WO2010036959A2 - Human anti-pd-1, pd-l1, and pd-l2 antibodies and uses therefor - Google Patents

Human anti-pd-1, pd-l1, and pd-l2 antibodies and uses therefor Download PDF

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Publication number
WO2010036959A2
WO2010036959A2 PCT/US2009/058475 US2009058475W WO2010036959A2 WO 2010036959 A2 WO2010036959 A2 WO 2010036959A2 US 2009058475 W US2009058475 W US 2009058475W WO 2010036959 A2 WO2010036959 A2 WO 2010036959A2
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WO
WIPO (PCT)
Prior art keywords
antibody
antigen
seq
binding fragment
isolated antibody
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/US2009/058475
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English (en)
French (fr)
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WO2010036959A3 (en
Inventor
Gordon Freeman
Rafi Ahmed
Timothy D. Jones
Francis J. Carr
James P. Gregson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dana Farber Cancer Institute Inc
Emory University
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Dana Farber Cancer Institute Inc
Emory University
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Priority to JP2011529280A priority Critical patent/JP6087503B2/ja
Priority to KR1020177037176A priority patent/KR101924874B1/ko
Priority to MX2011003195A priority patent/MX2011003195A/es
Priority to US13/120,406 priority patent/US8552154B2/en
Priority to AU2009296392A priority patent/AU2009296392B2/en
Priority to DK09816950.1T priority patent/DK2342226T3/en
Priority to KR1020117009345A priority patent/KR101814408B1/ko
Priority to EP09816950.1A priority patent/EP2342226B1/en
Priority to ES09816950.1T priority patent/ES2592216T3/es
Priority to KR1020187034308A priority patent/KR102097887B1/ko
Priority to MX2013007065A priority patent/MX349463B/es
Priority to KR1020197026614A priority patent/KR102197527B1/ko
Priority to BRPI0919377A priority patent/BRPI0919377A2/pt
Priority to CA2738252A priority patent/CA2738252C/en
Priority to EP16173372.0A priority patent/EP3133086B1/en
Application filed by Dana Farber Cancer Institute Inc, Emory University filed Critical Dana Farber Cancer Institute Inc
Priority to CN200980147059.0A priority patent/CN102264762B/zh
Priority to EP18175924.2A priority patent/EP3530672B1/en
Priority to SI200931522A priority patent/SI2342226T1/sl
Publication of WO2010036959A2 publication Critical patent/WO2010036959A2/en
Publication of WO2010036959A3 publication Critical patent/WO2010036959A3/en
Priority to IL211830A priority patent/IL211830A/en
Anticipated expiration legal-status Critical
Priority to US13/802,172 priority patent/US9102727B2/en
Priority to US14/822,651 priority patent/US10011656B2/en
Priority to IL249829A priority patent/IL249829A0/en
Priority to US15/995,584 priority patent/US10370448B2/en
Priority to IL265397A priority patent/IL265397B/en
Priority to US16/506,840 priority patent/US11261251B2/en
Ceased legal-status Critical Current

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    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
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Definitions

  • T cells For T cells to respond to foreign polypeptides, at least two signals must be provided by antigen-presenting cells (APCs) to resting T lymphocytes (Jenkins, M. and Schwartz, R. (1987) J. Exp. Med. 165:302-319; Mueller, D. L. et al. (1990) J. Immunol. 144:3701-3709).
  • the first signal which confers specificity to the immune response, is transduced via the T cell receptor (TCR) following recognition of foreign antigenic peptide presented in the context of the major histocompatibility complex (MHC).
  • TCR T cell receptor
  • MHC major histocompatibility complex
  • the second signal termed costimulation, induces T cells to proliferate and become functional (Lenschow et al. (1996) Annu. Rev.
  • B7-1 CD80
  • B7-2 CD86
  • B7-2 plays a predominant role during primary immune responses
  • B7-1 which is upregulated later during an immune response, may be important for prolonging primary T cell responses or costimulating secondary T cell responses (Bluestone (1995) Immunity 2:555).
  • CD28 is a ligand for both B7-1 and B7-2 that is constitutively expressed by resting T cells and increases in expression following T cell activation. Ligation of CD28 in conjunction with a TCR signal results in transduction of a costimulatory signal that induces T cells to proliferate and secrete IL-2 (Linsley, P. S. et al. (1991) J. Exp. Med. 173:721-730; Gimmi, C. D. et al. (1991) Proc. Natl. Acad. Sci. USA 88:6575-6579; June, C. H. et al. (1990) Immunol. Today 11:211-6; Harding, F. A. et al.
  • CTLA4 (CD 152)
  • CD28 A second B7-1 and B7-2 ligand, CTLA4 (CD 152)
  • CTLA4 expression occurs following T cell activation (Brunet, J. F. et al. (1987) Nature 328:267-270).
  • Ligation of CTLA4 results in transduction of an inhibitory signal that prevents T cell proliferation and cytokine secretion.
  • CTLA4 is a critical negative regulator of T cell responses (Waterhouse et al. (1995) Science 270:985) (Allison and Krummel (1995) Science 270:932).
  • the third member of the CD28 family to be discovered is ICOS (Hutloff et al.
  • PD-I programmed death 1
  • CD279 programmed death 1 receptor and its ligands
  • B7-H1 CD274
  • PD-L2 B7-DC; CD273
  • PD-I is a member of the CD28/CTLA4 family that is expressed on activated, but not resting T cells (Nishimura et al. (1996) Int. Immunol. 8:773).
  • PD-Ll is a B7 family member that is expressed on many cell types, including APCs and activated T cells (Yamazaki et al. (2002) J. Immunol. 169:5538). PD-Ll binds to both PD-I and B7-1. Both binding of T-cell-expressed B7-1 by PD-Ll and binding of T-cell-expressed PD-Ll by B7-1 result in T cell inhibition (Butte et al. (2007) Immunity 27: 111). There is also evidence that, like other B7 family members, PD-Ll can also provide costimulatory signals to T cells (Subudhi e/ 1 ⁇ /. (2004) J. Clin. Invest.
  • PD-L2 is a B7 family member expressed on various APCs, including dendritic cells, macrophages and bone-marrow derived mast cells (Zhong et al. (2007) Eur. J. Immunol. 37:2405). APC-expressed PD-L2 is able to both inhibit T cell activation through ligation of PD- 1 and costimulate T cell activation, through a PD-I independent mechanism (Shin et al. (2005) J. Exp. Med. 201:1531).
  • the present invention is based on the generation and isolation of novel composite, human monoclonal antibodies which specifically bind to human PD-I, human PD-Ll, and human PD-L2, as well as the characterization of such novel antibodies and the demonstration of their therapeutic value in treating a variety of conditions mediated by PD-I, PD-Ll, and/or PD- L2.
  • Common techniques used to humanize murine antibodies frequently produce humanized antibodies that have reduced antigen binding affinities compared to the original murine antibodies (Almagro and Fransson (2008) Frontiers in Bioscience 13:1619-1633; Foote and Winter (1992) J. MoI. Biol. 224:487-499; Hwang et al. (2005) Methods 36: 35-42).
  • the composite, human antibodies of the present invention have been shown to bind to PD-I, PD-Ll or PD-L2 with affinities closely approximating those of the murine antibodies.
  • conventional humanization techniques produce humanized antibodies that retain some murine sequence.
  • such antibodies can retain immunogenicity when administered to humans.
  • the humanized antibody CAMPATH® elicits immunogenicity in about 50% of patients.
  • the composite, human antibodies of the present invention are completely derived from sequences of human origin. Therefore, they are likely to be significantly less immunogenic and more therapeutically effective and useful when administered to human patients than other anti-human PD-I, PD-Ll, and/or PD-L2 antibodies.
  • the composite, human antibodies of the present invention provide an improved means for treating and preventing disorders mediated by PD-I, PD-Ll, and/or PD-L2, attributable in part to their unique specificity, affinity, structure, functional activity and the fact that they are derived from human antibody sequences.
  • the present invention is also based on the discovery of new therapeutic applications, including treatment of persistent infectious diseases, asthma, inflammatory diseases, and cancers, by administering the composite, human antibodies described herein.
  • One embodiment of the invention is an isolated antibody, or an antigen-binding fragment thereof, that binds to a PD-I protein, a PD-Ll protein, or a PD-L2 protein (such as human PD-I, PD-Ll, or PD-L2 protein), wherein the isolated antibody, or antigen-binding fragment thereof, is chimeric, humanized, composite, human or human, and comprising one, two, three, four, five, or six CDR sequences selected from the group consisting of SEQ ID NO: 7-24.
  • the invention also provides an isolated antibody, or an antigen-binding fragment thereof, that binds to a PD-I protein (such as a PD-I protein comprising the amino acid sequence of SEQ ID NO:2), wherein the isolated antibody, or antigen-binding fragment thereof, is chimeric, humanized, composite, human or human, and comprising a heavy chain variable region sequence comprising SEQ ID NOs:7-9 (CDRl sequence of SEQ ID NO:7, CDR2 sequence of SEQ ID NO:8, and CDR3 sequence of SEQ ID NO:9) and/or a light chain variable region sequence comprising SEQ ID NO: 10-12 (CDRl sequence of SEQ ID NO: 10, CDR2 sequence of SEQ ID NO: 11, and CDR3 sequence of SEQ ID NO: 12).
  • a PD-I protein such as a PD-I protein comprising the amino acid sequence of SEQ ID NO:2
  • the isolated antibody, or antigen-binding fragment thereof is chimeric, humanized, composite, human or human, and compris
  • the invention also provides an isolated antibody, or an antigen-binding fragment thereof, that binds to a PD-Ll protein (such as a PD-Ll protein comprising the amino acid sequence of SEQ ID NO:4), wherein the isolated antibody, or antigen-binding fragment thereof, is chimeric, humanized, composite, human or human, and comprising a heavy chain variable region sequence comprising SEQ ID NOs: 13- 15 (CDRl sequence of SEQ ID NO: 13, CDR2 sequence of SEQ ID NO: 14, and CDR3 sequence of SEQ ID NO: 15), and/or a light chain variable region sequence comprising SEQ ID NO:16-18 (CDRl sequence of SEQ ID NO:16, CDR2 sequence of SEQ ID NO: 17, and CDR3 sequence of SEQ ID NO: 18).
  • a PD-Ll protein such as a PD-Ll protein comprising the amino acid sequence of SEQ ID NO:4
  • the isolated antibody, or antigen-binding fragment thereof is chimeric, humanized, composite
  • the invention also provides an isolated antibody, or an antigen-binding fragment thereof, that binds to a PD-L2 protein (such as a PD-L2 protein comprising the amino acid sequence of SEQ ID NO:6), wherein the isolated antibody, or antigen-binding fragment thereof, is chimeric, humanized, composite, human or human, and comprising a heavy chain variable region sequence comprising SEQ ID NOs: 19-21 (CDRl sequence of SEQ ID NO: 19, CDR2 sequence of SEQ ID NO:20, and CDR3 sequence of SEQ ID NO:21), and/or a light chain variable region sequence comprising SEQ ID NO:22-24 (CDRl sequence of SEQ ID NO:22, CDR2 sequence of SEQ ID NO:23, and CDR3 sequence of SEQ ID NO:24).
  • a PD-L2 protein such as a PD-L2 protein comprising the amino acid sequence of SEQ ID NO:6
  • the isolated antibody, or antigen-binding fragment thereof is chimeric, humanized,
  • the invention also includes an isolated antibody, or an antigen-binding fragment thereof, that binds to a PD-I protein, a PD-Ll protein, or a PD-L2 protein (such as human PD-I, PD-Ll, or PD-L2 protein) wherein the isolated antibody, or antigen-binding fragment thereof, is chimeric, humanized, composite, and/or human, and comprising a heavy chain sequence selected from the group consisting of SEQ ID NO: 25-29, 34-38, or 43-47 or a sequence with at least about 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more identical homology to SEQ ID NO: 25-29, 34-38, or 43-47, and/or a light chain sequence selected from the group consisting of SEQ ID NO: 30-33, 39-42, or 48-51, or a sequence with at least about 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or
  • the invention also provides an isolated antibody, or an antigen-binding fragment thereof, that binds to a PD-I protein comprising the amino acid sequence of SEQ ID NO:2, wherein the isolated antibody, or antigen-binding fragment thereof, is chimeric, humanized, composite, or human, and comprising a heavy chain sequence selected from the group consisting of SEQ ID NO: 25-29, or a sequence with at least about 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more identical or homology to SEQ ID NO: 25-29, and/or a light chain sequence selected from the group consisting of SEQ ID NO: 30-33, or a sequence with at least about 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more identical or homology to SEQ ID NO: 30-33.
  • the antibody or antigen binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 27 or 28, and a light chain variable region sequence of SEQ ID NOs: 32 or 33.
  • the antibody or antigen binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 28, and a light chain variable region sequence of SEQ ID NOs: 32.
  • the invention also provides an isolated antibody, or an antigen-binding fragment thereof, that binds to a PD-Ll protein comprising the amino acid sequence of SEQ ID NO:4, wherein the isolated antibody, or antigen-binding fragment thereof, is chimeric, humanized, composite, or human, and comprising a heavy chain sequence selected from the group consisting of SEQ ID NO: 34-38, or a sequence with at least about 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more identical or homology to SEQ ID NO: 34-38, and/or a light chain sequence selected from the group consisting of SEQ ID NO: 39-42, or a sequence with at least about 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more identical or homology to SEQ ID NO: 39-42.
  • the antibody or antigen binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 35 or 37, and a light chain variable region sequence of SEQ ID NO: 39, 40 or 42.
  • the antibody or antigen binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 35, and a light chain variable region sequence of SEQ ID NO: 42.
  • the invention also provides an isolated antibody, or an antigen-binding fragment thereof, that binds to a PD-L2 protein comprising the amino acid sequence of SEQ ID NO:6, wherein the isolated antibody, or antigen-binding fragment thereof, is chimeric, humanized, composite, or human, and comprising a heavy chain sequence selected from the group consisting of SEQ ID NO: 43-47, or a sequence with at least about 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more identical or homology to SEQ ID NO: 43-47, and/or a light chain sequence selected from the group consisting of SEQ ID NO: 48-51, or a sequence with at least about 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more identical or homology to SEQ ID NO: 48-51.
  • the antibody or antigen binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 44 or 46, and a light chain variable region sequence of SEQ ID NO: 49, 50 or 51.
  • the antibody or antigen binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 46, and a light chain variable region sequence of SEQ ID NO: 51.
  • Another embodiment of the invention is an isolated antibody described herein, or an antigen-binding fragment thereof, that binds to a PD- 1 protein, wherein the isolated antibody inhibits the binding of biotinylated EH12.2H7 antibody to Fc-PD-I in a competition ELISA assay.
  • Another embodiment is an isolated antibody described herein, or an antigen-binding fragment thereof, that binds to a PD-Ll protein, wherein the isolated antibody inhibits the binding of biotinylated 29E2A3 antibody to Fc-PD-Ll in a competition ELISA assay.
  • Another embodiment is an isolated antibody described herein, or an antigen-binding fragment thereof, that binds to a PD-L2 protein, wherein the isolated antibody inhibits the binding of biotinylated 24F.10C12 antibody to Fc-PD-L2 in a competition ELISA assay.
  • Another embodiment of the invention is an isolated antibody described herein, or an antigen-binding fragment thereof, that binds to a PD- 1 protein, wherein the isolated antibody inhibits a PD-I -mediated signal.
  • Another embodiment is an isolated antibody described herein, or an antigen-binding fragment thereof, that binds to a PD-Ll protein wherein the isolated antibody inhibits a PD-Ll -mediated signal.
  • Another embodiment is an isolated antibody described herein, or an antigen-binding fragment thereof, that binds to a PD-L2 protein wherein the isolated antibody inhibits a PD-L2-mediated signal.
  • an embodiment of the invention is an isolated nucleic acid encoding a polypeptide, wherein the polypeptide comprises a sequence selected from the group consisting of SEQ ID NO: 25-51, or a sequence with at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical or homology to SEQ ID NO: 25-51.
  • Another embodiment is a vector, host cell or animal comprising one or more of these nucleic acids.
  • nucleic acid that hybridizes, under stringent conditions, with the complement of a nucleic acid encoding a polypeptide selected from the group consisting of SEQ ID NO: 25- 51, or a sequence with at least about at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical homology to SEQ ID NO: 25-51.
  • the invention also provides an isolated nucleic acid encoding a heavy chain variable region and/or a light chain variable region of any of the antibodies or antigen binding-fragments thereof described herein.
  • the nucleic acid is in a vector, such as an expression vector.
  • the invention also provides a host cell comprising one or more nucleic acids encoding the heavy and/or light chain of the antibodies or antigen-binding fragments described herein. In some embodiments, the host cell produces the antibodies or antigen-binding fragments.
  • the invention also provides methods of producing the antibody or antigen-binding fragment described herein, comprising culturing a cell that produces the antibody or antigen- binding fragment, and recovering the antibody or antigen-binding fragment from the cell culture.
  • the invention further includes a pharmaceutical composition, comprising an isolated antibody described herein, or an antigen-binding fragment thereof, and a pharmaceutically- acceptable carrier.
  • the invention encompasses a method of reactivating an exhausted T cell, comprising contacting a population of T cells wherein at least some cells express PD-, PD-Ll and/or PD-L2 using an antibody described herein or an antigen-binding fragment thereof either in vitro, ex vivo, or in vivo.
  • the invention further pertains to a method of treating a subject suffering from a persistent infection, including a viral infection, a bacterial infection, a helminth infection, or a protozoan infection, comprising administering to the subject a composition comprising an effective amount of an isolated antibody described herein, or an antigen-binding fragment thereof.
  • the invention further encompasses a method of treating cancer, comprising administering to the subject a composition comprising an effective amount of an isolated antibody described herein, or an antigen-binding fragment thereof, including wherein the isolated antibody induces antibody-mediated cytotoxicity or is modified to induce antibody- mediated cytotoxicity or conjugated to an agent selected from the group consisting of a toxin and an imaging agent.
  • the antibody or the antigen-binding fragment that binds to a PD-Ll is administered to the subject having a cancer over-expressing PD-Ll.
  • the antibody or the antigen-binding fragment that binds to a PD-L2 is administered to the subject having a cancer over-expressing PD-L2.
  • the invention further pertains to a method of treating a subject suffering from asthma, comprising administering to the subject a composition comprising an effective amount of an isolated antibody that binds to a PD-L2 protein described herein, or an antigen-binding fragment thereof.
  • the invention also encompasses a method of treating a subject suffering from an inflammatory disease or transplant rejection, comprising administering to the subject a composition comprising an effective amount of an isolated antibody described herein, or an antigen-binding fragment thereof, that binds to a PD-Ll protein or a PD-L2 protein.
  • the invention also encompasses an antibody, an antigen-binding fragment or a polypeptide described herein for use in any of the methods described herein.
  • the invention also encompasses the use of an antibody, an antigen-binding fragment or a polypeptide described herein for the manufacture of a medicament, such as a medicament for treating any of the diseases described herein in a subject.
  • Figure 1 shows a schematic diagram of expression vectors used for cloning the assembled human immunoglobulin sequences of the present invention.
  • Figures 2A-2E show composite, human heavy chain (Figure 2A, VHl; Figure 2B,
  • variable region sequences designed to correspond to that of the mouse anti-human PD-I antibody, EH12.2H7.
  • Figures 3A-3D show composite, human light chain (Figure 3A, V ⁇ l; Figure 3B, V ⁇ 2;
  • variable region sequences designed to correspond to that of the mouse anti-human PD-I antibody, EH12.2H7.
  • Figures 4A-4E show composite, human heavy chain (Figure 4A, VHl; Figure 4B,
  • variable region sequences designed to correspond to that of the mouse anti-human PD-Ll antibody, 29E.2A3.
  • Figures 5A-5D show composite, human light chain (Figure 5A, V ⁇ l; Figure 5B, V ⁇ 2;
  • variable region sequences designed to correspond to that of the mouse anti-human PD-Ll antibody, 29E.2A3.
  • Figures 6A-6E show composite, human heavy chain (Figure 6A, VHl; Figure 6B,
  • variable region sequences designed to correspond to that of the mouse anti-human PD-L2 antibody, 24F.10C12.
  • variable region sequences designed to correspond to that of the mouse anti-human PD-L2 antibody, 24F.10C12.
  • Figures 8A-8C show SDS-PAGE results of 1 ⁇ g of composite, human antibodies corresponding to the mouse anti-human antibodies, EH12.2H7, 29E.2A3, and 24F.10C12, respectively.
  • Figure 9A-9C show ELISA competition results of human antibodies corresponding to and relative to the mouse anti-human antibodies, EH12.2H7, 29E.2A3, and 24F.10C12, respectively.
  • the binding of the purified antibodies to human PD-I was tested via competition ELISA. Varying concentrations of each antibody (0.06 ⁇ g/ml to 8 ⁇ g/ml) were mixed with a fixed concentration of biotinylated EH12.2H7 (40 ng/ml) and bound to a PD-I coated immulon maxisorb plate. Binding was detected via streptavidin-HRP and OPD substrate.
  • Figure 13 shows the amino acid sequences of the variable regions of some of the Composite, Human Antibodies described herein.
  • Figures 14A and 14B shows effect of a humanized anti-PD- 1 antibody and a humanized anti-PD-Ll antibody on the proliferative capacity of SIV Gag-specific CD8 T cells in vitro. Each symbol represents an individual macaque. Numbers in parenthesis represent fold increase in proliferation in the presence of a blocking Ab compared to no blocking Ab. [0043] Figure 15 shows that PD-Ll blockage restores antigen-driven proliferation of intrahepatic CD8 T cells (representative data from animal 1564).
  • the present invention provides novel antibody-based therapeutics for treating and diagnosing a variety of disorders mediated by PD-I, PD-Ll, and/or PD-L2 (e.g., treatment of persistent infectious diseases, asthma, inflammatory diseases, transplant rejections and cancers).
  • PD-I PD-I
  • PD-Ll PD-L2
  • PD-I variants or isoforms which are naturally expressed by cells, and/or fragments thereof having at least one biological activity of the full-length polypeptide, unless otherwise expressly defined.
  • PD-I ligand includes either or both PD-Ll (Freeman et al. (2000J J. Exp. Med. 192:1027) and PD-L2 (Latchman et al. (2001) Nat. Immunol. 2:261) and any variants or isoforms which are naturally expressed by cells, and/or fragments thereof having at least one biological activity of the full-length polypeptides.
  • PD-I, PD-Ll, and PD-L2 sequences from different species, including humans are well known in the art (see, for example, herein incorporated in their entirety by reference, Honjo et al., U.S. Pat. No.
  • the term “antibody” includes whole antibodies and any antigen binding fragment (i.e., "antigen-binding portion") or single chain thereof.
  • An “antibody” refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CHl, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • CDRs Kabat Complementarity Determining Regions
  • the end of the Chothia CDR-Hl loop when numbered using the Kabat numbering convention varies between H32 and H34 (see below) depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35 A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34).
  • the AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular' s AbM antibody modeling software.
  • the "contact" hypervariable regions are based on an analysis of the available complex crystal structures. The residues from each of these hypervariable regions are noted below. Loop Kabat AbM Chothia Contact
  • Hypervariable regions may comprise "extended hypervariable regions” as follows: 24- 36 or 24-34 (Ll), 46-56 or 50-56 (L2) and 89-97 (L3) in the VL and 26-35B (Hl), 50-65, 47-65 or 49-65 (H2) and 93-102, 94-102 or 95-102 (H3) in the VH.
  • extended hypervariable regions are typically combinations of the Kabat and Chothia definitions, which may optionally further include residues identified using the Contact definition.
  • the variable domain residues are numbered according to Kabat et al., supra for each of these definitions.
  • "Framework" or "FR" residues are those variable-domain residues other than the HVR residues as herein defined.
  • variable-domain residue-numbering as in Kabat or "amino-acid- position numbering as in Kabat,” and variations thereof, refers to the numbering system used for heavy-chain variable domains or light-chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain.
  • a heavy-chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g. residues 82a, 82b, and 82c, etc. according to Kabat) after heavy-chain FR residue 82.
  • the Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a "standard" Kabat numbered sequence.
  • Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions.
  • the human IgG heavy-chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof.
  • the C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody.
  • a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue.
  • Suitable native- sequence Fc regions for use in the antibodies of the invention include human IgGl, IgG2 (IgG2A, IgG2B), IgG3 and IgG4.
  • Fc receptor or "FcR” describes a receptor that binds to the Fc region of an antibody.
  • the preferred FcR is a native sequence human FcR.
  • a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and alternatively spliced forms of these receptors, Fc ⁇ RII receptors include Fc ⁇ RIIA (an “activating receptor”) and Fc ⁇ RIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
  • Activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain.
  • ITAM immunoreceptor tyrosine-based activation motif
  • Inhibiting receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain, (see M. Daeron, Annu. Rev. Immunol. 1 ⁇ :203-234 (1997). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991); Capel et al, Immunomethods 4: 25-34 (1994); and de Haas et al, J. Lab. Clin. Med. 126: 330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term "FcR" herein.
  • ITIM immunoreceptor tyrosine-based inhibition motif
  • CDR complementarity determining region
  • CDRLl light chain variable region
  • CDRLHl heavy chain variable region
  • CDRH2 heavy chain variable region
  • CDRs contribute to the functional activity of an antibody molecule and are separated by amino acid sequences that comprise scaffolding or framework regions.
  • the exact definitional CDR boundaries and lengths are subject to different classification and numbering systems. CDRs may therefore be referred to by Kabat, Chothia, contact or any other boundary definitions, including the numbering system described herein.
  • CDR definitions according to these systems may therefore differ in length and boundary areas with respect to the adjacent framework region. See for example Kabat, Chothia, and/or MacCallum et al, (Kabat et al, in "Sequences of Proteins of Immunological Interest," 5 th Edition, U.S. Department of Health and Human Services, 1992; Chothia et al, J. MoI. Biol, 1987, 196: 901; and MacCallum et al, J. MoI. Biol., 1996, 262: 732, each of which is incorporated by reference in its entirety).
  • the term "antigen-binding portion" of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen ⁇ e.g., PD-I, PD-Ll, and/or PD-L2). It has been shown that the antigen- binding function of an antibody can be performed by fragments of a full-length antibody.
  • binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the V H , V L , CL and CHl domains; (ii) a F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the V H and CHl domains; (iv) a Fv fragment consisting of the V H and V L domains of a single arm of an antibody, (v) a dAb fragment (Ward et al, (1989) Nature 341:544 546), which consists of a V H domain; and (vi) an isolated complementarity determining region (CDR) or (vii) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker.
  • a Fab fragment a monovalent fragment consisting of the V H , V L , CL
  • the two domains of the Fv fragment, V H and V L are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the V H and V L regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al (1988) Science 242:423 426; and Huston et al (1988) Proc. Natl. Acad. Sci. USA 85:5879 5883).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody.
  • Antibodies may be polyclonal or monoclonal; xenogeneic, allogeneic, or syngeneic; or modified forms thereof (e.g., humanized, chimeric, etc.). Antibodies may also be fully human. Preferably, antibodies of the invention bind specifically or substantially specifically to PD-I, PD-Ll, or PD-L2 polypeptides.
  • human monoclonal antibody refers to an antibody which displays a single binding specificity and which has variable and constant regions derived from human germline or non-germline immunoglobulin sequences.
  • human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic non- human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.
  • an "isolated antibody” is intended to refer to an antibody which is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to PD-I, PD-Ll, or PD-L2 is substantially free of antibodies that do not bind to PD-I, PD-Ll, or PD-L2, respectively).
  • An isolated antibody that specifically binds to an epitope of PD-I, PD-Ll, and/or PD-L2 may, however, have cross- reactivity to other PD-I, PD-Ll, and/or PD-L2 proteins, respectively, from different species.
  • the antibody preferably always binds to human PD-I, PD-Ll, and/or PD-L2.
  • an isolated antibody is typically substantially free of other cellular material and/or chemicals.
  • a combination of "isolated" monoclonal antibodies having different specificities to PD-I, PD-Ll, and/or PD-L2 are combined in a well defined composition.
  • humanized antibody refers to an antibody that consists of the CDR of antibodies derived from mammals other than human, and the FR region and the constant region of a human antibody.
  • a humanized antibody is useful as an effective component in a therapeutic agent according to the present invention since antigenicity of the humanized antibody in human body is lowered.
  • composite antibody refers to an antibody which has variable regions comprising germline or non-germline immunoglobulin sequences from two or more unrelated variable regions.
  • composite, human antibody refers to an antibody which has constant regions derived from human germline or non-germline immunoglobulin sequences and variable regions comprising human germline or non-germline sequences from two or more unrelated human variable regions.
  • a composite, human antibody is useful as an effective component in a therapeutic agent according to the present invention since the antigenicity of the composite, human antibody in human body is lowered.
  • the term "recombinant human antibody” includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom (described further in Section I, below), (b) antibodies isolated from a host cell transformed to express the antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences.
  • Such recombinant human antibodies have variable and constant regions derived from human germline and/or non- germline immunoglobulin sequences.
  • such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V H and V L regions of the recombinant antibodies are sequences that, while derived from and related to human germline V H and V L sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • heterologous antibody is defined in relation to the transgenic non-human organism producing such an antibody. This term refers to an antibody having an amino acid sequence or an encoding nucleic acid sequence corresponding to that found in an organism not consisting of the transgenic non-human animal, and generally from a species other than that of the transgenic non-human animal.
  • K D is intended to refer to the dissociation equilibrium constant of a particular antibody-antigen interaction.
  • the term "specific binding” refers to antibody binding to a predetermined antigen.
  • the antibody binds with an affinity (K D ) of approximately less than 10 ⁇ 7 M, such as approximately less than 10 ⁇ 8 M, 10 ⁇ 9 M or 10 ⁇ 10 M or even lower when determined by surface plasmon resonance (SPR) technology in a BIACORE 3000 instrument using recombinant human PD-I, PD-Ll, or PD-L2 as the analyte and the antibody as the ligand, and binds to the predetermined antigen with an affinity that is at least Ll-, 1.2- , 1.3-, 1.4-, 1.5-, 1.6-, 1.7-, 1.8-, 1.9-, 2.0-, 2.5-, 3.0-, 3.5-, 4.0-, 4.5-, 5.0-, 6.0-, 7.0-, 8.0-, 9.0-, or 10.0-fold or greater than its affinity for binding to a non-specific antigen (K D ) of approximately less than 10
  • glycosylation pattern is defined as the pattern of carbohydrate units that are covalently attached to a protein, more specifically to an immunoglobulin protein.
  • a glycosylation pattern of a heterologous antibody can be characterized as being substantially similar to glycosylation patterns which occur naturally on antibodies produced by the species of the nonhuman transgenic animal, when one of ordinary skill in the art would recognize the glycosylation pattern of the heterologous antibody as being more similar to said pattern of glycosylation in the species of the nonhuman transgenic animal than to the species from which the CH genes of the transgene were derived.
  • the term "naturally- occurring" as applied to an object refers to the fact that an object can be found in nature.
  • a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory is naturally- occurring.
  • the term "rearranged” refers to a configuration of a heavy chain or light chain immunoglobulin locus wherein a V segment is positioned immediately adjacent to a D-J or J segment in a conformation encoding essentially a complete V H and V L domain, respectively.
  • a rearranged immunoglobulin gene locus can be identified by comparison to germline DNA; a rearranged locus will have at least one recombined heptamer/nonamer homology element.
  • the term "unrearranged” or "germline configuration" in reference to a V segment refers to the configuration wherein the V segment is not recombined so as to be immediately adjacent to a D or J segment.
  • nucleic acid molecule is intended to include DNA molecules and RNA molecules.
  • a nucleic acid molecule may be single-stranded or double- stranded, but preferably is double- stranded DNA.
  • isolated nucleic acid molecule in reference to nucleic acids encoding antibodies or antibody portions (e.g., V H, V L , CDR3) that bind to PD-I, PD-Ll, or PD- L2, is intended to refer to a nucleic acid molecule in which the nucleotide sequences encoding the antibody or antibody portion are free of other nucleotide sequences encoding antibodies or antibody portions that bind antigens other than PD-I, PD-Ll, or PD-L2, respectively, which other sequences may naturally flank the nucleic acid in human genomic DNA.
  • Figures 2-7 correspond to the nucleotide and amino acid sequences comprising the heavy chain (V H ) and light chain (V L ) variable regions of the human anti-PD-1, PD-Ll, or PD-L2 antibodies of the present invention, respectively.
  • the present invention also encompasses "conservative sequence modifications" of the sequences set forth in the figures (e.g., Figures 2-7), including nucleotide and amino acid sequence modifications which do not significantly affect or alter the binding characteristics of the antibody encoded by the nucleotide sequence or containing the amino acid sequence.
  • conservative sequence modifications include nucleotide and amino acid substitutions, additions and deletions.
  • Modifications can be introduced into the sequence set forth in the figures (e.g., Figures 2-7) by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.
  • Conservative amino acid substitutions include ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain.
  • Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
  • a predicted nonessential amino acid residue in a human anti-PD-1, anti-PD-Ll, or anti-PD-L2 antibody
  • mutations can be introduced randomly along all or part of a human anti-PD-1, PD-Ll, or PD-L2 antibody coding sequence, such as by saturation mutagenesis, and the resulting modified human anti-PD-1, anti-PD-Ll, or anti-PD-L2 antibodies can be screened for binding activity.
  • antibodies encoded by the heavy and light chain variable region nucleotide sequences disclosed herein and/or containing the heavy and light chain variable region amino acid sequences disclosed herein include substantially similar antibodies encoded by or containing similar sequences which have been conservatively modified. Further discussion as to how such substantially similar antibodies can be generated based on the sequences (i.e., heavy and light chain variable regions) disclosed herein (e.g., Figures 2-7) is provided below.
  • nucleic acids the term “substantial homology” indicates that two nucleic acids, or designated sequences thereof, when optimally aligned and compared, are identical, with appropriate nucleotide insertions or deletions, in at least about 80% of the nucleotides, usually at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, or more of the nucleotides, and more preferably at least about 97%, 98%, 99% or more of the nucleotides.
  • substantial homology exists when the segments will hybridize under selective hybridization conditions, to the complement of the strand.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.
  • the percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (available on the world wide web at the GCG company website), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6.
  • the percent identity between two nucleotide or amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4:11 17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. MoI. Biol. (48):444 453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available on the world wide web at the GCG company website), using either a Blosum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. [0080]
  • the nucleic acid and protein sequences of the present invention can further be used as a "query sequence" to perform a search against public databases to, for example, identify related sequences.
  • Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. MoI. Biol. 215:403 10.
  • Gapped BLAST can be utilized as described in Altschul et al, (1997) Nucleic Acids Res. 25(17):3389 3402.
  • the default parameters of the respective programs ⁇ e.g., XBLAST and NBLAST) can be used (available on the world wide web at the NCBI website).
  • the nucleic acids may be present in whole cells, in a cell lysate, or in a partially purified or substantially pure form.
  • a nucleic acid is "isolated” or “rendered substantially pure” when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, by standard techniques, including alkaline/SDS treatment, CsCl banding, column chromatography, agarose gel electrophoresis and others well known in the art. See, F. Ausubel, et al, ed. Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York (1987).
  • nucleic acid compositions of the present invention while often in a native sequence (except for modified restriction sites and the like), from either cDNA, genomic or mixtures thereof may be mutated, in accordance with standard techniques to provide gene sequences. For coding sequences, these mutations, may affect amino acid sequence as desired.
  • DNA sequences substantially homologous to or derived from native V, D, J, constant, switches and other such sequences described herein are contemplated (where "derived" indicates that a sequence is identical or modified from another sequence).
  • a nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence.
  • a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence.
  • operably linked means that the DNA sequences being linked are contiguous and, where necessary to join two protein coding regions, contiguous and in reading frame.
  • operably linked indicates that the sequences are capable of effecting switch recombination.
  • vector is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • plasmid refers to a circular double stranded DNA loop into which additional DNA segments may be ligated.
  • viral vector Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome.
  • Certain vectors are capable of autonomous replication in a host cell into which they are introduced ⁇ e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors).
  • vectors e.g., non-episomal mammalian vectors
  • vectors can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome.
  • certain vectors are capable of directing the expression of genes to which they are operatively linked.
  • Such vectors are referred to herein as "recombinant expression vectors” (or simply, “expression vectors”).
  • expression vectors of utility in recombinant DNA techniques are often in the form of plasmids.
  • plasmid and vector may be used interchangeably as the plasmid is the most commonly used form of vector.
  • the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.
  • viral vectors e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses
  • the term "recombinant host cell” is intended to refer to a cell into which a recombinant expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term "host cell” as used herein.
  • the term "subject” includes any human or non-human animal.
  • the methods and compositions of the present invention can be used to treat a subject with an inflammatory disease, such as arthritis, e.g., rheumatoid arthritis.
  • non-human animal includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dog, cow, chickens, amphibians, reptiles, etc.
  • modulate includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response.
  • the term “inhibit” includes the decrease, limitation, or blockage, of, for example a particular action, function, or interaction.
  • Immune cell refers to cells that play a role in the immune response. Immune cells are of hematopoietic origin, and include lymphocytes, such as B cells and T cells; natural killer cells; myeloid cells, such as monocytes, macrophages, eosinophils, mast cells, basophils, and granulocytes.
  • lymphocytes such as B cells and T cells
  • natural killer cells such as myeloid cells, such as monocytes, macrophages, eosinophils, mast cells, basophils, and granulocytes.
  • immune response includes T cell mediated and/or B cell mediated immune responses that are influenced by modulation of T cell costimulation.
  • exemplary immune responses include T cell responses, e.g., cytokine production, and cellular cytotoxicity.
  • immune response includes immune responses that are indirectly affected by T cell activation, e.g., antibody production (humoral responses) and activation of cytokine responsive cells, e.g., macrophages.
  • costimulate includes the ability of a costimulatory polypeptide to provide a second, non-activating receptor mediated signal (a "costimulatory signal") that induces proliferation and/or effector function.
  • a costimulatory signal can result in cytokine secretion, e.g., in a T cell that has received a T cell-receptor-mediated signal.
  • Immune cells that have received a cell- receptor mediated signal, e.g., via an activating receptor are referred to herein as "activated immune cells.”
  • the term "inhibitory signal” refers to a signal transmitted via an inhibitory receptor (e.g., CTLA4 or PD-I) for a polypeptide on an immune cell.
  • an inhibitory receptor e.g., CTLA4 or PD-I
  • Such a signal antagonizes a signal via an activating receptor (e.g., via a TCR or CD3 polypeptide) and can result in, e.g., inhibition of second messenger generation; an inhibition of proliferation; an inhibition of effector function in the immune cell, e.g., reduced phagocytosis, reduced antibody production, reduced cellular cytotoxicity, the failure of the immune cell to produce mediators, (such as cytokines (e.g., IL-2) and/or mediators of allergic responses); or the development of anergy.
  • mediators such as cytokines (e.g., IL-2) and/or mediators of allergic responses
  • the term "unresponsiveness” includes refractivity of immune cells to stimulation, e.g., stimulation via an activating receptor or a cytokine. Unresponsiveness can occur, e.g., because of exposure to immunosuppressants or exposure to high doses of antigen.
  • the term “anergy” or “tolerance” includes refractivity to activating receptor- mediated stimulation. Such refractivity is generally antigen- specific and persists after exposure to the tolerizing antigen has ceased. For example, anergy in T cells (as opposed to unresponsiveness) is characterized by lack of cytokine production, e.g., IL-2.
  • T cell anergy occurs when T cells are exposed to antigen and receive a first signal (a T cell receptor or CD-3 mediated signal) in the absence of a second signal (a costimulatory signal). Under these conditions, reexposure of the cells to the same antigen (even if reexposure occurs in the presence of a costimulatory polypeptide) results in failure to produce cytokines and, thus, failure to proliferate.
  • Anergic T cells can, however, proliferate if cultured with cytokines (e.g., IL-2).
  • cytokines e.g., IL-2
  • T cell anergy can also be observed by the lack of IL-2 production by T lymphocytes as measured by ELISA or by a proliferation assay using an indicator cell line.
  • a reporter gene construct can be used.
  • anergic T cells fail to initiate IL-2 gene transcription induced by a heterologous promoter under the control of the 5' IL-2 gene enhancer or by a multimer of the API sequence that can be found within the enhancer (Kang et al. (1992) Science 257: 1134).
  • the term "activity,” when used with respect to a polypeptide, e.g., PD- 1, PD-Ll, or PD-L2 polypeptide, includes activities which are inherent in the structure of the protein.
  • the term "activity” includes the ability to modulate immune cell costimulation (e.g. by modulating a costimulatory signal in an activated immune cell) or to modulate inhibition by modulating an inhibitory signal in an immune cell (e.g., by engaging a natural receptor on an immune cell).
  • a costimulatory signal can be generated in the immune cell.
  • a costimulatory signal can be generated in the immune cell.
  • an inhibitory signal is generated in the immune cell.
  • an inhibitory signal can be generated in the immune cell.
  • a PD-I ligand binds to a B7-1 polypeptide, an inhibitory signal can be generated (Butte et al. (2007) Immunity 27:111).
  • the term "activity" includes the ability of a PD-I polypeptide to modulate an inhibitory signal in an immune cell, e.g., by engaging a natural PD-I ligand on an antigen presenting cell.
  • PD-I transmits an inhibitory signal to an immune cell in a manner similar to CTLA4. Modulation of an inhibitory signal in an immune cell results in modulation of proliferation of, and/or cytokine secretion by, an immune cell.
  • the term "PD-I activity” includes the ability of a PD-I polypeptide to bind its natural ligand(s), the ability to modulate immune cell costimulatory or inhibitory signals, and the ability to modulate the immune response.
  • nucleic acid molecules that encode polypeptides of the present invention (e.g., those in Figures 2-7) or biologically active portions thereof, as well as nucleic acid fragments sufficient for use as hybridization probes to identify nucleic acid molecules encoding these polypeptides and fragments for use as PCR primers for the amplification or mutation of the nucleic acid molecules.
  • nucleic acid molecule is intended to include DNA molecules (e.g., cDNA or genomic DNA) and RNA molecules (e.g., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs.
  • the nucleic acid molecule can be single- stranded or double-stranded, but preferably is double- stranded DNA.
  • isolated nucleic acid molecule includes nucleic acid molecules which are separated from other nucleic acid molecules which are present in the natural source of the nucleic acid.
  • isolated includes nucleic acid molecules which are separated from the chromosome with which the genomic DNA is naturally associated.
  • an "isolated" nucleic acid molecule is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5' and 3' ends of the nucleic acid molecule) in the genomic DNA of the organism from which the nucleic acid is derived.
  • an "isolated" nucleic acid molecule such as a cDNA molecule
  • a nucleic acid molecule of the present invention can be isolated using standard molecular biology techniques and the sequence information provided herein.
  • a nucleic acid molecule encompassing all or a portion of sequences shown in Figures 2-7 can be isolated by the polymerase chain reaction (PCR) using synthetic oligonucleotide primers designed based upon the sequences shown in Figures 2-7.
  • a nucleic acid molecule of the invention can be amplified using cDNA, mRNA or, alternatively, genomic DNA as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques.
  • the nucleic acid molecule so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis.
  • oligonucleotides corresponding to nucleic acid sequences of the invention can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.
  • an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule which is a complement of a nucleic acid molecule of the present invention (e.g., those in Figures 2-7), or a portion thereof.
  • a nucleic acid molecule which is complementary to a nucleic acid molecule of the present invention (e.g., those in Figures 2-7), or a portion thereof, is one which is sufficiently complementary to the nucleotide sequence shown in Figures 2-7, such that it can hybridize to the respective nucleotide sequence shown in Figures 2-7, thereby forming a stable duplex.
  • an isolated nucleic acid molecule of the present invention comprises a nucleotide sequence which is at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the entire length of the nucleotide sequence shown in Figures 2-7, or a portion of any of these nucleotide sequences.
  • the nucleic acid molecule of the invention can comprise only a portion of a nucleic acid molecule of the present invention (e.g., those in Figures 2-7), or a portion thereof, for example, a fragment which can be used as a probe or primer or a fragment which encodes a portion of a polypeptide of the invention, e.g., those in Figures 2-7.
  • the probe/primer typically comprises substantially purified oligonucleotide.
  • the oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12 or 15, preferably about 20 or 25, more preferably about 30, 35, 40, 45, 50, 55, 60, 65, or 75 consecutive nucleotides of a nucleic acid molecule of the present invention (e.g., those in
  • Figures 2-7 ); of an anti-sense sequence of a nucleic acid molecule of the present invention (e.g., those in Figures 2-7); or of a mutant of a nucleic acid molecule of the present invention (e.g., those in Figures 2-7).
  • Probes based on a nucleic acid molecule of the present invention e.g., those in Figures
  • the probe further comprises a label group attached thereto, e.g., the label group can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor.
  • a nucleic acid fragment encoding a "biologically active portion of a polypeptide of the invention” can be prepared by isolating a portion of the nucleotide sequence of a nucleic acid molecule of the present invention (e.g., those in Figures 2-7) which encodes a polypeptide having a biological activity of a polypeptide of the invention (e.g., the ability to bind to its antigenic target), expressing the encoded portion of the polypeptide of the invention (e.g., by recombinant expression in vitro) and assessing the activity of the encoded portion of the polypeptide of the invention.
  • the invention further encompasses nucleic acid molecules that differ from nucleotide sequence(s) shown in Figures 2-7 due to degeneracy of the genetic code and thus encode the same polypeptides as those encoded by the respective nucleotide sequence shown in Figures 2-7.
  • an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a polypeptide of the present invention (e.g., those in Figures 2-7).
  • Nucleic acid molecules corresponding to homologues of a nucleic acid molecule of the present invention can be isolated based on their homology to the nucleic acids disclosed herein using the cDNAs disclosed herein, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.
  • an isolated nucleic acid molecule of the invention is at least 15, 20, 25, 30 or more nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising a nucleic acid molecule of the present invention (e.g., those in Figures 2-7).
  • hybridizes under stringent conditions is intended to describe conditions for hybridization and washing under which nucleotide sequences that are significantly identical or homologous to each other remain hybridized to each other.
  • the conditions are such that sequences at least about 70%, more preferably at least about 80%, even more preferably at least about 85% or 90% identical to each other remain hybridized to each other.
  • stringent conditions are known to those skilled in the art and can be found in Current Protocols in Molecular Biology, Ausubel et al., eds., John Wiley & Sons, Inc. (1995), sections 2, 4 and 6.
  • stringent hybridization conditions includes hybridization in 4x or 6x sodium chloride/sodium citrate (SSC), at about 65-70°C (or hybridization in 4x SSC plus 50% formamide at about 42-50°C) followed by one or more washes in Ix SSC, at about 65-70°C.
  • SSC sodium chloride/sodium citrate
  • a further non-limiting example of stringent hybridization conditions includes hybridization at 6x SSC at 45°C, followed by one or more washes in 0.2x SSC, 0.1% SDS at 65°C.
  • a non-limiting example of highly stringent hybridization conditions includes hybridization in Ix SSC, at about 65-70°C (or hybridization in Ix SSC plus 50% formamide at about 42-50°C) followed by one or more washes in 0.3x SSC, at about 65-70°C.
  • a non-limiting example of reduced stringency hybridization conditions includes hybridization in 4x or 6x SSC, at about 50-60°C (or alternatively hybridization in 6x SSC plus 50% formamide at about 40-45°C) followed by one or more washes in 2x, at about 50-60°C. Ranges intermediate to the above-recited values, e.g., at 65-70°C or at 42-50°C are also intended to be encompassed by the present invention.
  • SSPE 0.15M NaCl, 1OmM NaH 2 PO 4 , and 1.25 mM EDTA, pH 7.4
  • SSC 0.15M NaCl and 15mM sodium citrate
  • additional reagents may be added to hybridization and/or wash buffers to decrease non-specific hybridization of nucleic acid molecules to membranes, for example, nitrocellulose or nylon membranes, including but not limited to blocking agents (e.g., BSA or salmon or herring sperm carrier DNA), detergents (e.g., SDS), chelating agents (e.g., EDTA), Ficoll, PVP and the like.
  • blocking agents e.g., BSA or salmon or herring sperm carrier DNA
  • detergents e.g., SDS
  • chelating agents e.g., EDTA
  • Ficoll e.g., Ficoll, PVP and the like.
  • an additional non-limiting example of stringent hybridization conditions is hybridization in 0.25-0.5M NaH 2 PO 4 , 7% SDS at about 65°C, followed by one or more washes at 0.02M NaH 2 PO 4 , 1% SDS at 65°C, see e.g., Church and Gilbert (1984) Proc. Natl. Acad. Sci. USA 81:1991-1995 (or alternatively 0.2x SSC, 1% SDS).
  • nucleic acid molecule of the present invention e.g., those in Figures 2-7)
  • changes can be introduced by mutation into a nucleic acid molecule of the present invention (e.g., those in Figures 2-7), thereby leading to changes in the amino acid sequence of the encoded polypeptides of the present invention, without altering the functional ability of the polypeptides.
  • nucleotide substitutions leading to amino acid substitutions at "non-essential" amino acid residues can be made in a nucleic acid molecule of the present invention (e.g., those in Figures 2-7).
  • non-essential amino acid residue is a residue that can be altered from a nucleic acid molecule of the present invention (e.g., those in Figures 2-7) without altering the biological activity, whereas an "essential" amino acid residue is required for biological activity.
  • amino acid residues that are conserved among the polypeptides of the present invention, e.g., those required for binding of the polypeptides to its target antigen are predicted to be particularly unamenable to alteration.
  • nucleic acid molecules encoding polypeptides of the present invention (e.g., those in Figures 2-7) that contain changes in amino acid residues that are not essential for activity. Such polypeptides differ in amino acid sequence from those in Figures 2-7, yet retain biological activity.
  • the isolated nucleic acid molecule comprises a nucleotide sequence encoding a polypeptide, wherein the polypeptide comprises an amino acid sequence at least about 71%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to those in Figures 2-7.
  • An isolated nucleic acid molecule encoding a polypeptide identical to the polypeptides of those in Figures 2-7 can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of those in Figures 2-7 such that one or more amino acid substitutions, additions or deletions are introduced into the encoded polypeptide. Mutations can be introduced into nucleic acid molecules of the present invention (e.g., those in Figures 2-7) by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. In one embodiment, conservative amino acid substitutions are made at one or more predicted non-essential amino acid residues.
  • a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain.
  • Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta- branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
  • a predicted nonessential amino acid residue in a polypeptide of the invention can be replaced with another amino acid residue from the same side chain family.
  • mutations can be introduced randomly along all or part of a nucleic acid molecule(s) of the present invention (e.g., those in Figures 2-7), such as by saturation mutagenesis, and the resultant mutants can be screened for biological activity to identify mutants that retain activity.
  • the encoded polypeptide can be expressed recombinantly and the activity of the polypeptide can be determined.
  • a mutant polypeptide of the invention can be assayed for the ability to bind to and/or modulate the activity of a natural PD-I (e.g., PD-I ligands) or PD-I ligand partner (e.g., PD-I and B7-1), modulate intra- or intercellular signaling, modulate activation of T lymphocytes, and/or modulate the immune response of an organism.
  • a natural PD-I e.g., PD-I ligands
  • PD-I ligand partner e.g., PD-I and B7-1
  • Yet another aspect of the invention pertains to isolated nucleic acid molecules encoding fusion proteins.
  • nucleic acid molecules comprising at least a first nucleotide sequence encoding a polypeptide of the invention (e.g., those in Figures 2-7) operatively linked to a second nucleotide sequence encoding a polypeptide of the invention (e.g., those in Figures 2-7) can be prepared by standard recombinant DNA techniques.
  • nucleic acid molecules of the present invention within a cell line or microorganism may be modified by inserting a heterologous DNA regulatory element into the genome of a stable cell line or cloned microorganism such that the inserted regulatory element is operatively linked with the a nucleic acid molecules of the present invention (e.g., those in Figures 2-7).
  • a heterologous regulatory element may be inserted into a stable cell line or cloned microorganism, such that it is operatively linked with a nucleic acid molecules of the present invention (e.g., those in Figures 2-7), using techniques, such as targeted homologous recombination, which are well known to those of skill in the art, and described, e.g., in Chappel, U.S. Pat. No. 5,272,071; PCT publication No. WO 91/06667, published May 16, 1991.
  • polypeptides of the present invention including antibodies and antigen-binding fragments thereof described herein, and those in Figures 2-7), and biologically active portions thereof.
  • polypeptides of the present invention e.g., those in Figures 2-7), and biologically active portions thereof can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques.
  • polypeptides of the present invention e.g., those in Figures 2-7), and biologically active portions thereof are produced by recombinant DNA techniques.
  • polypeptides of the present invention e.g., those in Figures 2-7), and biologically active portions thereof can be chemically synthesized using standard peptide synthesis techniques.
  • an "isolated” or “purified” polypeptide or biologically active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the polypeptides of the present invention (e.g., those in Figures 2-7) is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized.
  • the language “substantially free of cellular material” includes preparations of polypeptide(s) of the present invention (e.g., those in Figures 2-7), and biologically active portions thereof, in which the polypeptide is separated from cellular components of the cells from which it is isolated or recombinantly produced.
  • the language "substantially free of cellular material” includes preparations of polypeptide(s) of the present invention (e.g., those in Figures 2-7), and biologically active portions thereof having less than about 30% (by dry weight) of proteins not of the present invention (also referred to herein as a "contaminating protein"), more preferably less than about 20% of proteins not of the present invention, still more preferably less than about 10% of proteins not of the present invention, and most preferably less than about 5% of proteins not of the present invention.
  • polypeptides of the present invention e.g., those in Figures 2-7) or biologically active portion thereof are recombinantly produced
  • it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% of the volume of the protein preparation.
  • the language "substantially free of chemical precursors or other chemicals” includes preparations of polypeptide(s) of the present invention (e.g., those in Figures 2-7) or biologically active portion thereof in which the polypeptide is separated from chemical precursors or other chemicals which are involved in the synthesis of the polypeptide.
  • the language "substantially free of chemical precursors or other chemicals” includes preparations of polypeptide(s) of the present invention (e.g., those in Figures 2-7) or biologically active portion thereof having less than about 30% (by dry weight) of chemical precursors or of proteins not of the present invention, more preferably less than about 20% chemical precursors or of proteins not of the present invention, still more preferably less than about 10% chemical precursors or of proteins not of the present invention, and most preferably less than about 5% chemical precursors or of proteins not of the present invention.
  • a "biologically active portion" of polypeptide(s) of the present invention include polypeptides which participates in an interaction between PD-I and a non-PD-1 molecule, PD-Ll and a non-PD-Ll molecule, or PD-L2 and a non-PD-L2 molecule, e.g., a natural ligand of PD-I, e.g., PD-I ligands, or a natural ligand of PD-I ligands, e.g., PD-I or B7-1, respectively.
  • Biologically active portions of a polypeptide(s) of the present invention include peptides comprising amino acid sequences sufficiently identical to or derived from the amino acid sequence of polypeptide(s) of the present invention (e.g., those in Figures 2-7), which include fewer amino acids than the respective, full length polypeptide(s) of the present invention (e.g., those in Figures 2-7), and exhibit at least one activity of the respective polypeptide(s) of the present invention (e.g., those in Figures 2-7).
  • biologically active portions comprise a domain or motif with the ability to specifically bind PD-I or a PD-Ll ligand according to the antigen, respectively, to which it was raised or designed to bind.
  • Biologically active portions of polypeptide(s) of the present invention e.g., those in Figures 2-7) can be used as targets for developing agents which modulate an activity mediated by PD-I, PD-Ll, or PD-L2, e.g., immune cell activation or suppression.
  • polypeptide(s) of the present invention has an amino acid sequence shown in Figures 2-7.
  • the polypeptide is substantially identical to polypeptide(s) shown in Figures 2-7, and retains the functional activity of the respective polypeptide(s) shown in Figures 2-7, yet differs in amino acid sequence due to mutagenesis, as described in detail in subsection I above.
  • a polypeptide(s) of the present invention is a polypeptide which comprises an amino acid sequence at least about 71%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96% 97%, 98%, 99%, 99.5%, or 99.9% or more identical to a polypeptide(s) shown in Figures 2-7.
  • the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-identical sequences can be disregarded for comparison purposes).
  • the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, and even more preferably at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% of the length of the reference sequence.
  • amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared.
  • a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid "identity” is equivalent to amino acid or nucleic acid "homology”).
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
  • the invention also provides chimeric or fusion proteins.
  • a "chimeric protein” or “fusion protein” comprises a polypeptide(s) of the present invention (e.g., those in Figures 2-7) operatively linked to a polypeptide not of the present invention.
  • a "polypeptide(s) of the present invention” refers to a polypeptide having an amino acid sequence corresponding to a polypeptide shown in Figures 2-7
  • a “polypeptide not of the present invention” refers to a polypeptide not having an amino acid sequence corresponding to a polypeptide which is not substantially homologous to a polypeptide shown in Figures 2-7, e.g., a polypeptide which is different from a polypeptide shown in Figures 2-7 and which is derived from the same or a different organism.
  • the term "operatively linked" is intended to indicate that the polypeptide(s) of the present invention and the polypeptide(s) not of the present invention are fused in-frame to each other.
  • the polypeptide(s) not of the present invention can be fused to the N-terminus or C-terminus of the polypeptide(s) of the present invention and corresponds to a moiety that alters the solubility, binding affinity, stability, or valency of the polypeptide(s) of the present invention.
  • the fusion protein is a GST fusion protein with a polypeptide(s) of the present invention.
  • Such fusion proteins can facilitate the purification of recombinant polypeptides of the invention.
  • the fusion protein contains a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of polypeptide(s) of the present invention can be increased through use of a heterologous signal sequence.
  • a chimeric or fusion polypeptide(s) of the present invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, for example by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation.
  • the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers.
  • PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, for example, Current Protocols in Molecular Biology, Ausubel et al., eds., John Wiley & Sons: 1992).
  • anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and reamplified to generate a chimeric gene sequence
  • many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide).
  • polypeptide(s) of the present invention e.g., those in Figures 2-7) identified herein will enable those of skill in the art to produce polypeptides corresponding to polypeptide(s) of the present invention (e.g., those in Figures 2-7).
  • polypeptides can be produced in prokaryotic or eukaryotic host cells by expression of polynucleotides encoding a polypeptide(s) of the present invention (e.g., those in Figures 2-7.
  • such peptides can be synthesized by chemical methods.
  • Antibodies to PD-I, PD-Ll, or PD-L2 described herein may be produced using any methods described herein or known in the art.
  • Monoclonal antibodies (e.g., human antibodies) of the invention can be produced using a variety of known techniques, such as the standard somatic cell hybridization technique described by Kohler and Milstein, Nature 256: 495 (1975). Although somatic cell hybridization procedures are preferred, in principle, other techniques for producing monoclonal antibodies also can be employed, e.g., viral or oncogenic transformation of B lymphocytes, phage display technique using libraries of human antibody genes.
  • One method for generating hybridomas which produce monoclonal antibodies of the invention is the murine system. Hybridoma production in the mouse is well known in the art, including immunization protocols and techniques for isolating and fusing immunized splenocytes.
  • Polyclonal antibodies can be prepared as described above by immunizing a suitable subject with a polypeptide immunogen.
  • the polypeptide antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized polypeptide.
  • ELISA enzyme linked immunosorbent assay
  • the antibody directed against the antigen can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as protein A chromatography to obtain the IgG fraction.
  • antibody- producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein (1975) Nature 256:495-497) (see also Brown et al. (1981) /. Immunol. 127:539-46; Brown et al. (1980) /. Biol. Chem. 255:4980-83; Yeh et al. (1976) Proc. Natl. Acad. ScL 76:2927-31; and Yeh et al. (1982) Int. J.
  • an immortal cell line (typically a myeloma) is fused to lymphocytes (typically splenocytes) from a mammal immunized with an immunogen as described above, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma producing a monoclonal antibody that binds to the polypeptide antigen, preferably specifically.
  • lymphocytes typically splenocytes
  • Any of the many well known protocols used for fusing lymphocytes and immortalized cell lines can be applied for the purpose of generating an anti-PD-1, PD-Ll, or PD-L2 monoclonal antibody (see, e.g., Galfre, G.
  • the immortal cell line ⁇ e.g., a myeloma cell line
  • murine hybridomas can be made by fusing lymphocytes from a mouse immunized with an immunogenic preparation of the present invention with an immortalized mouse cell line.
  • Preferred immortal cell lines are mouse myeloma cell lines that are sensitive to culture medium containing hypoxanthine, aminopterin and thymidine ("HAT medium").
  • HAT medium any of a number of myeloma cell lines can be used as a fusion partner according to standard techniques, e.g., the P3-NSl/l-Ag4-l, P3-x63-Ag8.653 or Sp2/O-Agl4 myeloma lines. These myeloma lines are available from the American Type Culture Collection (ATCC), Rockville, Md.
  • ATCC American Type Culture Collection
  • HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol ("PEG").
  • Hybridoma cells resulting from the fusion are then selected using HAT medium, which kills unfused and unproductively fused myeloma cells (unfused splenocytes die after several days because they are not transformed).
  • Hybridoma cells producing a monoclonal antibody of the invention are detected by screening the hybridoma culture supernatants for antibodies that bind a given polypeptide, e.g., using a standard ELISA assay.
  • a monoclonal specific for one of the above described polypeptides can be identified and isolated by screening a recombinant combinatorial immunoglobulin library ⁇ e.g., an antibody phage display library) with the appropriate polypeptide to thereby isolate immunoglobulin library members that bind the polypeptide.
  • Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No.
  • recombinant anti-PD-1, PD-Ll, or PD-L2_antibodies such as chimeric, composite, and humanized monoclonal antibodies, which can be made using standard recombinant DNA techniques, can be generated.
  • chimeric, composite, and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in Robinson et al. International Patent Publication PCT/US86/02269; Akira et al. European Patent Application 184,187; Taniguchi, M. European Patent Application 171,496; Morrison et al. European Patent Application 173,494; Neuberger et al.
  • antibody chains or specific binding pair members can be produced by recombination between vectors comprising nucleic acid molecules encoding a fusion of a polypeptide chain of a specific binding pair member and a component of a replicable generic display package and vectors containing nucleic acid molecules encoding a second polypeptide chain of a single binding pair member using techniques known in the art, e.g., as described in US patents 5,565,332, 5,871,907, or 5,733,743.
  • the use of intracellular antibodies to inhibit protein function in a cell is also known in the art (see e.g., Carlson, J. R. (1988) MoI. Cell. Biol. 8:2638-2646; Biocca, S. et al.
  • human monoclonal antibodies directed against PD-I, PD-Ll, or PD-L2 can be generated using transgenic or transchromosomal mice carrying parts of the human immune system rather than the mouse system.
  • transgenic mice referred to herein as "HuMAb mice” which contain a human immunoglobulin gene miniloci that encodes unrearranged human heavy ( ⁇ and ⁇ ) and K light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous ⁇ and K chain loci (Lonberg, N. et al. (1994) Nature 368(6474): 856 859).
  • mice exhibit reduced expression of mouse IgM or K, and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgG ⁇ monoclonal antibodies
  • the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgG ⁇ monoclonal antibodies
  • HuMAb mice The preparation of HuMAb mice is described in Taylor, L. et al.
  • an antibody for use in the invention is a bispecific antibody.
  • a bispecific antibody has binding sites for two different antigens within a single antibody polypeptide. Antigen binding may be simultaneous or sequential.
  • Triomas and hybrid hybridomas are two examples of cell lines that can secrete bispecific antibodies. Examples of bispecific antibodies produced by a hybrid hybridoma or a trioma are disclosed in U.S. Pat. 4,474,893. Bispecific antibodies have been constructed by chemical means (Staerz et al. (1985) Nature 314:628, and Perez et al. (1985) Nature 316:354) and hybridoma technology (Staerz and Bevan (1986) Proc. Natl. Acad. Sci.
  • Bispecific antibodies are also described in U.S. patent 5,959,084. Fragments of bispecific antibodies are described in US patent 5,798,229. Bispecific agents can also be generated by making heterohybridomas by fusing hybridomas or other cells making different antibodies, followed by identification of clones producing and co-assembling both antibodies. They can also be generated by chemical or genetic conjugation of complete immunoglobulin chains or portions thereof such as Fab and Fv sequences. The antibody component can bind to PD-I, PD-Ll, and/or a PD-L2 polypeptide.
  • the bispecific antibody could specifically bind to both a PD-I ligand and a PD-I polypeptide.
  • Yet another aspect of the invention pertains to anti-PD-1, PD-Ll, or PD-L2 polypeptide antibodies that are obtainable by a process comprising, immunizing an animal with an immunogenic PD-I, PD-Ll, or PD-L2 polypeptide, respectively, or an immunogenic portion thereof; and then isolating from the animal antibodies that specifically bind to the polypeptide.
  • partial or known antibody sequences can be used to generate and/or express new antibodies.
  • Antibodies interact with target antigens predominantly through amino acid residues that are located in the six heavy and light chain complementarity determining regions (CDRs). For this reason, the amino acid sequences within CDRs are more diverse between individual antibodies than sequences outside of CDRs. Because CDR sequences are responsible for most antibody-antigen interactions, it is possible to express recombinant antibodies that mimic the properties of specific naturally occurring antibodies by constructing expression vectors that include CDR sequences from the specific naturally occurring antibody grafted onto framework sequences from a different antibody with different properties (see, e.g., Riechmann, L. et al, 1998, Nature 332:323 327; Jones, P. et al, 1986, Nature 321:522 525; and Queen, C.
  • Such framework sequences can be obtained from public DNA databases that include germline or non-germline antibody gene sequences. These germline sequences will differ from mature antibody gene sequences because they will not include completely assembled variable genes, which are formed by V(D)J joining during B cell maturation. Germline gene sequences will also differ from the sequences of a high affinity secondary repertoire antibody at individual evenly across the variable region. For example, somatic mutations are relatively infrequent in the amino-terminal portion of framework region. For example, somatic mutations are relatively infrequent in the amino terminal portion of framework region 1 and in the carboxy-terminal portion of framework region 4.
  • Partial heavy and light chain sequence spanning the CDR regions is typically sufficient for this purpose.
  • the partial sequence is used to determine which germline and/or non-germline variable and joining gene segments contributed to the recombined antibody variable genes.
  • the germline and/or non-germline sequence is then used to fill in missing portions of the variable regions.
  • Heavy and light chain leader sequences are cleaved during protein maturation and do not contribute to the properties of the final antibody.
  • variable region cloned cDNA sequences can be combined with synthetic oligonucleotides by ligation or PCR amplification.
  • the entire variable region can be synthesized as a set of short, overlapping, oligonucleotides and combined by PCR amplification to create an entirely synthetic variable region clone.
  • This process has certain advantages such as elimination or inclusion or particular restriction sites, or optimization of particular codons.
  • the process can also be used to screen libraries of particular immunoglobulin encoding sequences in one species (e.g., human) to design cognate immunoglobulin encoding sequences from known antibody sequence in another species (e.g., mouse) (see, for example, the Examples section below).
  • the nucleotide sequences of heavy and light chain transcripts from a hybridoma are used to design an overlapping set of synthetic oligonucleotides to create synthetic V sequences with identical amino acid coding capacities as the natural sequences.
  • the synthetic heavy and kappa chain sequences can differ from the natural sequences in three ways: strings of repeated nucleotide bases are interrupted to facilitate oligonucleotide synthesis and PCR amplification; optimal translation initiation sites are incorporated according to Kozak's rules (Kozak, 1991, J. Biol. Chem. 266L19867019870); and, HindIII sites are engineered upstream of the translation initiation sites.
  • the optimized coding, and corresponding non-coding, strand sequences are broken down into 30-50 nucleotide approximately the midpoint of the corresponding non-coding oligonucleotide.
  • the oligonucleotides can be assembled into overlapping double stranded sets that span segments of 150-400 nucleotides. The pools are then used as templates to produce PCR amplification products of 150-400 nucleotides.
  • a single variable region oligonucleotide set will be broken down into two pools which are separately amplified to generate two overlapping PCR products. These overlapping products are then combined by PCR amplification to form the complete variable region.
  • the heavy and light chain expression constructs can be combined into a single vector, co-transfected, serially transfected, or separately transfected into host cells which are then fused to form a host cell expressing both chains.
  • Plasmids for this use are known in the art and include the plasmids provided in the Examples section below.
  • Fully human and chimeric antibodies of the present invention also include IgG2, IgG3, IgE, IgA, IgM, and IgD antibodies. Similar plasmids can be constructed for expression of other heavy chain isotypes, or for expression of antibodies comprising lambda light chains.
  • the structural features of known, non-human or human antibodies are used to create structurally related human anti-human PD-I, PD-Ll, or PD-L2 antibodies that retain at least one functional property of the antibodies of the invention, such as binding to PD-I, PD-Ll, or PD-L2.
  • a mouse anti-human anti-PD-1, PD-Ll, or PD-L2 antibody such as antibodies EH12.2H7, 29E.2A3, and 24F.10C12 respectively
  • structurally related human anti-human PD-I, PD-Ll, or PD-L2 antibodies that retain at least one functional property of the antibodies of the invention, such as binding to PD-I, PD-Ll, or PD-L2.
  • Another functional property includes inhibiting binding of EH12.2H7 to PD-I, 29E.2A3 to PD-Ll, or 24F.10C12 to PD-L2 in a competition ELISA assay.
  • the structurally related anti-human PD-I, PD-Ll, or PD-L2 antibodies have a lower binding affinity to the antigen as compared to antibody EH12.2H7, 29E.2A3, or 24F.10C12 as measured by the IC50 value as described in Example 2 (e.g., the affinity of the murine reference antibody is no greater than any of 3.0, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2 or 1.1 fold of the structurally related antibody).
  • the structurally related anti-human PD-I, PD-Ll, or PD-L2 antibodies have a higher affinity to the antigen as compared to antibody EH12.2H7, 29E.2A3, or 24F.10C12 as measured by the IC50 value as described in Example 2 (such as the affinity of the structurally related antibody is at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 fold of the reference antibody).
  • one or more CDR or variable regions of the present invention can be combined recombinantly with known human framework regions and CDRs to create additional, recombinantly-engineered, human anti-PD-1, PD-Ll, or PD-L2 antibodies of the invention.
  • the recombinant antibodies of the invention prepared as set forth above preferably comprise the heavy and light chain CDR3s of variable regions of the present invention (e.g., Figures 2-7).
  • the antibodies further can comprise the CDR2s of variable regions of the present invention (e.g., Figures 2-7).
  • the antibodies further can comprise the CDRIs of variable regions of the present invention (e.g., Figures 2-7).
  • the antibodies can further comprise any combinations of the CDRs.
  • the CDRl, 2, and/or 3 regions of the engineered antibodies described above can comprise the exact amino acid sequence(s) as those of variable regions of the present invention (e.g., Figures 2-7) disclosed herein.
  • the ordinarily skilled artisan will appreciate that some deviation from the exact CDR sequences may be possible while still retaining the ability of the antibody to bind PD-I, PD-Ll, or PD-L2 effectively (e.g., conservative sequence modifications).
  • the engineered antibody may be composed of one or more CDRs that are, for example, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical to one or more CDRs of the present invention (e.g., Figures 2-7).
  • engineered antibodies such as those described above may be selected for their retention of other functional properties of antibodies of the invention, such as:
  • PD-Ll ligands e.g., PD-I and/or B7-1
  • Antibodies' activity in inhibiting binding of PD-I, PD-Ll, or PD-L2 to its ligand(s) can be determined by testing the ability of the antibody from blocking the binding between PD-I, PD-Ll, or PD-L2 and its ligand.
  • a competition ELISA assay in the presence of a labeled ligand and the antibody may be used.
  • a competitive binding experiment is performed. Cells expressing PD-Ll is preincubated with the anti-PD-Ll antibody followed by the addition of biotinylated PD-I-Ig fusion protein.
  • the anti-PD-Ll antibody blocks the binding of PD-I-Ig in a dose-dependent manner and with high avidity, the antib-PD-Ll antibody is considered as being effective in inhibiting the interaction between PD-I and PD-Ll. Similar tests may be carried out to test antibodies that are effective in inhibiting the interaction of PD-I and PD-L2. IV. Recombinant Expression Vectors and Host Cells
  • vectors preferably expression vectors, containing one, two, or more nucleic acid molecules encoding one or more polypeptides of the present invention (e.g., Figures 2-7) (or a portion thereof).
  • vector refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • plasmid refers to a circular double stranded DNA loop into which additional DNA segments can be ligated.
  • viral vector wherein additional DNA segments can be ligated into the viral genome.
  • vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors).
  • Other vectors e.g., non-episomal mammalian vectors
  • certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "expression vectors”.
  • expression vectors of utility in recombinant DNA techniques are often in the form of plasmids.
  • plasmid and “vector” can be used interchangeably as the plasmid is the most commonly used form of vector.
  • the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.
  • viral vectors e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses
  • the recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operatively linked to the nucleic acid sequence to be expressed.
  • operably linked is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).
  • regulatory sequence is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel (1990) Methods Enzymol. 185:3-7.
  • Regulatory sequences include those which direct constitutive expression of a nucleotide sequence in many types of host cells and those which direct expression of the nucleotide sequence only in certain host cells (e.g., tissue- specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, and the like.
  • the expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein.
  • the recombinant expression vectors of the invention can be designed for expression of polypeptides of the present invention (e.g., Figures 2-7 ) in prokaryotic or eukaryotic cells.
  • the polypeptides can be expressed in bacterial cells such as E. coli, insect cells (using baculovirus expression vectors), yeast cells, or mammalian cells. Suitable host cells are discussed further in Goeddel (1990) supra.
  • the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.
  • Fusion vectors add a number of amino acids to a polypeptide encoded therein, usually to the amino terminus of the recombinant polypeptide.
  • Such fusion vectors typically serve three purposes: 1) to increase expression of recombinant polypeptide; 2) to increase the solubility of the recombinant polypeptide; and 3) to aid in the purification of the recombinant polypeptide by acting as a ligand in affinity purification.
  • a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant polypeptide to enable separation of the recombinant polypeptide from the fusion moiety subsequent to purification of the fusion protein.
  • enzymes, and their cognate recognition sequences include Factor Xa, thrombin and enterokinase.
  • Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith, D. B. and Johnson, K. S.
  • GST glutathione S-transferase
  • Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al. (1988) Gene 69:301-315) and pET 1 Id (Studier et al. (1990) Methods Enzymol. 185:60-89).
  • Target gene expression from the pTrc vector relies on host RNA polymerase transcription from a hybrid trp-lac fusion promoter.
  • Target gene expression from the pET H d vector relies on transcription from a T7 gnlO-lac fusion promoter mediated by a coexpressed viral RNA polymerase (T7 gnl). This viral polymerase is supplied by host strains BL21(DE3) or HMS174(DE3) from a resident prophage harboring a T7 gnl gene under the transcriptional control of the lacUV 5 promoter.
  • One strategy to maximize recombinant polypeptide expression in E. coli is to express the polypeptide in host bacteria with impaired capacity to proteolytically cleave the recombinant polypeptide (Gottesman, S. (1990) Methods Enzymol. 185:119-128).
  • Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (Wada et al. (1992) Nucleic Acids Res. 20:2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques.
  • the expression vector is a yeast expression vector.
  • yeast expression vectors for expression in yeast S. cerevisiae include pYepSecl (Baldari et al. (1987) EMBO J. 6:229-234), pMFa (Kurjan and Herskowitz (1982) Cell 30:933-943), pJRY88 (Schultz et al. (1987) Gene 54:113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and picZ (Invitrogen Corp, San Diego, Calif.).
  • polypeptides of the present invention can be expressed in insect cells using baculovirus expression vectors.
  • Baculovirus vectors available for expression of polypeptides in cultured insect cells include the pAc 'series (Smith et al. (1983) MoI. Cell Biol. 3:2156-2165) and the pVL series (Lucklow and Summers (1989) Virology 170:31-39).
  • a nucleic acid of the present invention is expressed in mammalian cells using a mammalian expression vector.
  • mammalian expression vectors include pCDM8 (Seed, B. (1987) Nature 329:840) and pMT2PC (Kaufman et al. (1987) EMBO J. 6:187-195).
  • the expression vector's control functions are often provided by viral regulatory elements.
  • commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40.
  • the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid).
  • tissue-specific regulatory elements are known in the art.
  • suitable tissue-specific promoters include the albumin promoter (liver- specific; Pinkert et al. (1987) Genes Dev.
  • lymphoid- specific promoters Calame and Eaton (1988) Adv. Immunol. 43:235-275
  • particular promoters of T cell receptors Winoto and Baltimore (1989) EMBO J. 8:729-733
  • immunoglobulins Bonerji et al. (1983) Cell 33:729-740; Queen and Baltimore (1983) Cell 33:741-748
  • neuron- specific promoters e.g., the neurofilament promoter; Byrne and Ruddle (1989) Proc. Natl. Acad. Sci. USA 86:5473-5477
  • pancreas-specific promoters Edlund et al.
  • mammary gland-specific promoters e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166.
  • Developmentally-regulated promoters are also encompassed, for example by the murine hox promoters (Kessel and Grass (1990) Science 249:374-379) and the .alpha. -fetoprotein promoter (Campes and Tilghman (1989) Genes Dev. 3:537-546).
  • Another aspect of the invention pertains to host cells into which a nucleic acid molecule of the present invention (e.g., Figures 2-7) is introduced within a recombinant expression vector or a nucleic acid molecule containing sequences which allow it to homologously recombine into a specific site of the host cell's genome.
  • the terms "host cell” and “recombinant host cell” are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.
  • a host cell can be any prokaryotic or eukaryotic cell.
  • a polypeptide of the present invention e.g., Figures 2-7 can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells).
  • bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells).
  • CHO Chinese hamster ovary cells
  • COS cells Other suitable host cells are known to those skilled in the art.
  • Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques.
  • transformation and “transfection” are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook et al. (Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y., 1989), and other laboratory manuals.
  • a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest.
  • selectable markers include those which confer resistance to drugs, such as G418, hygromycin and methotrexate.
  • Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding a PD-L2 polypeptide or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).
  • a host cell of the invention such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) a polypeptide of the present invention (e.g., Figures 2-7). Accordingly, the invention further provides methods for producing a polypeptide of the present invention (e.g., Figures 2-7) using the host cells of the present invention.
  • the method comprises culturing the host cell of the invention (into which a recombinant expression vector encoding a polypeptide of the present invention (e.g., Figures 2-7) has been introduced) in a suitable medium such that a polypeptide of the present invention (e.g., Figures 2-7) is produced.
  • the method further comprises isolating a polypeptide of the present invention (e.g., Figures 2-7) from the medium or the host cell.
  • a polypeptide of the present invention e.g., Figures 2-7
  • the host cells of the invention can also be used to produce non-human transgenic animals, as described below.
  • the invention provides transgenic and transchromosomal non- human animals, such as transgenic or transchromosomal mice, which are capable of expressing human monoclonal antibodies that specifically bind to PD-I, PD-Ll, or PD-L2.
  • the invention provides a transgenic or transchromosomal mouse having a genome comprising a human heavy chain transgene, such that the mouse produces human anti- PD-I, PD-Ll, or PD-L2 antibodies when immunized with PD-I, PD-Ll, or PD-L2 antigen and/or cells expressing PD-I, PD-Ll, or PD-L2.
  • the human heavy chain transgene can be integrated into the chromosomal DNA of the mouse, as is the case for transgenic, e.g., HuMAb, mice accordingly to methods well known in the art.
  • the human heavy chain transgene can be maintained extrachromosomally, as is the case for transchromosomal (e.g., KM) mice as described in WO 02/43478.
  • transgenic and transchromosomal mice are capable of producing multiple isotypes of human monoclonal antibodies to PD-I, PD-Ll, or PD-L2 (e.g., IgG, IgA and/or IgE) by undergoing V-D-J recombination and isotype switching.
  • Isotype switching may occur by, e.g., classical or non-classical isotype switching.
  • the design of a transgenic or transchromsomal non-human animal that responds to foreign antigen stimulation with a heterologous antibody repertoire requires that the heterologous immunoglobulin transgenes contained within the transgenic animal function correctly throughout the pathway of B-cell development. This includes, for example, isotype switching of the heterologous heavy chain transgene.
  • the transgene need not activate allelic exclusion.
  • the transgene comprises a functionally rearranged heavy and/or light chain immunoglobulin gene
  • the second criteria of functional gene rearrangement is unnecessary, at least for that transgene which is already rearranged.
  • Such switch sequences may be those which occur naturally in the germline immunoglobulin locus from the species that serves as the source of the transgene CH genes, or such switch sequences may be derived from those which occur in the species that is to receive the transgene construct (the transgenic animal).
  • a human transgene construct that is used to produce a transgenic mouse may produce a higher frequency of isotype switching events if it incorporates switch sequences similar to those that occur naturally in the mouse heavy chain locus, as presumably the mouse switch sequences are optimized to function with the mouse switch recombinase enzyme system, whereas the human switch sequences are not.
  • Switch sequences may be isolated and cloned by conventional cloning methods, or may be synthesized de novo from overlapping synthetic oligonucleotides designed on the basis of published sequence information relating to immunoglobulin switch region sequences (Mills et al, Nucl. Acids Res. 15:7305 7316 (1991); Sideras et al, Intl. Immunol. 1:631 642 (1989)).
  • functionally rearranged heterologous heavy and light chain immunoglobulin transgenes are found in a significant fraction of the B -cells of the transgenic animal (at least 10 percent).
  • the transgenes used to generate the transgenic animals of the invention include a heavy chain transgene comprising DNA encoding at least one variable gene segment, one diversity gene segment, one joining gene segment and at least one constant region gene segment.
  • the immunoglobulin light chain transgene comprises DNA encoding at least one variable gene segment, one joining gene segment and at least one constant region gene segment.
  • the gene segments encoding the light and heavy chain gene segments are heterologous to the transgenic non-human animal in that they are derived from, or correspond to, DNA encoding immunoglobulin heavy and light chain gene segments from a species not consisting of the transgenic non-human animal.
  • the transgene is constructed such that the individual gene segments are unrearranged, i.e., not rearranged so as to encode a functional immunoglobulin light or heavy chain.
  • Such unrearranged transgenes support recombination of the V, D, and J gene segments (functional rearrangement) and preferably support incorporation of all or a portion of a D region gene segment in the resultant rearranged immunoglobulin heavy chain within the transgenic non-human animal when exposed to the PD- 1, PD-Ll, or PD-L2 antigen.
  • the transgenes comprise an unrearranged "mini-locus". Such transgenes typically comprise a substantial portion of the C, D, and J segments as well as a subset of the V gene segments.
  • the various regulatory sequences e.g., promoters, enhancers, class switch regions, splice-donor and splice-acceptor sequences for RNA processing, recombination signals and the like, comprise corresponding sequences derived from the heterologous DNA.
  • Such regulatory sequences may be incorporated into the transgene from the same or a related species of the non-human animal used in the invention.
  • human immunoglobulin gene segments may be combined in a transgene with a rodent immunoglobulin enhancer sequence for use in a transgenic mouse.
  • synthetic regulatory sequences may be incorporated into the transgene, wherein such synthetic regulatory sequences are not homologous to a functional DNA sequence that is known to occur naturally in the genomes of mammals. Synthetic regulatory sequences are designed according to consensus rules, such as, for example, those specifying the permissible sequences of a splice- acceptor site or a promoter/enhancer motif.
  • a minilocus comprises a portion of the genomic immunoglobulin locus having at least one internal (i.e., not at a terminus of the portion) deletion of a non-essential DNA portion (e.g., intervening sequence; intron or portion thereof) as compared to the naturally- occurring germline Ig locus.
  • a non-essential DNA portion e.g., intervening sequence; intron or portion thereof
  • the repertoire will ideally approximate that shown in a native mouse, usually at least about 10% as high, or 25 to 50% or more.
  • immunoglobulins ideally IgG
  • these immunoglobulins will typically recognize about one -half or more of highly antigenic proteins, e.g., staphylococcus protein A.
  • the immunoglobulins will exhibit an affinity (K D ) for preselected antigens of below 10 "7 M, such as of below 10 "8 M, 10 "9 M or 10 "10 M or even lower.
  • a heavy chain transgene having a predetermined repertoire may comprise, for example, human V H genes which are preferentially used in antibody responses to the predetermined antigen type in humans.
  • some V H genes may be excluded from a defined repertoire for various reasons (e.g., have a low likelihood of encoding high affinity V regions for the predetermined antigen; have a low propensity to undergo somatic mutation and affinity sharpening; or are immunogenic to certain humans).
  • a transgene containing various heavy or light chain gene segments such gene segments may be readily identified, e.g. by hybridization or DNA sequencing, as being from a species of organism other than the transgenic animal.
  • the immunoglobulins can be human antibodies (also referred to as "human sequence antibodies”), wherein the heavy and light chain polypeptides are encoded by human transgene sequences, which may include sequences derived by somatic mutation and V region recombinatorial joints, as well as germline-encoded sequences; these human antibodies can be referred to as being substantially identical to a polypeptide sequence encoded by a human V L or V H gene segment and a human J L or D H and J H segment, even though other non-germline sequences may be present as a result of somatic mutation and differential V-J and V-D-J recombination joints.
  • variable regions of each antibody chain are typically at least 80 percent encoded by human germline V, J, and, in the case of heavy chains, D, gene segments; frequently at least 85 percent of the variable regions are encoded by human germline sequences present on the transgene; often 90 or 95 percent or more of the variable region sequences are encoded by human germline sequences present on the transgene.
  • the human sequence antibodies will frequently have some variable region sequences (and less frequently constant region sequences) which are not encoded by human V, D, or J gene segments as found in the human transgene(s) in the germline of the mice.
  • Human antibodies which bind to the predetermined antigen can result from isotype switching, such that human antibodies comprising a human sequence ⁇ chain (such as ⁇ l, ⁇ 2a, ⁇ 2B, or ⁇ 3) and a human sequence light chain (such as kappa) are produced.
  • Such isotype- switched human antibodies often contain one or more somatic mutation(s), typically in the variable region and often in or within about 10 residues of a CDR) as a result of affinity maturation and selection of B cells by antigen, particularly subsequent to secondary (or subsequent) antigen challenge.
  • high affinity human antibodies may have binding affinities (K n ) of below 10 "7 M, such as of below 10 "8 M, 10 "9 M, 10 "10 M, 10 "10 M or even lower.
  • K n binding affinities
  • Another aspect of the invention includes B cells derived from transgenic or transchromosomal mice as described herein. The B cells can be used to generate hybridomas expressing human monoclonal antibodies which bind with high affinity (e.g., lower than 10 "7 M) to human PD-I, PD-Ll, or PD-L2.
  • the V region transgene is a yeast artificial chromosome comprising a portion of a human V H or V L (V K ) gene segment array, as may naturally occur in a human genome or as may be spliced together separately by recombinant methods, which may include out-of-order or omitted V gene segments. Often at least five or more functional V gene segments are contained on the YAC.
  • a transgenic mouse produced by the V repertoire expansion method, wherein the mouse expresses an immunoglobulin chain comprising a variable region sequence encoded by a V region gene segment present on the V region transgene and a C region encoded on the human Ig transgene.
  • transgenic mice having at least 5 distinct V genes can be generated; as can mice containing at least about 24 V genes or more.
  • Some V gene segments may be non-functional (e.g., pseudogenes and the like); these segments may be retained or may be selectively deleted by recombinant methods available to the skilled artisan, if desired.
  • the mouse germline has been engineered to contain a functional YAC having an expanded V segment repertoire, substantially not present in the human Ig transgene containing the J and C gene segments, the trait can be propagated and bred into other genetic backgrounds, including backgrounds where the functional YAC having an expanded V segment repertoire is bred into a mouse germline having a different human Ig transgene.
  • YAC transgenes having an expanded V segment repertoire may be bred into a germline to work with a human Ig transgene (or multiple human Ig transgenes).
  • YAC transgenes when integrated into the genome may substantially lack yeast sequences, such as sequences required for autonomous replication in yeast; such sequences may optionally be removed by genetic engineering (e.g., restriction digestion and pulsed- field gel electrophoresis or other suitable method) after replication in yeast is no longer necessary (i.e., prior to introduction into a mouse ES cell or mouse prozygote).
  • the present invention features human PD-I, PD-Ll, or PD-L2 antibodies conjugated to a therapeutic moiety, such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radioisotope.
  • a therapeutic moiety such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radioisotope.
  • cytotoxins include any agent that is detrimental to (e.g., kills) cells.
  • Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof.
  • Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g.
  • Conjugated human PD-I, PD-Ll, or PD-L2 antibodies can be used diagnostically or prognostically to monitor polypeptide levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i e., physically linking) the antibody to a detectable substance.
  • detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials.
  • suitable enzymes include horseradish peroxidase, alkaline phosphatase, P-galactosidase, or acetylcholinesterase;
  • suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin;
  • suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin;
  • an example of a luminescent material includes luminol;
  • examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include 12 sl, 131 I, .
  • the antibody conjugates of the invention can be used to modify a given biological response.
  • the therapeutic moiety is not to be construed as limited to classical chemical therapeutic agents.
  • the drug moiety may be a protein or polypeptide possessing a desired biological activity.
  • proteins may include, for example, an enzymatically active toxin, or active fragment thereof, such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor or interferon-.
  • IL-I interleukin- 1
  • IL- 2 interleukin-2
  • IL-6 interleukin-6
  • GM-CSF granulocyte macrophage colony stimulating factor
  • G-CSF granulocyte colony stimulating factor
  • Techniques for conjugating such therapeutic moiety to antibodies are well known, see, e.g., Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243 56 (Alan R.
  • the present invention provides a composition, e.g., a pharmaceutical composition, containing one or a combination of the monoclonal antibodies, or antigen-binding portion(s) thereof (such as antigen-binding fragments), of the present invention, formulated together with a pharmaceutically acceptable carrier.
  • the compositions include a combination of multiple (e.g., two or more) isolated human antibodies of the invention.
  • each of the antibodies of the composition binds to a distinct, pre-selected epitope of
  • PD-I PD-I
  • PD-Ll PD-L2
  • PD-L2 PD-L2
  • compositions of the invention also can be administered in combination therapy, i.e., combined with other agents.
  • the combination therapy can include a composition of the present invention with at least one or more additional therapeutic agents, such as anti-inflammatory agents, DMARDs (disease-modifying anti-rheumatic drugs), immunosuppressive agents, chemotherapeutics, and psoriasis agents.
  • additional therapeutic agents such as anti-inflammatory agents, DMARDs (disease-modifying anti-rheumatic drugs), immunosuppressive agents, chemotherapeutics, and psoriasis agents.
  • the pharmaceutical compositions of the invention can also be administered in conjunction with radiation therapy. Co-administration with other antibodies, such as CD4 specific antibodies and IL-2 specific antibodies, are also encompassed by the invention.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
  • the active compound i.e., antibody, bispecific and multispecific molecule, may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.
  • a "pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S. M., et al. (1977) J. Pharm. Sci. 66:1 19). Examples of such salts include acid addition salts and base addition salts.
  • Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
  • a composition of the present invention can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • the compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
  • suitable diluents include saline and aqueous buffer solutions.
  • Liposomes include water-in-oil-in- water CGF emulsions as well as conventional liposomes (Strejan et al. (1984) J. Neuroimmunol. 7:27).
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • the human antibodies of the invention may be administered once or twice weekly by subcutaneous injection or once or twice monthly by subcutaneous injection. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • an agent of the invention is an antibody.
  • a therapeutically effective amount of antibody ranges from about 0.001 to 30 mg/kg body weight, or about 0.01 to 25 mg/kg body weight, or about 0.1 to 20 mg/kg body weight, or about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.
  • treatment of a subject with a therapeutically effective amount of an antibody can include a single treatment or, preferably, can include a series of treatments. It will also be appreciated that the effective dosage of antibody used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result from the results of diagnostic assays.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.001 percent to about ninety percent of active ingredient, alternatively from about 0.005 percent to about 70 percent, or alternatively from about 0.01 percent to about 30 percent.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of compositions of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compositions of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect.
  • Such an effective dose will generally depend upon the factors described above. It is preferred that administration be intravenous, intramuscular, intraperitoneal, or subcutaneous, preferably administered proximal to the site of the target.
  • the effective daily dose of a therapeutic composition may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
  • compositions can be administered with medical devices known in the art.
  • a therapeutic composition of the invention can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Pat. Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556.
  • a needleless hypodermic injection device such as the devices disclosed in U.S. Pat. Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556.
  • Examples of well-known implants and modules useful in the present invention include: U.S. Pat. No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Pat. No. 4,486,194, which discloses a therapeutic device for administering medicants through the skin; U.S. Pat. No.
  • the human monoclonal antibodies of the invention can be formulated to ensure proper distribution in vivo.
  • the blood-brain barrier (BBB) excludes many highly hydrophilic compounds.
  • the therapeutic compounds of the invention cross the BBB (if desired), they can be formulated, for example, in liposomes.
  • liposomes For methods of manufacturing liposomes, see, e.g., U.S. Pat. Nos. 4,522,811; 5,374,548; and 5,399,331.
  • the liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery (see, e.g., V. V. Ranade (1989) J. Clin. Pharmacol. 29:685).
  • targeting moieties include folate or biotin (see, e.g., U.S. Pat. No.
  • the therapeutic compounds of the invention are formulated in liposomes; in another embodiment, the liposomes include a targeting moiety. In yet another embodiment, the therapeutic compounds in the liposomes are delivered by bolus injection to a site proximal to the tumor or infection.
  • the composition must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the composition must be sterile and fluid to the extent that the composition is deliverable by syringe.
  • the carrier can be an isotonic buffered saline solution, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by use of coating such as lecithin, by maintenance of required particle size in the case of dispersion and by use of surfactants.
  • the active compound when suitably protected, as described above, the compound may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the antibodies described herein can be used in a variety of in vitro and in vivo diagnostic and therapeutic applications (e.g., by up- or down-modulating the immune response).
  • PD-I ligand binding to PD-I or B7-1 transmits an inhibitory signal.
  • modulation of the interaction between PD-I and a PD-I ligand, or between a PD-I ligand and a B7 polypeptide results in modulation of the immune response.
  • PD-I ligands can also costimulate T cells.
  • antibodies which block the interaction between a PD-I ligand and PD-I or B7 can prevent inhibitory signaling.
  • antibodies that block costimulatory signal of the PD-I ligand block a costimulatory signal to an immune cell.
  • ligation of PD-L2 can induce cytokine secretion and survival of dendritic cells.
  • antibodies that block PD-L2 ligation can inhibit dendritic cell survival and reduce cytokine expression by dendritic cells, and through these mechanisms inhibit an immune response.
  • antibodies described herein are useful for diagnostic, prognostic, prevention, and therapeutic applications related to particular conditions mediated by PD-I, PD- Ll, and/or PD-L2, as discussed, for example, in Keir et al. (2008) Annu. Rev. Immunol. 26:677; Sharpe et al, (2007) Nat. Immunol. 8:239; Freeman et al. (2007) J. Exp. Med. 10:2223; each of which is hereby incorporated by reference in their entirety.
  • the antibodies and the antigen-binding fragments of the present invention are useful for diagnostic, prognostic, prevention, and therapeutic applications regarding neurodegenerative diseases (geriopsychosis, Alzheimer disease, Down syndrome, Parkinson's disease, Creutzfeldt-jakob disease, diabetic neuropathy, Parkinson syndrome, Huntington's disease, Machado-Joseph disease, amyotrophic lateral sclerosis, diabetic neuropathy, and Creutzfeldt Creutzfeldt- Jakob disease).
  • neurodegenerative diseases geriopsychosis, Alzheimer disease, Down syndrome, Parkinson's disease, Creutzfeldt-jakob disease, diabetic neuropathy, Parkinson syndrome, Huntington's disease, Machado-Joseph disease, amyotrophic lateral sclerosis, diabetic neuropathy, and Creutzfeldt Creutzfeldt- Jakob disease.
  • the antibodies and the antigen-binding fragments of the present invention are useful diagnostic, prognostic, prevention, and therapeutic applications (such as treating, and delaying the onset or progression of the diseases) for diseases that accelerate the immune reaction, for example, asthma, autoimmune diseases (glomerular nephritis, arthritis, dilated cardiomyopathy-like disease, ulceous colitis, Sjogren syndrome, Crohn disease, systemic erythematodes, chronic rheumatoid arthritis, multiple sclerosis, psoriasis, allergic contact dermatitis, polymyosiis, pachyderma, periarteritis nodosa, rheumatic fever, vitiligo vulgaris, insulin dependent diabetes mellitus, Behcet disease, Hashimoto disease, Addison disease, dermatomyositis, myasthenia gravis, Reiter syndrome, Graves' disease, anaemia perniciosa, Goodpasture syndrome, ster
  • the antibodies and the antigen-binding fragments of the present invention are useful diagnostic, prognostic, prevention, and therapeutic applications (such as treating, and delaying the onset or progression of the diseases) for therapy and/or prevention for persistent infectious disease (e.g., viral infectious diseases including HPV, HBV, hepatitis C Virus (HCV), retroviruses such as human immunodeficiency virus (HIV-I and HIV- 2), herpes viruses such as Epstein Barr Virus (EBV), cytomegalovirus (CMV), HSV-I and HSV- 2, and influenza virus.
  • viral infectious diseases including HPV, HBV, hepatitis C Virus (HCV), retroviruses such as human immunodeficiency virus (HIV-I and HIV- 2), herpes viruses such as Epstein Barr Virus (EBV), cytomegalovirus (CMV), HSV-I and HSV- 2, and influenza virus.
  • HCV hepatitis C Virus
  • retroviruses such as human immunodefic
  • antigens associated with pathogens that can be utilized as described herein are antigens of various parasites, includes malaria, preferably malaria peptide based on repeats of NANP.
  • bacterial, fungal and other pathogenic diseases are included, such as Aspergillus, Brugia, Candida, Chlamydia, Coccidia, Cryptococcus, Dirofilaria, Gonococcus, Histoplasma, Leishmania, Mycobacterium, Mycoplasma, Paramecium, Pertussis, Plasmodium, Pneumococcus, Pneumocystis, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Toxoplasma and Vibriocholerae.
  • Exemplary species include Neisseria gonorrhea, Mycobacterium tuberculosis, Candida albicans, Candida tropicalis, Trichomonas vaginalis, Haemophilus vaginalis, Group B Streptococcus sp., Microplasma hominis, Hemophilus ducreyi, Granuloma inguinale, Lymphopathia venereum, Treponema pallidum, Brucella abortus.
  • NIAID National Institute of Allergy and Infectious Diseases
  • Category A agents such as variola major (smallpox), Bacillus anthracis (anthrax), Yersinia pestis (plague), Clostridium botulinum toxin (botulism), Francisella tularensis (tularaemia), filoviruses (Ebola hemorrhagic fever, Marburg hemorrhagic fever), arenaviruses (Lassa (Lassa fever), Junin (Argentine hemorrhagic fever) and related viruses);
  • Category B agents such as Coxiella burnetii (Q fever), Brucella species (brucellosis), Burkholderia mallei (glanders), alphaviruses (Venezuelan encephalomyelitis, eastern & western equine encephalomyelitis), ricin toxin from Ricinus communis (castor beans), ep
  • the antibodies or the antigen-binding fragments of the present invention are useful for diagnostic, prognostic, prevention, and therapeutic applications for organ graft rejection, graft-versus-host disease (GVHD), allergic disease, and diseases caused by attenuation of immune reaction, which PD-I, PD-Ll, and/or PD-L2 participates, for example, cancer and infectious disease.
  • organ graft rejection graft-versus-host disease (GVHD)
  • GVHD graft-versus-host disease
  • allergic disease graft-versus-host disease
  • diseases caused by attenuation of immune reaction which PD-I, PD-Ll, and/or PD-L2 participates, for example, cancer and infectious disease.
  • the antibodies or antigen-binding fragments described herein are administered to a subject in accord with known methods, such as by intravenous (e.g., as a bolus or by continuous infusion over a period of time), subcutaneous, intramuscular, intraperitoneal, intracerobrospinal, intra- articular, intrasynovial, intrathecal, or inhalation routes administration.
  • intravenous e.g., as a bolus or by continuous infusion over a period of time
  • subcutaneous, intramuscular, intraperitoneal, intracerobrospinal, intra- articular, intrasynovial, intrathecal, or inhalation routes administration e.g., as a bolus or by continuous infusion over a period of time
  • intravenous e.g., as a bolus or by continuous infusion over a period of time
  • subcutaneous e.g., intramuscular, intraperitoneal, intracerobrospinal, intra- articular, intra
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals.
  • One aspect of the present invention relates to methods of using antibodies of the present to modulate an immune response by modulating costimulation (such as antibodies that modulate the function of PD-I, PD-Ll, or PD-L2).
  • Such methods utilize screening assays, including cell based and non-cell based assays.
  • the assays provide a method for identifying antibodies which modulate the interaction of a PD-I ligand and PD-I.
  • the assays provide a method for identifying antibodies which modulate the interaction between a PD-I ligand and a B7 polypeptide.
  • the invention relates to assays for screening candidate or test antibodies which bind to, or modulate the activity of, PD-I, PD-Ll, or PD-L2, e.g., modulate the ability of the polypeptide to interact with (e.g., bind to) its cognate binding partner.
  • a method for identifying an antibody to modulate an immune response entails determining the ability of the antibody to modulate, e.g. enhance or inhibit, the interaction between PD-I and a PD-I ligand, and further determining the ability of the antibody to modulate the interaction between a PD-I ligand and a B7 polypeptide.
  • an antibody that modulates the interaction between the PD-I ligand and PD-I (e.g., without modulating the interaction between the PD-I ligand and the B7 polypeptide is selected).
  • an antibody that modulates the interaction between a PD-I ligand and a B7 polypeptide (e.g., without modulating the interaction between the PD-I ligand and PD-I) is selected.
  • a method for identifying an antibody to decrease an immune response entails determining the ability of a candidate antibody to enhance the interaction between a PD-I ligand and a B7 polypeptide and selecting an antibody that inhibits the interaction between the PD-I ligand and the B7 polypeptide.
  • an assay is a cell-based assay, comprising contacting a cell expressing PD-I, PD-Ll, or PD-L2, with a test antibody and determining the ability of the test antibody to modulate (e.g. stimulate or inhibit) the binding of PD-I or the PD-I ligand target to its binding partner. Determining the ability of the PD-I, PD-I ligand or B7 polypeptide to bind to, or interact with, its binding partner can be accomplished, e.g., by measuring direct binding or by measuring a parameter of immune cell activation.
  • the PD-I or PD-I ligand protein in a direct binding assay, can be coupled with a radioisotope or enzymatic label such that binding of PD- 1 ligand to PD- 1 or to the B7 polypeptide can be determined by detecting the labeled protein in a complex.
  • PD-I or PD-I can be labeled with 125 1, 35 S, 14 C, or 3 H, either directly or indirectly, and the radioisotope detected by direct counting of radioemmission or by scintillation counting.
  • PD-I or PD-I ligand can be enzymatically labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product.
  • a microphysiometer can be used to detect the interaction of PD-I and a PD-I ligand, or between a PD-I ligand and a B7 polypeptide, with its target polypeptide, without the labeling of either PD-I, PD-I ligand, B7 polypeptide, or the target polypeptide (McConnell, H. M. et al. (1992) Science 257:1906-1912).
  • a “microphysiometer” e.g., Cytosensor
  • LAPS light-addressable potentiometric sensor
  • determining the ability of the antibody to antagonize the interaction between a given set of polypeptides can be accomplished by determining the activity of one or more members of the set of polypeptides.
  • the activity of PD-I or a PD-I ligand can be determined by detecting induction of a cellular second messenger (e.g., tyrosine kinase activity), detecting catalytic/enzymatic activity of an appropriate substrate, detecting the induction of a reporter gene (comprising a target-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., chloramphenicol acetyl transferase), or detecting a cellular response regulated by PD-I or the PD-I ligand.
  • a cellular second messenger e.g., tyrosine kinase activity
  • detecting catalytic/enzymatic activity of an appropriate substrate detecting the induction of a reporter gene (com
  • Determining the ability of the antibody to bind to or interact with said polypeptide can be accomplished, for example, by measuring the ability of a compound to modulate immune cell costimulation or inhibition in a proliferation assay, or by interfering with the ability of said polypeptide to bind to antibodies that recognize a portion thereof.
  • Antibodies that block or inhibit interaction of a PD-I ligand with a costimulatory receptor as well as antibodies that promote a PD-I ligand- mediated inhibitory signal can be identified by their ability to inhibit immune cell proliferation, and/or effector function, or to induce anergy when added to an in vitro assay.
  • cells can be cultured in the presence of an agent that stimulates signal transduction via an activating receptor.
  • a number of recognized readouts of cell activation can be employed to measure, cell proliferation or effector function (e.g., antibody production, cytokine production, phagocytosis) in the presence of the activating agent.
  • the ability of a test antibody to block this activation can be readily determined by measuring the ability of the antibody to affect a decrease in proliferation or effector function being measured, using techniques known in the art.
  • antibodies of the present invention can be tested for the ability to inhibit or enhance costimulation in a T cell assay, as described in Freeman et al. (2000) J. Exp. Med. 192:1027 and Latchman et al. (2001) Nat. Immunol. 2:261.
  • CD4+ T cells can be isolated from human PBMCs and stimulated with activating anti-CD3 antibody. Proliferation of T cells can be measured by 3 H thymidine incorporation.
  • An assay can be performed with or without CD28 costimulation in the assay. Similar assays can be performed with Jurkat T cells and PHA -blasts from PBMCs.
  • an assay of the present invention is a cell-free assay in which PD-I or a PD-I ligand or a biologically active portion thereof, is contacted with a test antibody, and the ability of the test antibody to bind to the polypeptide, or biologically active portion thereof, is determined. Binding of the test antibody to the PD-I or PD-I ligand polypeptide can be determined either directly or indirectly as described above.
  • a PD-I ligand and a PD-I polypeptide can be used to form an assay mixture and the ability of a test antibody to block this interaction can be tested by determining the ability of PD- 1 to bind the PD- 1 ligand and determining the ability of the PD- 1 ligand to bind the PD-I polypeptide, by one of the methods described above for determining binding. Determining the ability of a PD-I polypeptide to bind a PD-I ligand and determining the ability of a PD-I ligand to bind a B7 polypeptide can also be accomplished using a technology such as real-time Biomolecular Interaction Analysis (BIA) (Sjolander, S.
  • BIOS Biomolecular Interaction Analysis
  • BIOA is a technology for studying biospecific interactions in real time, without labeling any of the interactants (e.g., BIAcore). Changes in the optical phenomenon of surface plasmon resonance (SPR) can be used as an indication of real-time reactions between biological polypeptides.
  • SPR surface plasmon resonance
  • the cell-free assays of the present invention are amenable to use of both soluble and/or membrane-bound forms of proteins ⁇ e.g., a PD-I ligand or PD-I proteins or biologically active portions thereof, or binding partners to which a PD-I ligand or PD-I binds).
  • a membrane-bound form protein e.g., a cell surface PD-I ligand or PD-I receptor
  • non- ionic detergents such as n-
  • PD-I PD-I ligand
  • B7 polypeptide B7 polypeptide
  • an appropriate target polypeptide binding of a test antibody to PD-I or a PD-I ligand can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes.
  • a fusion protein can be provided which adds a domain that allows one or both of the proteins to be bound to a matrix.
  • glutathione-S-transferase/ PD-I, PD-I ligand, or B7 polypeptide fusion proteins, or glutathione-S-transferase/target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized microtiter plates, which are then combined with the test compound, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of PD-I, PD-I ligand, or B7 polypeptide binding or activity determined using standard techniques.
  • determining the ability of the test compound to modulate the activity of PD- 1 or a PD- 1 ligand can be accomplished by determining the ability of the test antibody to modulate the activity of a polypeptide that functions downstream of PD-I or the PD- 1 ligand, e.g., a. polypeptide that interacts with the PD-I ligand, or a polypeptide that functions downstream of PD-I, e.g., by interacting with the cytoplasmic domain of PD-I.
  • levels of second messengers can be determined, the activity of the interactor polypeptide on an appropriate target can be determined, or the binding of the interactor to an appropriate target can be determined as previously described.
  • This invention further pertains to novel antibodies identified by the above-described screening assays. Accordingly, it is within the scope of this invention to further use an antibody identified as described herein in an appropriate animal model. For example, an antibody identified as described herein can be used in an animal model to determine the efficacy, toxicity, or side effects of treatment with such an antibody. Alternatively, an antibody identified as described herein can be used in an animal model to determine the mechanism of action of such an antibody. Furthermore, this invention pertains to uses of novel antibodies identified by the above-described screening assays for treatments as described herein.
  • the invention relates to a method for preventing in a subject, a disease or condition associated with an unwanted or less than desirable immune response.
  • Subjects at risk for a disease that would benefit from treatment with the claimed antibodies or methods can be identified, for example, by any or a combination of diagnostic or prognostic assays known in the art.
  • Administration of a prophylactic antibody can occur prior to the manifestation of symptoms associated with an unwanted or less than desirable immune response.
  • the appropriate antibody used for treatment can be determined based on clinical indications and can be identified, e.g., using screening assays described herein.
  • Another aspect of the invention pertains to therapeutic methods of modulating an immune response, e.g., by modulating the interaction between PD-I and a PD-I ligand and/or a PD-I ligand and a B7 polypeptide.
  • modulation of the interaction between PD-I and a PD-I ligand, or between a PD-I ligand and a B7 polypeptide results in modulation of the immune response.
  • antibodies which block the interaction between PD-I and the PD-I ligand can prevent inhibitory signaling.
  • PD-I ligands can also enhance costimulatory signals in T cells.
  • antibodies that prevent PD-I ligand from providing a costimulatory signal can inhibit T cell costimulation.
  • modulatory antibodies can be administered in vitro (e.g., by contacting the cell with an antibody) or, alternatively, in vivo (e.g., by administering the agent to a subject).
  • the present invention relates to methods of treating an individual afflicted with a disease or disorder that would benefit from modulation of an immune response, e.g., by modulation of the interaction between a PD-I ligand and PD-I, or a B7 polypeptide.
  • Downregulation can be in the form of inhibiting or blocking an immune response already in progress, or may involve preventing the induction of an immune response.
  • the functions of activated immune cells can be inhibited by down-regulating immune cell responses, or by inducing specific anergy in immune cells, or both.
  • the immune response can be downmodulated using: anti-PD-1 ligand antibodies that blocks costimulation by PD-I ligand (e.g., while not affecting or increasing the interaction between PD-Ll and PD-I) or which promote the binding of a PD-I ligand with PD- 1, (e.g., while not affecting or while inhibiting costimulation by PD-I ligand).
  • anti-PD-1 ligand antibodies that blocks costimulation by PD-I ligand (e.g., while not affecting or increasing the interaction between PD-Ll and PD-I) or which promote the binding of a PD-I ligand with PD- 1, (e.g., while not affecting or while inhibiting costimulation by PD-I ligand).
  • tolerance is induced against specific antigens by co-administering an antigen with an antibody which blocks PD-I ligand costimulation.
  • tolerance can be induced to specific proteins.
  • immune responses to allergens, or to foreign proteins to which an immune response is undesirable can be inhibited.
  • patients that receive Factor VIII frequently generate antibodies against this clotting factor.
  • Co-administration of an antibody that blocks a PD-I ligand-mediated costimulatory signal or an antibody that stimulates a PD-I mediated inhibitory signal in combination with recombinant factor VIII (or by physically linked to Factor VIII, e.g., by cross-linking) can result in downmodulation.
  • two separate agents that downmodulate immune responses can be combined as a single composition or administered separately (simultaneously or sequentially) to more effectively downregulate immune cell mediated immune responses in a subject.
  • a therapeutically active amount of one or more of the subject antibodies can be used in conjunction with other downmodulating reagents to influence immune responses.
  • immunomodulating reagents include, without limitation, antibodies that block a costimulatory signal, (e.g., against CD28 or ICOS), antibodies that act as agonists of CTLA4, and/or antibodies against other immune cell markers (e.g., against CD40, against CD40 ligand, or against cytokines), fusion proteins (e.g., CTLA4-Fc), and immunosuppressive drugs, (e.g., rapamycin, cyclosporine A or FK506).
  • a costimulatory signal e.g., against CD28 or ICOS
  • antibodies that act as agonists of CTLA4 e.g., against CD40, against CD40 ligand, or against cytokines
  • fusion proteins e.g., CTLA4-Fc
  • immunosuppressive drugs e.g., rapamycin, cyclosporine A or FK506
  • Downregulating or preventing a PD-I ligand costimulation, or promoting an interaction between a PD-I ligand and PD-I is useful to downmodulate the immune response, e.g., in situations of tissue, skin and organ transplantation, in graft- versus-host disease (GVHD), or in inflammatory diseases such as systemic lupus erythematosus, and multiple sclerosis.
  • GVHD graft- versus-host disease
  • inflammatory diseases such as systemic lupus erythematosus
  • multiple sclerosis e.g., blockage of immune cell function results in reduced tissue destruction in tissue transplantation.
  • rejection of the transplant is initiated through its recognition as foreign by immune cells, followed by an immune reaction that destroys the transplant.
  • an antibody which inhibits PD-I ligand costimulation alone or in conjunction with another downmodulatory agent, prior to or at the time of transplantation can promote the generation of an inhibitory signal.
  • inhibition of PD-I ligand costimulatory signals, or promotion of a PD-I ligand or PD-I inhibitory signals may also be sufficient to anergize the immune cells, thereby inducing tolerance in a subject. Induction of long-term tolerance by blocking a PD-I ligand mediated costimulatory signal may avoid the necessity of repeated administration of these blocking reagents.
  • B7-1, B7-2, or B7-1 and B7-2 may also be desirable to block the costimulatory function of other polypeptides.
  • autoimmune disorders are the result of inappropriate activation of immune cells that are reactive against self tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases. Preventing the activation of autoreactive immune cells may reduce or eliminate disease symptoms.
  • reagents which block costimulation of immune cells by disrupting interactions between PD-I ligand and B7 polypeptides, or by promoting the interaction between PD-I ligand and PD-I, without modulating or while downmodulating the interaction between PD-I ligand and a B7 polypeptide are useful for inhibiting immune cell activation and preventing production of autoantibodies or cytokines which may be involved in the disease process. Additionally, agents that promote an inhibitory function of a PD-I ligand or PD-I may induce antigen- specific tolerance of autoreactive immune cells, which could lead to long-term relief from the disease.
  • the efficacy of reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases. Examples include murine experimental autoimmune encephalitis, systemic lupus erythematosus in MKL/lpr ⁇ pr mice or NZB hybrid mice, murine autoimmune collagen arthritis, diabetes mellitus in NOD mice and BB rats, and murine experimental myasthenia gravis (see, e.g., Paul ed., Fundamental Immunology, Raven Press, New York, Third Edition 1993, chapter 30).
  • Inhibition of immune cell activation is useful therapeutically in the treatment of allergy and allergic reactions, e.g., by inhibiting IgE production.
  • An antibody that promotes a PD-I ligand or PD-I inhibitory function can be administered to an allergic subject to inhibit immune cell mediated allergic responses in the subject.
  • Inhibition of PD-I ligand costimulation of immune cells or stimulation of a PD- 1 ligand or PD- 1 inhibitory pathway can be accompanied by exposure to allergen in conjunction with appropriate MHC polypeptides.
  • Allergic reactions can be systemic or local in nature, depending on the route of entry of the allergen and the pattern of deposition of IgE on mast cells or basophils.
  • inhibition of immune cell mediated allergic responses locally or systemically by administration of an inhibitory form of an agent that inhibits the interaction of a PD-I ligand with a co stimulatory receptor, or an antibody that promotes an inhibitory function of a PD-I ligand or PD-I.
  • Inhibition of immune cell activation through blockage of PD-I ligand costimulation, or through promotion of the interaction between a PD-I ligand and PD-I, may also be important therapeutically in viral infections of immune cells.
  • viral replication is stimulated by immune cell activation. Modulation of these interactions may result in inhibition of viral replication and thereby ameliorate the course of AIDS. Modulation of these interactions may also be useful in promoting the maintenance of pregnancy.
  • PD- 1 ligand is normally highly expressed in placental trophoblasts, the layer of cells that forms the interface between mother and fetus and may play a role in preventing maternal rejection of the fetus.
  • Females at risk for spontaneous abortion e.g., those who have previously had a spontaneous abortion or those who have had difficulty conceiving
  • immunologic rejection of the embryo or fetus can be treated with agents that modulate these interactions.
  • Downregulation of an immune response by modulation of PD-I ligand costimulation or by modulation of PD-I ligand / PD-I binding may also be useful in treating an autoimmune attack of autologous tissues.
  • PD-I ligand is normally highly expressed in the heart and may protect the heart from autoimmune attack. This is evidenced by the fact that the Balb/c PD-I knockout mouse exhibits massive autoimmune attack on the heart with thrombosis.
  • conditions that are caused or exacerbated by autoimmune attack e.g., in this example, heart disease, myocardial infarction or atherosclerosis
  • Such an antibody e.g., a non- activating antibody that blocks PD-Ll binding to PD-I
  • exemplary disorders include viral skin diseases, such as Herpes or shingles, in which case such an agent can be delivered topically to the skin.
  • systemic viral diseases such as influenza, the common cold, and encephalitis might be alleviated by systemic administration of such agents.
  • immune responses can be enhanced in an infected patient through an ex vivo approach, for instance, by removing immune cells from the patient, contacting immune cells in vitro with an antibody that blocks the interaction of a PD- 1 ligand with PD- 1 and reintroducing the in vitro stimulated immune cells into the patient.
  • it may be desirable to further administer other agents that upregulate immune responses for example, forms of other B7 family members that transduce signals via costimulatory receptors, in order to further augment the immune response.
  • An antibody that blocks the interaction of a PD-I ligand with PD-I or B7-1 can be used prophylactically in vaccines against various polypeptides (e.g., polypeptides derived from pathogens). Immunity against a pathogen (e.g., a virus) can be induced by vaccinating with a viral protein along with an antibody that blocks the interaction of a PD-I ligand with PD-I or B7-1 in an appropriate adjuvant.
  • a pathogen e.g., a virus
  • upregulation or enhancement of an immune response function is useful in the induction of tumor immunity
  • the immune response can be stimulated by the methods described herein, such that preexisting tolerance is overcome.
  • immune responses against antigens to which a subject cannot mount a significant immune response e.g., to an autologous antigen, such as a tumor specific antigens can be induced by administering an antibody that blocks the interaction of a PD-I ligand with PD-I.
  • an autologous antigen such as a tumor- specific antigen can be coadministered.
  • an immune response can be stimulated against an antigen (e.g., an autologous antigen) to treat a neurological disorder.
  • the subject agents can be used as adjuvants to boost responses to foreign antigens in the process of active immunization.
  • immune cells are obtained from a subject and cultured ex vivo in the presence of an antibody as described herein, to expand the population of immune cells and/or to enhance immune cell activation.
  • the immune cells are then administered to a subject.
  • Immune cells can be stimulated in vitro by, for example, providing to the immune cells a primary activation signal and a costimulatory signal, as is known in the art.
  • Various agents can also be used to costimulate proliferation of immune cells.
  • immune cells are cultured ex vivo according to the method described in PCT Application No. WO 94/29436.
  • the costimulatory polypeptide can be soluble, attached to a cell membrane, or attached to a solid surface, such as a bead.
  • Example 1 Design of Composite, Human Antibody Variable Region Sequences
  • Structural models of the mouse EH12.2H7, 29E.2A3 and 24F.10C12 V regions were produced using Swiss Pdb and analyzed in order to identify important "constraining" amino acids in the mouse V regions that might be essential for the binding properties of the antibodies. Only residues contained within the CDRs were considered to be important, including CDR residues defined under both Kabat and Chothia definitions.
  • composite, human forms of EH12.2H7, 29E.2A3 and 24F.10C12 could be created with wide latitude of sequences outside of CDRs but with a narrow menu of possible alternative residues within the CDR sequences.
  • Duplicate titrations of mouse reference antibody and composite, human antibody samples were generated (in the range 0.0078 ⁇ g/ml to 8 ⁇ g/ml) and mixed with a constant concentration (40 ng/ml) of biotinylated mouse reference antibody in PBS pH 7.4/2% BSA.
  • the titrations 100 ⁇ l/well, were added to washed (4x with PBS pH 7.4/0.05% Tween 20) assay plates and incubated at room temperature for 1 hour. Plates were washed as above and 100 ⁇ l/well of a 1/1000 dilution of streptavidin HRP (Sigma) in PBS pH 7.4/2% BSA was added and incubated for a further 1 hour at room temperature.
  • biotinylated reference antibody was detected with 100 ⁇ l/well OPD substrate. Absorbance was measured at 490nm and the binding curves of the test antibodies were compared to the mouse reference standard. Absorbance was plotted against sample concentration and straight lines were fitted through each of the data sets. The equations of the lines were used to calculate the concentration required to inhibit Biotin-EH12.2H7 binding to PD-I, Biotin-29E.2A3 binding to PD-Ll and Biotin-24F.10C12 binding to human PD-L2 by 50% (IC 50 ).
  • the antibodies with the best IC 50 were selected and cell lines for all these variants of EH12.2H7, 29E.2A3 and 24F.10C12 antibodies were bulked up to 100 ml and grown to saturation. Antibodies were purified from each culture via protein A affinity chromatography. Briefly, supernatants were pH adjusted with 0.1 volume of 10x PBS pH 7.4 and passed over ImI Mab Select Sure protein A columns (GE Healthcare). The columns were washed with 10 volumes of PBS pH 7.4 before elution with 5OmM citrate buffer pH 3.0. 1 ml fractions were collected and immediately neutralized with 0.1 ml of Im Tris-HCl pH 9.0.
  • Protein containing fractions (as judged by absorbance at 280nm) were pooled, buffer exchanged into PBS pH 7.4 and the purified antibodies stored at +4 0 C.
  • the purified antibodies were tested for binding to human Fc-PD-I, Fc-PD-Ll or Fc-PD-L2 via competition ELISA as described above. Titrations of the test antibodies were done from 0.0625 ⁇ g/ml to 8.0 ⁇ g/ml in duplicate. Absorbance at 490nm was measured and this was plotted against test antibody concentration ( Figures 9A-C, 1 OA-C).
  • Table 4 summarizes the results for the combinations of the composite VH and VK variant sequences for the anti-PD-1, PD-Ll and PD-L2 antibodies.
  • EH12.2H7 all the humanized antibodies have an IC50 that is improved compared to the mouse reference, particularly VH4/VK3 that has a two-fold increase in binding.
  • variants VH2/VK1 and VH2/VK4 have equivalent binding to the mouse reference whereas variants VH2/VK2 and VH4/VK2 have reduced binding by 1.75 and 1.36 fold respectively.
  • variants VH2/VK2 and VH4/VK2 have reduced binding by 1.75 and 1.36 fold respectively.
  • 24F.10C12 all selected variants have similar, but slightly reduced, binding compared to the mouse reference (1.13 fold).
  • VH3/VK3 0.93 VH2/VK1 0.27 VH2/VK2 0.58
  • VH3/VK4 0.74 VH2/VK2 0.49 VH2/VK3 0.59
  • VH4/VK3 0.57 VH4/VK2 0.38 VH4/VK2 0.60
  • VH4/VK4 0.91 VH2/VK4 0.29 VH4/VK4 0.58
  • composite, human antibodies specific for human PD-I, PD-Ll and PD-L2 have been constructed from amino acid sequence segments derived entirely from unrelated human antibody variable regions. All CDR and framework regions in the composite, human antibody variants comprised more than one unrelated human sequence segment (sourced from the human sequence database), and all composite, human antibodies were designed specifically to avoid T cell epitopes.
  • Four lead candidates were initially selected for binding to human PD-I, PD-Ll or PD-L2 and, upon subsequent analysis, were demonstrated to have binding within two-fold of the murine antibody.
  • Example 5 Enhanced stimulation of T cell activation by inhibition of PD-l:PD-ligand interaction
  • the PD-I signaling pathway inhibits moderate TCR/CD28 costimulatory signals, with cytokine production being reduced first without a decrease in T cell proliferation.
  • the PD-I pathway dominates, with a great reduction in cytokine production accompanied by a reduction in proliferation.
  • human antibodies of the invention enhances T cell activation, mixed lymphocyte reactions (MLRs) are performed.
  • Immature myeloid dendritic cells are isolated by culturing human peripheral blood monocytes in IL-4 and GM-CSF. Exposure of immature dendritic cells to an inflammatory cocktail of IL- l ⁇ , TNF- ⁇ , IL-6, and PGE 2 elicits the development of mature dendritic cells that function as APCs. However, the addition of IL-IO to the inflammatory cytokines given during the maturation phase results in APCs that function only 1/6 to 1/3 as well.
  • T cell activation assays are performed, using IL-IO treated dendritic cells as APCs, in the presence of composite, human antibodies to PD-I, PD-Ll and/or PD-L2, or control antibodies.
  • the addition of anti-PD-1, anti-PD-Ll and/or PD-L2 mAb to cultures of IL-I 0 treated dendritic cells plus allogeneic T cells is predicted to result in an increase in T cell proliferation and cytokine expression, as compared to control IgG treated cultures.
  • a combination of anti-PD-1 antibodies with anti-PD-Ll antibodies, anti-PD-L2 antibodies may also result in an increase in stimulation greater than that seen with either antibody alone.
  • LCMV lymphocytic choriomeningitis virus
  • the PD- 1 signalling is disrupted during chronic LCMV infection using composite, human anti-PD-1 antibodies, anti-PD-Ll antibodies and/or anti-PD-L2 antibodies of the invention.
  • the antibodies are administered every third day to mice infected with LCMV Cl-13 from day 23 to day 37 post-infection. It is expected that at day 37 there will be several-fold more LCMV specific CD8 T cells in treated mice relative to the untreated controls. It is also expected that the induction of proliferation will be specific to CD8 T cells since and the number of CD4 T cells in the spleen will probably be approximately the same in both treated mice and untreated mice.
  • CD8 T cell proliferation In addition to an increase in CD8 T cell proliferation, it is expected that the inhibition of PD-I signaling will also result in an increased production of anti-viral cytokines in virus-specific CD8 T cells.
  • the production of IFN-gamma and TNF-alpha by CD8 T cells will likely be several- fold higher in treated mice as compared to untreated mice. Viral clearance should also be accelerated, and reduced viral titers should be observed in the lung and kidney by day 37 postinfection in treated mice, while untreated mice likely will display significant levels of virus in all these tissues.
  • CD4 T cells play a key role in the generation and maintenance of CD8 T cell responses.
  • CD 8 T cells primed in the absence of CD4 T cells are incapable of mounting normal immune responses, and are thus often referred to as "helpless T cells.”
  • chronic LCMV infection is more severe in the absence of CD4 T cells.
  • helpless T cells generated during LCMV-Cl- 13 infection display an even more profound functional impairment than T cells generated in the presence of CD4 T cells.
  • CD4 T cells are depleted at the time of LCMV-Cl- 13 infection and mice are treated with composite, human anti-PD-1 antibodies, anti-PD-Ll antibodies and/or anti-PD-Ll antibodies of the present invention from day 46 to day 60 post-infection. It is expected that following treatment, treated mice likely will have several-fold more LCMV-specific CD8T cells in their spleen than untreated control mice. This increase in virus-specific CD8 T cells in treated mice likely will be the result to an increase in proliferation, as detected by BrdU incorporation. BrdU analysis is performed by introducing 1 mg/ml BrdU in the drinking water during treatment and staining is performed according to the manufacturer's protocol (BD Biosciences, San Diego, Calif.).
  • Example 7 Administration of a Vaccine with an inhibitor of PD-I Signaling
  • One approach for boosting T cell responses during a persistent infection is therapeutic vaccination.
  • the rationale for this approach is that endogenous antigens may not be presented in an optimal or immunogenic manner during chronic viral infection and that providing antigen in the form of a vaccine may provide a more effective stimulus for virus-specific T and B cells.
  • mice are administered a recombinant vaccinia virus expressing the LCMV GP33 epitope as a therapeutic vaccine (VVGP33), which results in a modest enhancement of CD 8 T cell responses in some chronically infected mice.
  • This therapeutic vaccination is combined with composite, human anti-PD-1 antibodies, anti-PD-Ll antibodies and/or anti-PD-L2 antibodies of the invention. It is expected that LCMV specific T cell responses will be boosted to a greater level than compared to either treatment alone and the effect of combined treatment will likely be more than additive.
  • Example 8 Chimpanzees as a Model for Immunotherapy of Persistent HCV Infection.
  • Chimpanzees provide a model of HCV persistence in humans. Defects in T cell immunity leading to life-long virus persistence both include a deficit in HCV-specific CD4 helper T cells and impaired or altered CD 8 effector T cell activity. Persistently infected chimpanzees are treated with composite, human anti-PD-1 antibodies, anti-PD-Ll antibodies and/or anti-PD-L2 antibodies of the invention. The efficacy of blockade of the inhibitory pathways, combined with vaccination using recombinant structural and non- structural HCV proteins, and whether such strategies can enhance the frequency and longevity of virus-specific memory T cells are determined. The defect in T cell immunity is exclusively HCV-specific in persistently infected humans and chimpanzees. Antiviral activity may then be restored by delivering to chimpanzees humanized monoclonal antibodies that block signaling through these molecules.
  • Persistently infected chimpanzees are treated with composite, human anti-PD-1 antibodies, anti-PD-Ll antibodies and/or anti-PD-L2 antibodies of the invention. After treatment with antibodies, the humoral and cellular immune responses as well as the HCV RNA load are determined. Samples are collected at weeks 1, 2, 3, 5, and 8, and then at monthly intervals.
  • Samples include: 1) serum for analysis of transaminases, autoantibodies, neutralizing antibodies to HCV, and cytokine responses, 2) plasma for viral load and genome evolution, 3) PBMC for in vitro measures of immunity, costimulatory/inhibitory receptor expression and function, 4) fresh (unfixed) liver for isolation of intrahepatic lymphocytes and RNA, and 5) fixed (formalin/paraffin embedded) liver for histology and immunohistochemical analysis.
  • Regional lymph nodes are also collected at 2 or 3 time points to assess expression of co-inhibitory molecules and splice variants by immunohistochemistry and molecular techniques.
  • chimpazees are treated as follows: 1) intramuscular immunization with recombinant envelope glycoproteins El and E2 (in MF59 adjuvant) and other proteins (core plus NS 3, 4, and 5 formulated with ISCOMS) at weeks 0, 4, and 24; 2) intramuscular immunization with the vaccine used in, but co-administered with composite, human anti-PD-1 antibodies, anti-PD-Ll antibodies and/or anti-PD-L2 antibodies of the invention antibodies.
  • HCV-specific T and B cell responses are monitored at monthly intervals after immunization for a period of 1 year.
  • Markers examined on HCV-tetramer positive and total T cells in this analysis include markers of differentiation (e.g. CD45RA/RO, CD62L, CCR7, and CD27), activation (e.g. CD25, CD69, CD38, and HLA-DR), survival/proliferation (e.g. bcl-2 and Ki67), cytotoxic potential (e.g. granzymes and perforin), and cytokine receptors (CD122 and CD127).
  • markers of differentiation e.g. CD45RA/RO, CD62L, CCR7, and CD27
  • activation e.g. CD25, CD69, CD38, and HLA-DR
  • survival/proliferation e.g. bcl-2 and Ki67
  • cytotoxic potential e.g. granzymes and perforin
  • CD122 and CD127 cytokine receptors
  • Example 9 Enhancing SIV-specific immunity in vivo by PD-I blockade
  • Immune restoration potential of blockade of PD-I during chronic simian immunodeficiency virus (SIV) infection was tested in macaques.
  • Fourteen Indian rhesus macaques (Macaca mulatta) infected with SIV were studied.
  • Eight macaques were used for the early chronic phase and were infected intravenously with 200 50% tissue culture infectious dose (TCID 50 ) of SIV251.
  • TCID 50 tissue culture infectious dose
  • Six macaques were used for the late chronic phase, three were infected with SIV251 intrarectally and three were infected with SIV239 intravenously.
  • Macaques were infused with either partially humanized mouse anti-human PD-I antibody (clone EH12-1540) (Dorfman et al., Am. J. Surg. Pathol. 30:802-810, 2006) or a control antibody (SYNAGIS).
  • the anti-PD-1 antibody has mouse variable heavy chain domain linked to human IgGl (mutated to reduce FcR and complement binding) and mouse variable light chain domain linked to human K.
  • SYNAGIS is a humanized mouse monoclonal antibody (IgGl ⁇ ) specific to F protein of respiratory syncytial virus. Antibodies were administered intravenously at 3 mg kg "1 of body weight on days 0, 3, 7 and 10.
  • Immune responses Peripheral blood mononuclear cells from blood and lymphocytes from rectal pinch biopsies were isolated as described previously (VeIu et al., J. Virol. 81:5819-5828, 2007).
  • PD-I blockade during chronic SIV infection resulted in a rapid expansion of SIV-specific CD8 T cells in the blood of all macaques.
  • MHC major histocompatibility complex
  • a 3-4-fold increase in the frequency of Gag-specific interferon (IFN)-y-positive CD8 T cells was also observed by day 14 after blockade in the two Mamu A*01-negative animals (RTdIl and RDbIl), demonstrating that PD-I blockade can enhance the frequency of virus-specific CD8 T cells that are restricted by non-Mamu A*01 alleles. Expansion of SIV-specific CD8 T cells was not observed in the control-antibody treated macaques. [0283] PD-I blockade was also associated with a significant increase in the frequency of virus- specific CD8 T cells that were undergoing active cell division in vivo with improved functional quality.
  • IFN Gag-specific interferon
  • PD-I blockade also enhanced the functional quality of anti-viral CD8 T cells and resulted in the generation of polyfunctional cells capable of co-producing the cytokines IFN-y, tumour-necrosis factor (TNF)-a and interleukin (IL)-2.
  • TNF tumour-necrosis factor
  • IL interleukin
  • the frequency of Gag-specific IFN- ⁇ -positive cells was low and they failed to co-express TNF-a and IL-2.
  • IFN- ⁇ positive cells peaked by 14-21 days and the peak levels were 2-10-fold higher than the respective day 0 levels.
  • Neutralization assays revealed a two-fold increase in titers against the easily neutralizable laboratory-adapted SIV251 and no increase in titers against hard-to-neutralize wild-type SIV251 or SIV239.
  • two of the nine animals treated with anti-PD- 1 antibody only a minimal ( ⁇ 2-fold) expansion of SIV-specific antibody after blockade.
  • the frequency of total memory B cells in these two animals was lower (-40% of total B cells) compared with the remaining seven animals (60-90% of total B cells) before blockade, indicating that the level of SIV-specific memory B cells before blockade may determine the level of expansion of SIV-specific antibody after blockade.
  • the viral RNA levels returned to pre-blockade levels by day 43. As expected, no significant reductions in the plasma viral loads were observed in any of the five macaques treated with the control antibody.
  • P 0.03
  • the frequencies of Gag CM9+ cells and Gag CM9+ cells co-expressing perforin, granzyme B or CD28 were not similar between the two treatment groups before in vivo blockade. This raises the possibility that these differences could have contributed to the expansion of Gag CM9+ cells after PD-I blockade.
  • the anti-PD-1 -antibody-treated group into was divided into two subgroups based on the frequency of Gag CM9+ cells before initiation of blockade such that one group has similar levels and the other group has higher levels of Gag CM9+ cells compared with the control-antibody-treated group.
  • Example 10 Enhanced proliferation of SIV-specific CD8 T cells following in vitro blockade of the PD-I :PDL pathway by a humanized PD-I antibody and a humanized PD-Ll antibody [0293] Effect of a humanized anti-PD-1 antibody derived from EH-12.2H7 and a humanized anti- PD-Ll antibody derived from 29E.2A3 on the proliferative capacity of SIV Gag-specific CD8 T cells was tested in vitro.
  • the humanized anti-PD-1 antibody has the heavy chain variable region sequence of SEQ ID NO:28, and the light chain variable region sequence of SEQ ID NO:32.
  • the humanized anti-PD-Ll antibody has the heavy chain variable region sequence of SEQ ID NO:35, and the light chain variable region sequence of SEQ ID NO:42.
  • the heavy chain constant region of the humanized antibodies is from human IgG4 with Ser 228 to Pro mutation (from CPSCP to CPPCP) so that the antibody forms dimers, and the light chain constant region is human kappa light chain constant region.
  • the amino acid numbering for Ser 228 is according to the EU numbering system. See Aalberse et al., Immunology 105:9-19, 2002.
  • PBMC obtained from SIV-infected macaques were stained with carboxyfluorescein diacetate succinimidyl ester (CFSE) and stimulated either with SIV Gag peptide pool or culture medium for 6 days in the presence or absence of a blocking antibody.
  • CFSE carboxyfluorescein diacetate succinimidyl ester
  • cells were stained for surface CD3 and CD8, and intracellular Ki-67.
  • Cells were then aquired on a FACS Calibur and analyzed using Flowjo software. Lymphocytes were identified based on the scatter, then CD8 T cells (CD3+, CD8+) were analyzed for co-staining for Ki-67 and CFSE. Ki- 67+, CFSE low cells were identified as proliferating cells.
  • Example 11 Restoration of HCV-specific T cell proliferation by intrahepatic mononuclear cells from a persistently infected chimpanzee
  • CFSE-labeled intrahepatic lymphocytes (2x10 ) were isolated from chimpanzee 1564 that had been chronically infected with the genotype Ia H77 strain of HCV for more than 10 years.
  • the intrahepatic lymphocytes were co-cultured for 6 days with 4x10 irradiated autologous CD8- depleted PBMC that were either unmanipulated or pulsed with overlapping peptides spanning the entire HCV polyprotein (genotype Ia H77 strain).
  • Cells were cultured in RPMI media supplemented with L-glutamine and 10% FCS, with and without an anti-PD-Ll blocking antibody (10 ⁇ g/ml, added at day 0 and day 2).
  • the humanized anti-PD-Ll antibody has the heavy chain variable region sequence of SEQ ID NO:35, and the light chain variable region sequence of SEQ ID NO:42.
  • the heavy chain constant region of the humanized antibodies is from human IgG4 with Ser 228 to Pro mutation (from CPSCP to CPPCP) so that the antibody forms dimers, and the light chain constant region is human kappa light chain constant region.
  • the amino acid numbering for Ser 228 is according to the EU numbering system. See Aalberse et al., Immunology 105:9-19, 2002.
  • any polynucleotide and polypeptide sequences which reference an accession number correlating to an entry in a public database, such as those maintained by The Institute for Genomic Research (TIGR) on the world wide web and/or the National Center for Biotechnology Information (NCBI) on the world wide web.
  • TIGR The Institute for Genomic Research
  • NCBI National Center for Biotechnology Information

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