human KIR genes and cDNAs, as well as their protein products, are
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`available in public databases, including GenBank. Non—limiting exemplary GenBank
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`entries of human Kle have the following accession numbers: KIR2Dle Genbank
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`accession number U24076, NM_014218, , AAR16197, or L41267; KIR2DL2:
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`Genbank accession number U24075 or L76669; KIR2DL3: Genbank accession
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`number U24074 or L4l268; KIR2DL4: Genbank accession number X97229;
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`KIR2DSl: Genbank accession number X89892; KIR2DS2: Genbank accession
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`number L76667; KIR2DS3: Genbank accession number NM_Ol23 12 or L76670
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`(splice variant); KIR3DL1: Genbank accession number L41269; and KIR2DS4:
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`Genbank accession number AAR26325. A KIR may comprise from 1 to 3
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`extracellular domains, and may have a long (i. e., more than 40 amino acids) or short
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`(i.e., less than 40 amino acids) cytoplasmic tail. As previously described herein, these
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`features determine the nomenclature of a KIR. Exemplary KIR2DL1, KIR2DL2,
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`KIR2DL3, and KIR2DS4 molecules comprise polypeptides having the following
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`respective amino acid sequences:
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`KlR2DLl extracellular domain:
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`HEGVHRKPSLLAHPGXLVKSEETVILQCWSDVMFEHFLLHREGMFNDTLRLI
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`GEHHDGVSKANFSISRMTQDLAGTYRCYGSVTHSPYQVSAPSDPLDIVIIGLY
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`EKPSLSAQXGPTVLAGENVTLSCSSRSSYDMYHLSREGEAHERRLPAGPKVN
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`GTFQADFPLGPATHGGTYRCFGSFHDSPYEWSKSSDPLLVSVTGNPSNSWPSP
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`TEPSSKTGNPRHLH (SEQ ID NOzl3), where “X” at position 16 is P or R, and
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`where “X” at position 114 is P or L, representing allelic variants.
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`KIR2DL2 extracellular domain:
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`HEGVHRKPSLLAHPGRLVKSEETVILQCWSDVRFEHFLLHREGKFKDTLHLIG
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`EHHDGVS KANFSIGPMMQDLAGTYRCYGSVTHSPYQLSAPSDPLDIVITGLYE
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`KPSLSAQPGPTVLAGESVTLSCSSRSSYDMYHLSREGEAHECRFSAGPKVNGT
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`FQADFPLGPATHGGTYRCFGSFRDSPYEWSNSSDPLLVSVIGNPSNSWPSPTEP
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`SSKTGNPRHLH SEQ ID NO: 14)
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`KIR2DL3 extracellular domain:
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`HEGVHRKPSLLAHPGPLVKSEETVILQCWSDVRFQHFLLHREGKFKDTLHLIG
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`EHHDGVS KANFSIGPMMQDLAGTYRCYGSVT