US20170158767A1 - Human monoclonal antibodies to programmed death ligand 1 (pd-l1) - Google Patents

Human monoclonal antibodies to programmed death ligand 1 (pd-l1) Download PDF

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Publication number
US20170158767A1
US20170158767A1 US15/413,244 US201715413244A US2017158767A1 US 20170158767 A1 US20170158767 A1 US 20170158767A1 US 201715413244 A US201715413244 A US 201715413244A US 2017158767 A1 US2017158767 A1 US 2017158767A1
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Prior art keywords
amino acid
seq
chain variable
variable region
set forth
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US15/413,244
Inventor
Alan J. Korman
Mark J. Selby
Changyu Wang
Mohan Srinivasan
David B. Passmore
Haichun Huang
Haibin Chen
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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Application filed by ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
Priority to US15/413,244 priority Critical patent/US20170158767A1/en
Publication of US20170158767A1 publication Critical patent/US20170158767A1/en
Priority to US16/448,721 priority patent/US20200062848A1/en
Priority to US17/842,540 priority patent/US20230061544A1/en
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Definitions

  • PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA.
  • Two cell surface glycoprotein ligands for PD-1 have been identified, PD-L1 and PD-L2, and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1 (Freeman et al.
  • Both PD-L1 (B7-H1) and PD-L2 (B7-DC) are B7 homologs that bind to PD-1, but do not bind to other CD28 family members (Blank et al. (2004). Expression of PD-L1 on the cell surface has also been shown to be upregulated through IFN- ⁇ stimulation.
  • PD-L1 expression has been found in several murine and human cancers, including human lung, ovarian and colon carcinoma and various myelomas (Iwai et al. (2002) PNAS 99:12293-7; Ohigashi et al. (2005) Clin Cancer Res 11:2947-53).
  • PD-L1 has been suggested to play a role in tumor immunity by increasing apoptosis of antigen-specific T-cell clones (Dong et al. (2002) Nat Med 8:793-800). It has also been suggested that PD-L1 might be involved in intestinal mucosal inflammation and inhibition of PD-L1 suppresses wasting disease associated with colitis (Kanai et al. (2003) J Immunol 171:4156-63).
  • the present invention provides isolated monoclonal antibodies, in particular human monoclonal antibodies that bind to PD-L1 and exhibit numerous desirable properties. These properties include high affinity binding to human PD-L1. Still further, antibodies of the invention have been shown to increase T-cell proliferation, IFN- ⁇ secretion, and IL-2 secretion in a mixed lymphocyte reaction.
  • the invention pertains to an isolated monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody exhibits at least one of the following properties:
  • the antibody binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 8 M or less, binds to human PD-L1 with a K D of 1 ⁇ 10 ⁇ 8 M or less, binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 9 M or less, binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 9 M or less, or binds to human PD-L1 with a K D of between 1 ⁇ 10 ⁇ 8 M and 1 ⁇ 10 ⁇ 10 M.
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, wherein the antibody cross-competes for binding to PD-L1 with a reference antibody comprising:
  • the invention pertains to an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-18 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-69 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-3 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 3-9 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L6 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L15 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K A27 gene, wherein the antibody specifically binds PD-L1.
  • the invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L18 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising:
  • the heavy chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and conservative modifications thereof; and the light chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and conservative modifications thereof.
  • the heavy chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, and conservative modifications thereof; and the light chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, and conservative modifications thereof.
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
  • the antibodies additionally comprise at least one of the following properties:
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising:
  • antibodies, or antigen-binding portions thereof are provided that compete for binding to PD-L1 with any of the aforementioned antibodies.
  • the antibodies of the instant disclosure can be, for example, full-length antibodies, for example of an IgG1 or IgG4 isotype.
  • the antibodies can be antibody fragments, such as Fab or Fab′2 fragments, or single chain antibodies.
  • the instant disclosure also provides an immunoconjugate comprising an antibody of the invention, or antigen-binding portion thereof, linked to a therapeutic agent, such as a cytotoxin or a radioactive isotope.
  • a therapeutic agent such as a cytotoxin or a radioactive isotope.
  • the invention also provides a bispecific molecule comprising an antibody, or antigen-binding portion thereof, of the invention, linked to a second functional moiety having a different binding specificity than said antibody, or antigen binding portion thereof.
  • compositions comprising an antibody, or antigen-binding portion thereof, or immunoconjugate or bispecific molecule of the instant disclosure and a pharmaceutically acceptable carrier are also provided.
  • Nucleic acid molecules encoding the antibodies, or antigen-binding portions thereof, of the invention are also encompassed by the invention, as well as expression vectors comprising such nucleic acids and host cells comprising such expression vectors.
  • the invention provides a transgenic mouse comprising human immunoglobulin heavy and light chain transgenes, wherein the mouse expresses an antibody of the invention, as well as hybridomas prepared from such a mouse, wherein the hybridoma produces the antibody of the invention.
  • the invention provides a method of modulating an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of the invention such that the immune response in the subject is modulated.
  • the antibody of the invention enhances, stimulates or increases the immune response in the subject.
  • the invention provides a method of inhibiting growth of tumor cells in a subject, comprising administering to a subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof.
  • the antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention).
  • a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of inhibiting tumor growth.
  • the invention provides a method of treating an infectious disease in a subject, comprising administering to a subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof.
  • the antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention).
  • a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of treating an infectious disease.
  • the invention provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) an anti-PD-L1 antibody, or antigen-binding portion thereof, such that an immune response to the antigen in the subject is enhanced.
  • the antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen.
  • the antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention).
  • a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of enhancing an immune response to an antigen in a subject.
  • the invention also provides methods for making “second generation” anti-PD-L1 antibodies based on the sequences of the anti-PD-L1 antibodies provided herein.
  • the invention provides a method for preparing an anti-PD-L1 antibody comprising:
  • a heavy chain variable region antibody sequence comprising a CDR1 sequence that is selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, a CDR2 sequence that is selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40; and a CDR3 sequence that is selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; or (ii) a light chain variable region antibody sequence comprising a CDR1 sequence that is selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, a CDR2 sequence that is selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and a CDR3 sequence that is selected from
  • FIG. 1A shows the nucleotide sequence (SEQ ID NO:81) and amino acid sequence (SEQ ID NO:1) of the heavy chain variable region of the 3G10 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:21), CDR2 (SEQ ID NO:31) and CDR3 (SEQ ID NO:41) regions are delineated and the V, D and J germline derivations are indicated.
  • FIG. 1B shows the nucleotide sequence (SEQ ID NO:91) and amino acid sequence (SEQ ID NO:11) of the light chain variable region of the 3G10 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:51), CDR2 (SEQ ID NO:61) and CDR3 (SEQ ID NO:71) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 2A shows the nucleotide sequence (SEQ ID NO:82) and amino acid sequence (SEQ ID NO:2) of the heavy chain variable region of the 12A4 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:22), CDR2 (SEQ ID NO:32) and CDR3 (SEQ ID NO:42) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 2B shows the nucleotide sequence (SEQ ID NO:92) and amino acid sequence (SEQ ID NO:12) of the light chain variable region of the 12A4 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:52), CDR2 (SEQ ID NO:62) and CDR3 (SEQ ID NO:72) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 3A shows the nucleotide sequence (SEQ ID NO:83) and amino acid sequence (SEQ ID NO:3) of the heavy chain variable region of the 10A5 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:23), CDR2 (SEQ ID NO:33) and CDR3 (SEQ ID NO:43) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 3B shows the nucleotide sequence (SEQ ID NO:93) and amino acid sequence (SEQ ID NO:13) of the light chain variable region of the 10A5 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:53), CDR2 (SEQ ID NO:63) and CDR3 (SEQ ID NO:73) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 4A shows the nucleotide sequence (SEQ ID NO:84) and amino acid sequence (SEQ ID NO:4) of the heavy chain variable region of the 5F8 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:24), CDR2 (SEQ ID NO:34) and CDR3 (SEQ ID NO:44) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 4B shows the nucleotide sequence (SEQ ID NO:94) and amino acid sequence (SEQ ID NO:14) of the light chain variable region of the 5F8 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:54), CDR2 (SEQ ID NO:64) and CDR3 (SEQ ID NO:74) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 5A shows the nucleotide sequence (SEQ ID NO:85) and amino acid sequence (SEQ ID NO:5) of the heavy chain variable region of the 10H10 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:25), CDR2 (SEQ ID NO:35) and CDR3 (SEQ ID NO:45) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 5B shows the nucleotide sequence (SEQ ID NO:95) and amino acid sequence (SEQ ID NO:15) of the light chain variable region of the 10H10 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:55), CDR2 (SEQ ID NO:65) and CDR3 (SEQ ID NO:75) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 6A shows the nucleotide sequence (SEQ ID NO:86) and amino acid sequence (SEQ ID NO:6) of the heavy chain variable region of the 1B12 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:26), CDR2 (SEQ ID NO:36) and CDR3 (SEQ ID NO:46) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 6B shows the nucleotide sequence (SEQ ID NO:96) and amino acid sequence (SEQ ID NO:16) of the light chain variable region of the 1B12 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:56), CDR2 (SEQ ID NO:66) and CDR3 (SEQ ID NO:76) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 7A shows the nucleotide sequence (SEQ ID NO:87) and amino acid sequence (SEQ ID NO:7) of the heavy chain variable region of the 7H1 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:27), CDR2 (SEQ ID NO:37) and CDR3 (SEQ ID NO:47) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 7B shows the nucleotide sequence (SEQ ID NO:97) and amino acid sequence (SEQ ID NO:17) of the light chain variable region of the 7H1 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:57), CDR2 (SEQ ID NO:67) and CDR3 (SEQ ID NO:77) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 8A shows the nucleotide sequence (SEQ ID NO:88) and amino acid sequence (SEQ ID NO: 8) of the heavy chain variable region of the 11E6 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:28), CDR2 (SEQ ID NO:38) and CDR3 (SEQ ID NO:48) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 8B shows the nucleotide sequence (SEQ ID NO:98) and amino acid sequence (SEQ ID NO:18) of the light chain variable region of the 11E6 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:58), CDR2 (SEQ ID NO:68) and CDR3 (SEQ ID NO:78) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 9A shows the nucleotide sequence (SEQ ID NO:89) and amino acid sequence (SEQ ID NO:9) of the heavy chain variable region of the 12B7 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:29), CDR2 (SEQ ID NO:39) and CDR3 (SEQ ID NO:49) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 9B shows the nucleotide sequence (SEQ ID NO:99) and amino acid sequence (SEQ ID NO:19) of the light chain variable region of the 12B7 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:59), CDR2 (SEQ ID NO:69) and CDR3 (SEQ ID NO:79) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 10A shows the nucleotide sequence (SEQ ID NO:90) and amino acid sequence (SEQ ID NO:10) of the heavy chain variable region of the 13G4 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:30), CDR2 (SEQ ID NO:40) and CDR3 (SEQ ID NO:50) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 10B shows the nucleotide sequence (SEQ ID NO:100) and amino acid sequence (SEQ ID NO:20) of the light chain variable region of the 13G4 human monoclonal antibody.
  • the CDR1 (SEQ ID NO:60), CDR2 (SEQ ID NO:70) and CDR3 (SEQ ID NO:80) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 11 shows the alignment of the amino acid sequence of the heavy chain variable region of 3G10 with the human germline V H 1-18 amino acid sequence (SEQ ID NO:101).
  • FIG. 12 shows the alignment of the amino acid sequence of the heavy chain variable region of 12A4 with the human germline V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 13 shows the alignment of the amino acid sequence of the heavy chain variable region of 10A5 with the human germline V H 1-3 amino acid sequence (SEQ ID NO:103).
  • FIG. 14 shows the alignment of the amino acid sequence of the heavy chain variable region of 5F8 with the human germline V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 15 shows the alignment of the amino acid sequence of the heavy chain variable region of 10H10 with the human germline V H 3-9 amino acid sequence (SEQ ID NO:104).
  • FIG. 16 shows the alignment of the amino acid sequence of the heavy chain variable region of 1B12 with the human germline V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 17 shows the alignment of the amino acid sequence of the heavy chain variable region of 7H1 with the human germline V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 18 shows the alignment of the amino acid sequence of the heavy chain variable region of 11E6 with the human germline V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 19 shows the alignment of the amino acid sequence of the heavy chain variable region of 12B7 with the human germline V H 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 20 shows the alignment of the amino acid sequence of the heavy chain variable region of 13G4 with the human germline V H 3-9 amino acid sequence (SEQ ID NO:104).
  • FIG. 21 shows the alignment of the amino acid sequence of the light chain variable region of 3G10 with the human germline V k L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 22 shows the alignment of the amino acid sequence of the light chain variable region of 12A4 with the human germline V k L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 23 shows the alignment of the amino acid sequence of the light chain variable region of 10A5 with the human germline V k L15 amino acid sequence (SEQ ID NO:106).
  • FIG. 24 shows the alignment of the amino acid sequence of the light chain variable region of 5F8 with the human germline V k A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 25 shows the alignment of the amino acid sequence of the light chain variable region of 10H10 with the human germline V k L15 amino acid sequence (SEQ ID NO:106).
  • FIG. 26 shows the alignment of the amino acid sequence of the light chain variable region of 1B12 with the human germline V k L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 27 shows the alignment of the amino acid sequence of the light chain variable region of 7H1 with the human germline V k L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 28 shows the alignment of the amino acid sequence of the light chain variable region of 11E6 with the human germline V k A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 29 shows the alignment of the amino acid sequence of the light chain variable region of 11E6a (SEQ ID NO:109) with the human germline V k A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 30 shows the alignment of the amino acid sequence of the light chain variable region of 12B7 with the human germline V k L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 31 shows the alignment of the amino acid sequence of the light chain variable region of 13G4 with the human germline V k L18 amino acid sequence (SEQ ID NO:108).
  • FIGS. 32A-32C show the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds the cell surface of CHO cells transfected with full-length human PD-L1.
  • FIG. 32A is a Flow cytometry plot for 3G10
  • FIG. 32B is a Flow cytometry plot for 10A5
  • FIG. 32C is a Flow cytometry plot for 12A4.
  • FIG. 33 shows the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds the cell surface of CHO cells transfected with full-length human PD-L1 in a concentration dependent manner.
  • FIG. 34 shows the results of ELISA experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds to PD-L1-Fc fusion protein.
  • FIG. 35 shows the results of experiments demonstrating HuMab titration on stimulated human CD4+ T cells.
  • FIG. 36 shows the results of experiments demonstrating HuMab titration on stimulated cynomolgus PBMC.
  • FIGS. 37A-37C show the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds to PD-L1 on the cell surface of activated T cells.
  • FIG. 37A is a Flow cytometry plot for 3G10
  • FIG. 37B is a Flow cytometry plot for 10A5
  • FIG. 37C is a Flow cytometry plot for 12A4.
  • FIG. 38 demonstrates binding of HuMabs to ES-2 cells.
  • FIGS. 39A-39D show the results of experiments demonstrating that human monoclonal antibodies against human PD-L1 promote T-cell proliferation, IFN- ⁇ secretion and IL-2 secretion in a mixed lymphocyte reaction assay.
  • FIG. 39A is a bar graph showing concentration dependent T-cell proliferation using HuMAb 10A5;
  • FIG. 39B is a bar graph showing concentration dependent IFN- ⁇ secretion using HuMAb 10A5;
  • FIG. 39C is a bar graph showing IFN- ⁇ secretion using HuMAbs 3G10 and 12A4;
  • FIG. 39D is a bar graph showing concentration dependent IL-2 secretion using HuMAb 10A5.
  • FIG. 40 demonstrates the effect of human anti-PD-L1 antibody on proliferation and IFN- ⁇ secretion in the MLR using allogeneic dendritic cells and T cells (CD4+ effector T cells) Dendritic Cells.
  • FIGS. 41A and 41B show the results of experiments demonstrating that human monoclonal antibodies against human PD-L1 promote T-cell proliferation and IFN- ⁇ secretion in MLR containing T regulatory cells.
  • FIG. 41A is a bar graph showing concentration dependent T-cell proliferation using HuMAb 10A5;
  • FIG. 41B is a bar graph showing concentration dependent IFN- ⁇ secretion using HuMAb 10A5.
  • FIG. 42 demonstrates the results of anti-PD-L1 antibodies on cell proliferation in a Mixed Lymphocyte Reaction in the presence of regulatory T cells.
  • FIG. 43 demonstrates the results of anti-PD-L1 antibodies on cytokine production in a Mixed Lymphocyte Reaction in the presence of regulatory T cells.
  • FIG. 44 demonstrates the results of anti-PD-L1 antibodies on CMV lysate stimulated human PBMC IFN- ⁇ secretion.
  • FIG. 45 shows the results of flow cytometry experiments demonstrating that human monoclonal antibodies against human PD-L1 block the binding of PD-L1 to CHO transfected cells expressing PD-1.
  • FIG. 46 shows that anti-PD-L1 antibodies block binding of PD-1 to IFN ⁇ treated ES-2 cells.
  • FIG. 47 shows the effect of anti-PD-L1 antibodies on tumor growth in vivo.
  • the present disclosure relates to isolated monoclonal antibodies, particularly human monoclonal antibodies that bind specifically to PD-L1.
  • the antibodies of the invention exhibit one or more desirable functional properties, such as high affinity binding to PD-L1, the ability to augment T cell proliferation, IFN- ⁇ and/or IL-2 secretion in mixed lymphocyte reactions, the ability to inhibit binding of PD-L1 to the PD-1 receptor, the ability to stimulate antibody responses and/or the ability to reverse the suppressive function of T regulatory cells.
  • the antibodies of the invention are derived from particular heavy and light chain germline sequences and/or comprise particular structural features such as CDR regions comprising particular amino acid sequences.
  • the instant disclosure provides, for example, isolated antibodies, methods of making such antibodies, immunoconjugates and bispecific molecules comprising such antibodies and pharmaceutical compositions containing the antibodies, immunconjugates or bispecific molecules of the invention.
  • the disclosure pertains to methods of inhibiting growth of tumor cells in a subject using anti-PD-L1 antibodies.
  • the invention also relates to methods of using the antibodies to modify an immune response, as well as to treat diseases such as cancer or infectious disease, or to stimulate a protective autoimmune response or to stimulate antigen-specific immune responses (e.g., by coadministration of anti-PD-L1 with an antigen of interest).
  • immune response refers to the action of, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by the above cells or the liver (including antibodies, cytokines, and complement) that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
  • a “signal transduction pathway” refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of a cell.
  • the phrase “cell surface receptor” includes, for example, molecules and complexes of molecules capable of receiving a signal and the transmission of such a signal across the plasma membrane of a cell.
  • An example of a “cell surface receptor” of the present invention is the PD-L1 receptor.
  • antibody as referred to herein includes whole antibodies and any antigen binding fragment (i.e., “antigen-binding portion”) or single chains 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, C H1 , C H2 and C H3 .
  • 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, C L .
  • the V H and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each V H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • antibody portion refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., PD-L1). 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 L , V H , C L and C H1 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 C H1 domains; (iv) a Fv fragment consisting of the V L and V H 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).
  • a Fab fragment a monovalent fragment consisting of the V L , V H , C L and C H1 domains
  • F(ab′) 2 fragment a bivalent fragment comprising two
  • the two domains of the Fv fragment, V L and V H 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 L and V H 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.
  • an “isolated antibody,” as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds PD-L1 is substantially free of antibodies that specifically bind antigens other than PD-L1).
  • An isolated antibody that specifically binds PD-L1 may, however, have cross-reactivity to other antigens, such as PD-L1 molecules from other species.
  • an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • monoclonal antibody or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition.
  • a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
  • human antibody is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences.
  • the human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term “human antibody,” as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • human monoclonal antibody refers to antibodies displaying a single binding specificity which have variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences.
  • the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman 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.
  • 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 below), (b) antibodies isolated from a host cell transformed to express the human 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 regions in which the framework and CDR regions are derived from human 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.
  • isotype refers to the antibody class (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes.
  • an antibody recognizing an antigen and “an antibody specific for an antigen” are used interchangeably herein with the term “an antibody which binds specifically to an antigen.”
  • human antibody derivatives refers to any modified form of the human antibody, e.g., a conjugate of the antibody and another agent or antibody.
  • humanized antibody is intended to refer to antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Additional framework region modifications may be made within the human framework sequences.
  • chimeric antibody is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.
  • an antibody that “specifically binds to human PD-L1” is intended to refer to an antibody that binds to human PD-L1 with a K D of 1 ⁇ 10 ⁇ 7 M or less, more preferably 5 ⁇ 10 ⁇ 8 M or less, more preferably 1 ⁇ 10 ⁇ 8 M or less, more preferably 5 ⁇ 10 ⁇ 9 M or less, even more preferably between 1 ⁇ 10 ⁇ 8 M and 1 ⁇ 10 ⁇ 10 M or less.
  • K assoc or “K a ,” as used herein, is intended to refer to the association rate of a particular antibody-antigen interaction
  • K dis or “K d ,” as used herein, is intended to refer to the dissociation rate of a particular antibody-antigen interaction
  • K D is intended to refer to the dissociation constant, which is obtained from the ratio of K d to K a (i.e., K d /K a ) and is expressed as a molar concentration (M).
  • K D values for antibodies can be determined using methods well established in the art. A preferred method for determining the K D of an antibody is by using surface plasmon resonance, preferably using a biosensor system such as a Biacore® system.
  • high affinity for an IgG antibody refers to an antibody having a K D of 10 ⁇ 8 M or less, more preferably 10 ⁇ 9 M or less and even more preferably 10 ⁇ 10 M or less for a target antigen.
  • “high affinity” binding can vary for other antibody isotypes.
  • “high affinity” binding for an IgM isotype refers to an antibody having a K D of 10 ⁇ 7 M or less, more preferably 10 ⁇ 8 M or less, even more preferably 10 ⁇ 9 M or less.
  • the term “subject” includes any human or nonhuman animal.
  • nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • the antibodies of the invention are characterized by particular functional features or properties of the antibodies.
  • the antibodies bind specifically to human PD-L1.
  • an antibody of the invention binds to PD-L1 with high affinity, for example with a K D of 1 ⁇ 10 ⁇ 7 M or less.
  • the anti-PD-L1 antibodies of the invention preferably exhibit one or more of the following characteristics:
  • the antibody binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 8 M or less, binds to human PD-L1 with a K D of 1 ⁇ 10 ⁇ 8 M or less, binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 9 M or less, binds to human PD-L1 with a K D of 4 ⁇ 10 ⁇ 9 M or less, binds to human PD-L1 with a K D of 2 ⁇ 10 ⁇ 9 M or less, or binds to human PD-L1 with a K D of between 1 ⁇ 10 ⁇ 9 M and 1 ⁇ 10 ⁇ 10 M or less.
  • Standard assays to evaluate the binding ability of the antibodies toward PD-L1 are known in the art, including for example, ELISAs, Western blots and RIAs. Suitable assays are described in detail in the Examples.
  • the binding kinetics (e.g., binding affinity) of the antibodies also can be assessed by standard assays known in the art, such as by Biacore® analysis.
  • Preferred antibodies of the invention are the human monoclonal antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, isolated and structurally characterized as described in Examples 1 and 2.
  • the V H amino acid sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, respectively.
  • V L amino acid sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, respectively.
  • V H and V L sequences can be “mixed and matched” to create other anti-PD-L1 binding molecules of the invention.
  • PD-L1 binding of such “mixed and matched” antibodies can be tested using the binding assays described above and in the Examples (e.g., ELISAs).
  • a V H sequence from a particular V H /V L pairing is replaced with a structurally similar V H sequence.
  • a V L sequence from a particular V H /V L pairing is replaced with a structurally similar V L sequence.
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof comprising:
  • a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20;
  • PD-L1 preferably human PD-L1.
  • Preferred heavy and light chain combinations include:
  • the invention provides antibodies that comprise the heavy chain and light chain CDR1s, CDR2s and CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, or combinations thereof.
  • the amino acid sequences of the V H CDR1s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively.
  • the amino acid sequences of the V H CDR2s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, respectively.
  • the amino acid sequences of the V H CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, respectively.
  • the amino acid sequences of the V k CDR1s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, respectively.
  • the amino acid sequences of the V k CDR2s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, respectively.
  • the amino acid sequences of the V k CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, respectively.
  • the CDR regions are delineated using the Kabat system (Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • V H CDR1, CDR2, and CDR3 sequences and V k CDR1, CDR2, and CDR3 sequences can be “mixed and matched” (i.e., CDRs from different antibodies can be mixed and match, although each antibody must contain a V H CDR1, CDR2, and CDR3 and a V k CDR1, CDR2, and CDR3) to create other anti-PD-L1 binding molecules of the invention.
  • PD-L1 binding of such “mixed and matched” antibodies can be tested using the binding assays described above and in the Examples (e.g., ELISAs, Biacore analysis).
  • the CDR1, CDR2 and/or CDR3 sequence from a particular V H sequence is replaced with a structurally similar CDR sequence(s).
  • V k CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular V k sequence preferably is replaced with a structurally similar CDR sequence(s).
  • V H and V L sequences can be created by substituting one or more V H and/or V L CDR region sequences with structurally similar sequences from the CDR sequences disclosed herein for monoclonal antibodies antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4.
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof comprising:
  • the antibody specifically binds PD-L1, preferably human PD-L1.
  • the antibody comprises:
  • the CDR3 domain independently from the CDR1 and/or CDR2 domain(s), alone can determine the binding specificity of an antibody for a cognate antigen and that multiple antibodies can predictably be generated having the same binding specificity based on a common CDR3 sequence. See, for example, Klimka et al., British J. of Cancer 83(2):252-260 (2000) (describing the production of a humanized anti-CD30 antibody using only the heavy chain variable domain CDR3 of murine anti-CD30 antibody Ki-4); Beiboer et al., J. Mol. Biol.
  • the present invention provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domain from a non-human antibody, such as a mouse or rat antibody, wherein the monoclonal antibody is capable of specifically binding to PD-L1.
  • inventive antibodies comprising one or more heavy and/or light chain CDR3 domain from a non-human antibody are capable of competing for binding with; (b) retain the functional characteristics; (c) bind to the same epitope; and/or (d) have a similar binding affinity as the corresponding parental non-human antibody.
  • the present invention provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domain from a first human antibody, such as, for example, a human antibody obtained from a non-human animal, wherein the first human antibody is capable of specifically binding to PD-L1 and wherein the CDR3 domain from the first human antibody replaces a CDR3 domain in a human antibody that is lacking binding specificity for PD-L1 to generate a second human antibody that is capable of specifically binding to PD-L1.
  • a first human antibody such as, for example, a human antibody obtained from a non-human animal
  • the first human antibody is capable of specifically binding to PD-L1
  • the CDR3 domain from the first human antibody replaces a CDR3 domain in a human antibody that is lacking binding specificity for PD-L1 to generate a second human antibody that is capable of specifically binding to PD-L1.
  • antibodies of the instant disclosure comprising one or more heavy and/or light chain CDR3 domain from the first human antibody (a) are capable of competing for binding with; (b) retain the functional characteristics; (c) bind to the same epitope; and/or (d) have a similar binding affinity as the corresponding parental first human antibody.
  • an antibody of the invention comprises a heavy chain variable region from a particular germline heavy chain immunoglobulin gene and/or a light chain variable region from a particular germline light chain immunoglobulin gene.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-18 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-69 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 1-3 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 3-9 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L6 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L15 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K A27 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L18 gene, wherein the antibody specifically binds PD-L1.
  • the invention provides an isolated monoclonal antibody, or antigen-binding portion thereof, wherein the antibody:
  • (a) comprises a heavy chain variable region that is the product of or derived from a human V H 1-18, 1-69, 1-3 or 3-9 gene (which encodes the amino acid sequences set forth in SEQ ID NOs:101, 102, 103 and 104, respectively);
  • (b) comprises a light chain variable region that is the product of or derived from a human V K L6, L15, A27 or L18 gene (which encodes the amino acid sequences set forth in SEQ ID NOs:105, 106, 107 and 108, respectively); and
  • (c) specifically binds to PD-L1, preferably human PD-L1.
  • An example of an antibody having V H and V K of V H 1-18 and V K L6, respectively, is 3G10.
  • An example of an antibody having V H and V K of V H 1-3 and V K L15, respectively, is 10A5.
  • Examples of antibodies having V H and V K of V H 1-69 and V K A27, respectively, are 5F8, 11E6 and 11E6a.
  • An example of an antibody having V H and V K of V H 3-9 and V K L15, respectively, is 10H10.
  • An example of an antibody having V H and V K of V H 1-3 and V K L15, respectively, is 10A5.
  • An example of an antibody having V H and V K of V H 3-9 and V K L18, respectively, is 13G4.
  • a human antibody comprises heavy or light chain variable regions that is “the product of” or “derived from” a particular germline sequence if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin genes.
  • Such systems include immunizing a transgenic mouse carrying human immunoglobulin genes with the antigen of interest or screening a human immunoglobulin gene library displayed on phage with the antigen of interest.
  • a human antibody that is “the product of” or “derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequences of human germline immunoglobulins and selecting the human germline immunoglobulin sequence that is closest in sequence (i.e., greatest % identity) to the sequence of the human antibody.
  • a human antibody that is “the product of” or “derived from” a particular human germline immunoglobulin sequence may contain amino acid differences as compared to the germline sequence, due to, for example, naturally-occurring somatic mutations or intentional introduction of site-directed mutation.
  • a selected human antibody is generally at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences).
  • a human antibody may be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene.
  • a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene.
  • the human antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene.
  • an antibody of the invention comprises heavy and light chain variable regions comprising amino acid sequences that are homologous to the amino acid sequences of the preferred antibodies described herein, and wherein the antibodies retain the desired functional properties of the anti-PD-L1 antibodies of the invention.
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
  • the V H and/or V L amino acid sequences may be 85%, 90%, 95%, 96%, 97%, 98% or 99% homologous to the sequences set forth above.
  • An antibody having V H and V L regions having high (i.e., 80% or greater) homology to the V H and V L regions of the sequences set forth above can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of nucleic acid molecules encoding SEQ ID NOs:25, 26, 27, 28, 29, and 30, followed by testing of the encoded altered antibody for retained function (i.e., the functions set forth in (c) through (h) above) using the functional assays described herein.
  • mutagenesis e.g., site-directed or PCR-mediated mutagenesis
  • the percent homology between two amino acid sequences is equivalent to the percent identity between the two sequences.
  • 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 amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller ( Comput. Appl. Biosci., 4:11-17 (1988)) 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. Mol. Biol.
  • the protein sequences of the present disclosure can be further 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 XBLAST program (version 2.0) of Altschul, et al. (1990) J. Mol. 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
  • the default parameters of the respective programs e.g., XBLAST and NBLAST
  • an antibody of the invention comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences, wherein one or more of these CDR sequences comprise specified amino acid sequences based on the preferred antibodies described herein (e.g., 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4), or conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the anti-PD-L1 antibodies of the invention.
  • the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein:
  • the heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, and conservative modifications thereof;
  • the light chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequence of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, and conservative modifications thereof;
  • the antibody binds to human PD-L1 with a K D of 1 ⁇ 10 ⁇ 7 M or less;
  • the antibody increases interferon- ⁇ production in an MLR assay
  • the heavy chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and conservative modifications thereof; and the light chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and conservative modifications thereof.
  • the heavy chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, and conservative modifications thereof; and the light chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, and conservative modifications thereof.
  • conservative sequence modifications is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are 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.
  • 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
  • aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine
  • one or more amino acid residues within the CDR regions of an antibody of the invention can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for retained function (i.e., the functions set forth in (c) through (h) above) using the functional assays described herein.
  • the invention provides antibodies that bind to the same epitope on human PD-L1 as any of the PD-L1 monoclonal antibodies of the invention (i.e., antibodies that have the ability to cross-compete for binding to PD-L1 with any of the monoclonal antibodies of the invention).
  • the reference antibody for cross-competition studies can be the monoclonal antibody 3G10 (having V H and V L sequences as shown in SEQ ID NOs:1 and 11, respectively), or the monoclonal antibody 12A4 (having V H and V L sequences as shown in SEQ ID NOs:2 and 12, respectively), or the monoclonal antibody 10A5 (having V H and V L sequences as shown in SEQ ID NOs:3 and 13, respectively), or the monoclonal antibody 10A5 (having V H and V L sequences as shown in SEQ ID NOs:3 and 13, respectively), or the monoclonal antibody 5F8 (having V H and V L sequences as shown in SEQ ID NOs:4 and 14, respectively), or the monoclonal antibody 10H10 (having V H and V L sequences as shown in SEQ ID NOs:5 and 15, respectively), or the monoclonal antibody 1B12 (having V H and V L sequences as shown in SEQ ID NOs:6 and 16, respectively), or
  • cross-competing antibodies can be identified based on their ability to cross-compete with 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 in standard PD-L1 binding assays.
  • BIAcore analysis, ELISA assays or flow cytometry may be used to demonstrate cross-competition with the antibodies of the current invention.
  • test antibody to inhibit the binding of, for example, 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4, to human PD-L1 demonstrates that the test antibody can compete with 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 for binding to human PD-L1 and thus binds to the same epitope on human PD-L1 as 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4.
  • the antibody that binds to the same epitope on human PD-L1 as 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 is a human monoclonal antibody.
  • human monoclonal antibodies can be prepared and isolated as described in the Examples.
  • An antibody of the invention further can be prepared using an antibody having one or more of the V H and/or V L sequences disclosed herein as starting material to engineer a modified antibody, which modified antibody may have altered properties from the starting antibody.
  • An antibody can be engineered by modifying one or more residues within one or both variable regions (i.e., V H and/or V L ), for example within one or more CDR regions and/or within one or more framework regions. Additionally or alternatively, an antibody can be engineered by modifying residues within the constant region(s), for example to alter the effector function(s) of the antibody.
  • CDR grafting One type of variable region engineering that can be performed is CDR grafting.
  • 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.
  • another embodiment of the invention pertains to an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and SEQ ID NOs:71, 72, 73, 74, 75, 76,
  • such antibodies contain the V H and V L CDR sequences of monoclonal antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 yet may contain different framework sequences from these antibodies.
  • Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • germline DNA sequences for human heavy and light chain variable region genes can be found in the “VBase” human germline sequence database (available on the Internet at www.mrc-cpe.cam.ac.uk/vbase), as well as in Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Tomlinson, I. M., et al.
  • Antibody protein sequences are compared against a compiled protein sequence database using one of the sequence similarity searching methods called the Gapped BLAST (Altschul et al. (1997) Nucleic Acids Research 25:3389-3402), which is well known to those skilled in the art.
  • BLAST is a heuristic algorithm in that a statistically significant alignment between the antibody sequence and the database sequence is likely to contain high-scoring segment pairs (HSP) of aligned words. Segment pairs whose scores cannot be improved by extension or trimming is called a hit.
  • HSP high-scoring segment pairs
  • nucleotide sequences of VBASE origin are translated and the region between and including FR1 through FR3 framework region is retained.
  • the database sequences have an average length of 98 residues. Duplicate sequences which are exact matches over the entire length of the protein are removed.
  • the nucleotide sequences are translated in all six frames and the frame with no stop codons in the matching segment of the database sequence is considered the potential hit. This is in turn confirmed using the BLAST program tblastx. This translates the antibody sequence in all six frames and compares those translations to the VBASE nucleotide sequences dynamically translated in all six frames.
  • the identities are exact amino acid matches between the antibody sequence and the protein database over the entire length of the sequence.
  • the positives are not identical but amino acid substitutions guided by the BLOSUM62 substitution matrix. If the antibody sequence matches two of the database sequences with same identity, the hit with most positives would be decided to be the matching sequence hit.
  • Preferred framework sequences for use in the antibodies of the invention are those that are structurally similar to the framework sequences used by selected antibodies of the invention, e.g., similar to the V H 1-18 framework sequences (SEQ ID NO:101) and/or the V H 1-69 framework sequences (SEQ ID NO:102) and/or the V H 1-3 framework sequences (SEQ ID NO:103) and/or the V H 3-9 framework sequences (SEQ ID NO:104) and/or the V K L6 framework sequences (SEQ ID NO:105) and/or the V K L15 framework sequences (SEQ ID NO:106) and/or the V K A27 framework sequences (SEQ ID NO:107) and/or the V K L18 framework sequences (SEQ ID NO:107) used by preferred monoclonal antibodies of the invention.
  • V H CDR1, CDR2, and CDR3 sequences can be grafted onto framework regions that have the identical sequence as that found in the germline immunoglobulin gene from which the framework sequence derive, or the CDR sequences can be grafted onto framework regions that contain one or more mutations as compared to the germline sequences.
  • variable region modification is to mutate amino acid residues within the V H and/or V K CDR1, CDR2 and/or CDR3 regions to thereby improve one or more binding properties (e.g., affinity) of the antibody of interest.
  • Site-directed mutagenesis or PCR-mediated mutagenesis can be performed to introduce the mutation(s) and the effect on antibody binding, or other functional property of interest, can be evaluated in in vitro or in vivo assays as described herein and provided in the Examples.
  • Preferably conservative modifications are introduced.
  • the mutations may be amino acid substitutions, additions or deletions, but are preferably substitutions.
  • typically no more than one, two, three, four or five residues within a CDR region are altered.
  • the invention provides isolated anti-PD-L1 monoclonal antibodies, or antigen binding portions thereof, comprising a heavy chain variable region comprising: (a) a V H CDR1 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30; (b) a V H CDR2 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40; (c) a V H CDR3 region comprising an amino acid sequence
  • Engineered antibodies of the invention include those in which modifications have been made to framework residues within V H and/or V K , e.g. to improve the properties of the antibody. Typically such framework modifications are made to decrease the immunogenicity of the antibody. For example, one approach is to “backmutate” one or more framework residues to the corresponding germline sequence. More specifically, an antibody that has undergone somatic mutation may contain framework residues that differ from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the antibody framework sequences to the germline sequences from which the antibody is derived.
  • the somatic mutations can be “backmutated” to the germline sequence by, for example, site-directed mutagenesis or PCR-mediated mutagenesis.
  • the alignment of the V H region for 3G10 against the parent germline V H 1-18 sequence is shown in FIG. 11 .
  • the alignment of the V H region for 12A4 against the parent germline V H 1-69 sequence is shown in FIG. 12 .
  • the alignment of the V H region for 10A5 against the parent germline V H 1-3 sequence is shown in FIG. 13 .
  • the alignment of the V H region for 5F8 against the parent germline V H 1-69 sequence is shown in FIG. 14 .
  • the alignment of the V H region for 10H10 against the parent germline V H 3-9 sequence is shown in FIG. 15 .
  • the alignment of the V H region for 1B12 against the parent germline V H 1-69 sequence is shown in FIG. 16 .
  • the alignment of the V H region for 7H1 against the parent germline V H 1-69 sequence is shown in FIG. 17 .
  • the alignment of the V H region for 11E6 against the parent germline V H 1-69 sequence is shown in FIG. 18 .
  • the alignment of the V H region for 12B7 against the parent germline V H 1-69 sequence is shown in FIG. 19 .
  • the alignment of the V H region for 13G4 against the parent germline V H 3-9 sequence is shown in FIG. 20 .
  • amino acid residue #79 (within FR3) of V H is a valine whereas this residue in the corresponding V H 1-18 germline sequence is an alanine.
  • the somatic mutations can be “backmutated” to the germline sequence by, for example, site-directed mutagenesis or PCR-mediated mutagenesis (e.g., residue #79 (residue #13 of FR3) of the V H of 3G10 can be “backmutated” from valine to alanine).
  • amino acid residue #24 (within FR1) of V H is a threonine whereas this residue in the corresponding V H 1-69 germline sequence is an alanine.
  • residue #24 of the V H of 12A4 can be “backmutated” from threonine to alanine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #27 (within FR1) of V H is an aspartic acid whereas this residue in the corresponding V H 1-69 germline sequence is a glycine.
  • residue #27 of the V H of 12A4 can be “backmutated” from aspartic acid to glycine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #95 (within FR3) of V H is a phenylalanine whereas this residue in the corresponding V H 1-69 germline sequence is a tyrosine.
  • residue #95 (residue #29 of FR3) of the V H of 12A4 can be “backmutated” from phenylalanine to tyrosine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #24 (within FR1) is a valine whereas this residue in the corresponding V H 1-69 germline sequence is an alanine.
  • residue #24 of the V H of 5F8 can be “backmutated” from valine to alanine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #28 (within FR1) is an isoleucine whereas this residue in the corresponding V H 1-69 germline sequence is an threonine.
  • residue #28 of the V H of 5F8 can be “backmutated” from isoleucine to threonine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #24 (within FR1) is a valine whereas this residue in the corresponding V H 3-9 germline sequence is an alanine.
  • residue #24 of the V H of 10H10 can be “backmutated” from valine to alanine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • an amino acid can be inserted following amino acid residue #97 (within FR3).
  • This amino acid is a valine.
  • the inserted amino acid following residue #97 of the V H of 10H10 can be “backmutated” to delete this valine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #24 (within FR1) is a threonine whereas this residue in the corresponding V H 1-69 germline sequence is an alanine.
  • residue #24 of the V H of 1B12 can be “backmutated” from threonine to alanine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #27 (within FR1) is an aspartic acid whereas this residue in the corresponding V H 1-69 germline sequence is an glycine.
  • residue #27 of the V H of 1B12 can be “backmutated” from aspartic acid to glycine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #95 (within FR3) is a phenylalanine whereas this residue in the corresponding V H 1-69 germline sequence is an tyrosine.
  • residue #95 residue #29 of FR3
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #24 (within FR1) is a threonine whereas this residue in the corresponding V H 1-69 germline sequence is an alanine.
  • residue #24 of the V H of 7H1 can be “backmutated” from threonine to alanine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #77 (within FR3) is a threonine whereas this residue in the corresponding V H 1-69 germline sequence is a serine.
  • residue #72 residue #11 of FR3 of the V H of 7H1 can be “backmutated” from threonine to serine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #78 (within FR3) is an alanine whereas this residue in the corresponding V H 1-69 germline sequence is a threonine.
  • residue #78 residue 12 of FR3 of the V H of 11E6 can be “backmutated” from alanine to threonine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #13 (within FR1) is a glutamic acid whereas this residue in the corresponding V H 1-69 germline sequence is an lysine.
  • residue #13 of the V H of 12B7 can be “backmutated” glutamic acid to lysine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #30 (within FR1) is an asparagine whereas this residue in the corresponding V H 1-69 germline sequence is an serine.
  • residue #30 of the V H of 12B7 can be “backmutated” from asparagine to serine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #77 (within FR3) is an asparagine whereas this residue in the corresponding V H 1-69 germline sequence is an serine.
  • residue #377 residue 11 of FR3 of the V H of 12B7 can be “backmutated” from asparagine to serine.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #82 (within FR3) is an aspartic acid whereas this residue in the corresponding V H 1-69 germline sequence is a glutamic acid.
  • residue #82 (residue #16 of FR3) of the V H of 12B7 can be “backmutated” from aspartic acid to glutamic acid.
  • Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • amino acid residue #27 (within FR1) is an isoleucine whereas this residue in the corresponding V H 1-69 germline sequence is an phenylalanine.
  • residue #27 of the V H of 12B7 can be “backmutated” from isoleucine to phenylalanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • Another type of framework modification involves mutating one or more residues within the framework region, or even within one or more CDR regions, to remove T cell epitopes to thereby reduce the potential immunogenicity of the antibody. This approach is also referred to as “deimmunization” and is described in further detail in U.S. Patent Publication No. 20030153043 by Carr et al.
  • antibodies of the invention may be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity.
  • an antibody of the invention may be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its glycosylation, again to alter one or more functional properties of the antibody.
  • the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased.
  • This approach is described further in U.S. Pat. No. 5,677,425 by Bodmer et al.
  • the number of cysteine residues in the hinge region of CH1 is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.
  • the Fc hinge region of an antibody is mutated to decrease the biological half life of the antibody. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has impaired Staphylococcyl protein A (SpA) binding relative to native Fc-hinge domain SpA binding.
  • SpA Staphylococcyl protein A
  • the antibody is modified to increase its biological half life.
  • Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375 to Ward.
  • the antibody can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Pat. Nos. 5,869,046 and 6,121,022 by Presta et al.
  • the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector function(s) of the antibody.
  • one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320 and 322 can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody.
  • the effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.
  • one or more amino acids selected from amino acid residues 329, 331 and 322 can be replaced with a different amino acid residue such that the antibody has altered C1q binding and/or reduced or abolished complement dependent cytotoxicity (CDC).
  • CDC complement dependent cytotoxicity
  • one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94/29351 by Bodmer et al.
  • the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or to increase the affinity of the antibody for an Fc ⁇ receptor by modifying one or more amino acids at the following positions: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438 or 439.
  • ADCC antibody dependent cellular cytotoxicity
  • the glycosylation of an antibody is modified.
  • an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation).
  • Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen.
  • carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence.
  • one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site.
  • Such aglycosylation may increase the affinity of the antibody for antigen.
  • an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures.
  • altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies.
  • carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation.
  • the cell lines Ms704, Ms705, and Ms709 lack the fucosyltransferase gene, FUT8 (alpha (1,6) fucosyltransferase), such that antibodies expressed in the Ms704, Ms705, and Ms709 cell lines lack fucose on their carbohydrates.
  • the Ms704, Ms705, and Ms709 FUT8 ⁇ / ⁇ cell lines were created by the targeted disruption of the FUT8 gene in CHO/DG44 cells using two replacement vectors (see U.S. Patent Publication No. 20040110704 by Yamane et al. and Yamane-Ohnuki et al. (2004) Biotechnol Bioeng 87:614-22).
  • EP 1,176,195 by Hanai et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation by reducing or eliminating the alpha 1,6 bond-related enzyme.
  • Hanai et al. also describe cell lines which have a low enzyme activity for adding fucose to the N-acetylglucosamine that binds to the Fc region of the antibody or does not have the enzyme activity, for example the rat myeloma cell line YB2/0 (ATCC CRL 1662).
  • PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Lec13 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields, R. L. et al. (2002) J. Biol. Chem. 277:26733-26740).
  • PCT Publication WO 99/54342 by Umana et al.
  • glycoprotein-modifying glycosyl transferases e.g., beta(1,4)-N-acetylglucosaminyltransferase III (GnTIII)
  • GnTIII glycoprotein-modifying glycosyl transferases
  • the fucose residues of the antibody may be cleaved off using a fucosidase enzyme.
  • the fucosidase alpha-L-fucosidase removes fucosyl residues from antibodies (Tarentino, A. L. et al. (1975) Biochem. 14:5516-23).
  • an antibody can be pegylated to, for example, increase the biological (e.g., serum) half life of the antibody.
  • the antibody, or fragment thereof typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment.
  • PEG polyethylene glycol
  • the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer).
  • polyethylene glycol is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (C1-C10) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide.
  • the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies of the invention. See for example, EP 0 154 316 by Nishimura et al. and EP 0 401 384 by Ishikawa et al.
  • the anti-PD-L1 antibodies having V H and V K sequences disclosed herein can be used to create new anti-PD-L1 antibodies by modifying the VH and/or V K sequences, or the constant region(s) attached thereto.
  • the structural features of an anti-PD-L1 antibody of the invention e.g. 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, or 13G4, are used to create structurally related anti-PD-L1 antibodies that retain at least one functional property of the antibodies of the invention, such as binding to human PD-L1.
  • one or more CDR regions of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, or 13G4 or mutations thereof can be combined recombinantly with known framework regions and/or other CDRs to create additional, recombinantly-engineered, anti-PD-L1 antibodies of the invention, as discussed above.
  • Other types of modifications include those described in the previous section.
  • the starting material for the engineering method is one or more of the V H and/or V K sequences provided herein, or one or more CDR regions thereof.
  • the engineered antibody it is not necessary to actually prepare (i.e., express as a protein) an antibody having one or more of the V H and/or V K sequences provided herein, or one or more CDR regions thereof. Rather, the information contained in the sequence(s) is used as the starting material to create a “second generation” sequence(s) derived from the original sequence(s) and then the “second generation” sequence(s) is prepared and expressed as a protein.
  • the invention provides a method for preparing an anti-PD-L1 antibody comprising:
  • a heavy chain variable region antibody sequence comprising a CDR1 sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, a CDR2 sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and/or a CDR3 sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; and/or (ii) a light chain variable region antibody sequence comprising a CDR1 sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, a CDR2 sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and/or a CDR3 sequence selected from the group consisting of SEQ ID NOs:61,
  • Standard molecular biology techniques can be used to prepare and express the altered antibody sequence.
  • the antibody encoded by the altered antibody sequence(s) is one that retains one, some or all of the functional properties of the anti-PD-L1 antibodies described herein, which functional properties include, but are not limited to:
  • the functional properties of the altered antibodies can be assessed using standard assays available in the art and/or described herein, such as those set forth in the Examples (e.g., flow cytometry, binding assays).
  • mutations can be introduced randomly or selectively along all or part of an anti-PD-L1 antibody coding sequence and the resulting modified anti-PD-L1 antibodies can be screened for binding activity and/or other functional properties as described herein.
  • Mutational methods have been described in the art.
  • PCT Publication WO 02/092780 by Short describes methods for creating and screening antibody mutations using saturation mutagenesis, synthetic ligation assembly, or a combination thereof.
  • PCT Publication WO 03/074679 by Lazar et al. describes methods of using computational screening methods to optimize physiochemical properties of antibodies.
  • nucleic acid molecules that encode the antibodies of the invention.
  • 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. (1987) Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York.
  • a nucleic acid of the invention can be, for example, DNA or RNA and may or may not contain intronic sequences.
  • the nucleic acid is a cDNA molecule.
  • Nucleic acids of the invention can be obtained using standard molecular biology techniques.
  • hybridomas e.g., hybridomas prepared from transgenic mice carrying human immunoglobulin genes as described further below
  • cDNAs encoding the light and heavy chains of the antibody made by the hybridoma can be obtained by standard PCR amplification or cDNA cloning techniques.
  • nucleic acid encoding the antibody can be recovered from the library.
  • Preferred nucleic acids molecules of the invention are those encoding the VH and VL sequences of the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, monoclonal antibodies.
  • DNA sequences encoding the VH sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, are shown in SEQ ID NOs:81, 82, 83, 84, 85, 86, 87, 88, 89 and 90, respectively.
  • DNA sequences encoding the VL sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, are shown in SEQ ID NOs:91, 92, 93, 94, 95, 96, 97, 98, 99 and 100, respectively.
  • VH and VL segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene.
  • a VL- or VH-encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker.
  • the term “operatively linked,” as used in this context, is intended to mean that the two DNA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
  • the isolated DNA encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding DNA to another DNA molecule encoding heavy chain constant regions (CH1, CH2 and CH3).
  • heavy chain constant regions CH1, CH2 and CH3
  • the sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat, E. A., el al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
  • the heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most preferably is an IgG1 or IgG4 constant region.
  • the VH-encoding DNA can be operatively linked to another DNA molecule encoding only the heavy chain CH1 constant region.
  • the isolated DNA encoding the VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL.
  • the sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
  • the light chain constant region can be a kappa or lambda constant region, but most preferably is a kappa constant region.
  • the VH- and VL-encoding DNA fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly 4 -Ser) 3 , such that the VH and VL sequences can be expressed as a contiguous single-chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., (1990) Nature 348:552-554).
  • a flexible linker e.g., encoding the amino acid sequence (Gly 4 -Ser) 3
  • Monoclonal antibodies (mAbs) of the present invention can be produced by a variety of techniques, including conventional monoclonal antibody methodology e.g., the standard somatic cell hybridization technique of Kohler and Milstein (1975) Nature 256: 495. Although somatic cell hybridization procedures are preferred, in principle, other techniques for producing monoclonal antibody can be employed e.g., viral or oncogenic transformation of B lymphocytes.
  • hybridomas The preferred animal system for preparing hybridomas is the murine system.
  • Hybridoma production in the mouse is a very well-established procedure. Immunization protocols and techniques for isolation of immunized splenocytes for fusion are known in the art. Fusion partners (e.g., murine myeloma cells) and fusion procedures are also known.
  • Chimeric or humanized antibodies of the present invention can be prepared based on the sequence of a murine monoclonal antibody prepared as described above.
  • DNA encoding the heavy and light chain immunoglobulins can be obtained from the murine hybridoma of interest and engineered to contain non-murine (e.g., human) immunoglobulin sequences using standard molecular biology techniques.
  • the murine variable regions can be linked to human constant regions using methods known in the art (see e.g., U.S. Pat. No. 4,816,567 to Cabilly et al.).
  • the murine CDR regions can be inserted into a human framework using methods known in the art (see e.g., U.S. Pat. No. 5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.).
  • the antibodies of the invention are human monoclonal antibodies.
  • Such human monoclonal antibodies directed against PD-L1 can be generated using transgenic or transchromosomic mice carrying parts of the human immune system rather than the mouse system.
  • transgenic and transchromosomic mice include mice referred to herein as HuMAb mice and KM MiceTM, respectively, and are collectively referred to herein as “human Ig mice.”
  • the HuMAb Mouse® (Medarex, Inc.) contains human immunoglobulin gene miniloci that encode unrearranged human heavy ( ⁇ and ⁇ ) and ⁇ light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous ⁇ and ⁇ chain loci (see e.g., Lonberg, et al. (1994) Nature 368(6474): 856-859). Accordingly, the mice exhibit reduced expression of mouse IgM or ⁇ , 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 (Lonberg, N. et al. (1994), supra; reviewed in Lonberg, N.
  • human antibodies of the invention can be raised using a mouse that carries human immunoglobulin sequences on transgenes and transchomosomes, such as a mouse that carries a human heavy chain transgene and a human light chain transchromosome.
  • KM MiceTM are described in detail in PCT Publication WO 02/43478 to Ishida et al.
  • transgenic animal systems expressing human immunoglobulin genes are available in the art and can be used to raise anti-PD-L1 antibodies of the invention.
  • an alternative transgenic system referred to as the Xenomouse (Abgenix, Inc.) can be used; such mice are described in, for example, U.S. Pat. Nos. 5,939,598; 6,075,181; 6,114,598; 6,150,584 and 6,162,963 to Kucherlapati et al.
  • mice carrying both a human heavy chain transchromosome and a human light chain tranchromosome referred to as “TC mice” can be used; such mice are described in Tomizuka et al. (2000) Proc. Natl. Acad. Sci. USA 97:722-727.
  • cows carrying human heavy and light chain transchromosomes have been described in the art (Kuroiwa et al. (2002) Nature Biotechnology 20:889-894) and can be used to raise anti-PD-L1 antibodies of the invention.
  • Human monoclonal antibodies of the invention can also be prepared using phage display methods for screening libraries of human immunoglobulin genes. Such phage display methods for isolating human antibodies are established in the art. See for example: U.S. Pat. Nos. 5,223,409; 5,403,484; and U.S. Pat. No. 5,571,698 to Ladner et al.; U.S. Pat. Nos. 5,427,908 and 5,580,717 to Dower et al.; U.S. Pat. Nos. 5,969,108 and 6,172,197 to McCafferty et al.; and U.S. Pat. Nos. 5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915 and 6,593,081 to Griffiths et al.
  • Human monoclonal antibodies of the invention can also be prepared using SCID mice into which human immune cells have been reconstituted such that a human antibody response can be generated upon immunization.
  • SCID mice into which human immune cells have been reconstituted such that a human antibody response can be generated upon immunization.
  • Such mice are described in, for example, U.S. Pat. Nos. 5,476,996 and 5,698,767 to Wilson et al.
  • mice When human Ig mice are used to raise human antibodies of the invention, such mice can be immunized with a purified or enriched preparation of PD-L1 antigen and/or recombinant PD-L1, or an PD-L1 fusion protein, as described by Lonberg, N. et al. (1994) Nature 368(6474): 856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851; and PCT Publication WO 98/24884 and WO 01/14424.
  • the mice will be 6-16 weeks of age upon the first infusion.
  • a purified or recombinant preparation (5-50 ⁇ g) of PD-L1 antigen can be used to immunize the human Ig mice intraperitoneally.
  • Example 1 Detailed procedures to generate fully human monoclonal antibodies to PD-L1 are described in Example 1 below. Cumulative experience with various antigens has shown that the transgenic mice respond when initially immunized intraperitoneally (IP) with antigen in complete Freund's adjuvant, followed by every other week IP immunizations (up to a total of 6) with antigen in incomplete Freund's adjuvant. However, adjuvants other than Freund's are also found to be effective. In addition, whole cells in the absence of adjuvant are found to be highly immunogenic. The immune response can be monitored over the course of the immunization protocol with plasma samples being obtained by retroorbital bleeds.
  • mice with sufficient titers of anti-PD-L1 human immunoglobulin can be used for fusions.
  • Mice can be boosted intravenously with antigen 3 days before sacrifice and removal of the spleen. It is expected that 2-3 fusions for each immunization may need to be performed. Between 6 and 24 mice are typically immunized for each antigen.
  • HCo7 and HCo12 strains are used.
  • both HCo7 and HCo12 transgene can be bred together into a single mouse having two different human heavy chain transgenes (HCo7/HCo12).
  • the KM MouseTM strain can be used, as described in Example 1.
  • splenocytes and/or lymph node cells from immunized mice can be isolated and fused to an appropriate immortalized cell line, such as a mouse myeloma cell line.
  • an appropriate immortalized cell line such as a mouse myeloma cell line.
  • the resulting hybridomas can be screened for the production of antigen-specific antibodies.
  • single cell suspensions of splenic lymphocytes from immunized mice can be fused to one-sixth the number of P3X63-Ag8.653 nonsecreting mouse myeloma cells (ATCC, CRL 1580) with 50% PEG.
  • Cells are plated at approximately 2 ⁇ 10 5 in flat bottom microtiter plate, followed by a two week incubation in selective medium containing 20% fetal Clone Serum, 18% “653” conditioned media, 5% origen (IGEN), 4 mM L-glutamine, 1 mM sodium pyruvate, 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 units/ml penicillin, 50 mg/ml streptomycin, 50 mg/ml gentamycin and 1 ⁇ HAT (Sigma; the HAT is added 24 hours after the fusion). After approximately two weeks, cells can be cultured in medium in which the HAT is replaced with HT.
  • selective medium containing 20% fetal Clone Serum, 18% “653” conditioned media, 5% origen (IGEN), 4 mM L-glutamine, 1 mM sodium pyruvate, 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 units/ml penicillin
  • selected hybridomas can be grown in two-liter spinner-flasks for monoclonal antibody purification.
  • Supernatants can be filtered and concentrated before affinity chromatography with protein A-sepharose (Pharmacia, Piscataway, N.J.).
  • Eluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity.
  • the buffer solution can be exchanged into PBS, and the concentration can be determined by OD280 using 1.43 extinction coefficient.
  • the monoclonal antibodies can be aliquoted and stored at ⁇ 80° C.
  • Antibodies of the invention also can be produced in a host cell transfectoma using, for example, a combination of recombinant DNA techniques and gene transfection methods as is well known in the art (e.g., Morrison, S. (1985) Science 229:1202).
  • DNAs encoding partial or full-length light and heavy chains can be obtained by standard molecular biology techniques (e.g., PCR amplification or cDNA cloning using a hybridoma that expresses the antibody of interest) and the DNAs can be inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences.
  • operatively linked is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene.
  • the expression vector and expression control sequences are chosen to be compatible with the expression host cell used.
  • the antibody light chain gene and the antibody heavy chain gene can be inserted into separate vector or, more typically, both genes are inserted into the same expression vector.
  • the antibody genes are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present).
  • the light and heavy chain variable regions of the antibodies described herein can be used to create full-length antibody genes of any antibody isotype by inserting them into expression vectors already encoding heavy chain constant and light chain constant regions of the desired isotype such that the V H segment is operatively linked to the C H segment(s) within the vector and the V K segment is operatively linked to the C L segment within the vector.
  • the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell.
  • the antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene.
  • the signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
  • the recombinant expression vectors of the invention carry regulatory sequences that control the expression of the antibody chain genes in a host cell.
  • the term “regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes.
  • Such regulatory sequences are described, for example, in Goeddel (Gene Expression Technology. Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990)). It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences, may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc.
  • Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV), Simian Virus 40 (SV40), adenovirus, (e.g., the adenovirus major late promoter (AdMLP) and polyoma.
  • CMV cytomegalovirus
  • SV40 Simian Virus 40
  • AdMLP adenovirus major late promoter
  • nonviral regulatory sequences may be used, such as the ubiquitin promoter or ⁇ -globin promoter.
  • regulatory elements composed of sequences from different sources such as the SR ⁇ promoter system, which contains sequences from the SV40 early promoter and the long terminal repeat of human T cell leukemia virus type 1 (Takebe, Y. et al. (1988) Mol. Cell. Biol. 8:466-472).
  • the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
  • the selectable marker gene facilitates selection of host cells into which the vector has been introduced (see, e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al.).
  • the selectable marker gene confers resistance to drugs, such as G418, hygromycin or methotrexate, on a host cell into which the vector has been introduced.
  • Preferred selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr-host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
  • DHFR dihydrofolate reductase
  • the expression vector(s) encoding the heavy and light chains is transfected into a host cell by standard techniques.
  • the various forms of the term “transfection” are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like.
  • Preferred mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr-CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R. J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621), NSO myeloma cells, COS cells and SP2 cells.
  • another preferred expression system is the GS gene expression system disclosed in WO 87/04462, WO 89/01036 and EP 338,841.
  • the antibodies When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.
  • Antibodies of the invention can be tested for binding to PD-L1 by, for example, standard ELISA. Briefly, microtiter plates are coated with purified PD-L1 at 0.25 ⁇ g/ml in PBS, and then blocked with 5% bovine serum albumin in PBS. Dilutions of antibody (e.g., dilutions of plasma from PD-L1-immunized mice) are added to each well and incubated for 1-2 hours at 37° C.
  • the plates are washed with PBS/Tween and then incubated with secondary reagent (e.g., for human antibodies, a goat-anti-human IgG Fc-specific polyclonal reagent) conjugated to alkaline phosphatase for 1 hour at 37° C. After washing, the plates are developed with pNPP substrate (1 mg/ml), and analyzed at OD of 405-650. Preferably, mice which develop the highest titers will be used for fusions.
  • secondary reagent e.g., for human antibodies, a goat-anti-human IgG Fc-specific polyclonal reagent conjugated to alkaline phosphatase for 1 hour at 37° C.
  • secondary reagent e.g., for human antibodies, a goat-anti-human IgG Fc-specific polyclonal reagent conjugated to alkaline phosphatase for 1 hour at 37° C.
  • secondary reagent e.g., for human antibodies,
  • An ELISA assay as described above can also be used to screen for hybridomas that show positive reactivity with PD-L1 immunogen.
  • Hybridomas that bind with high avidity to PD-L1 are subcloned and further characterized.
  • One clone from each hybridoma, which retains the reactivity of the parent cells (by ELISA) can be chosen for making a 5-10 vial cell bank stored at ⁇ 140° C., and for antibody purification.
  • selected hybridomas can be grown in two-liter spinner-flasks for monoclonal antibody purification.
  • Supernatants can be filtered and concentrated before affinity chromatography with protein A-sepharose (Pharmacia, Piscataway, N.J.).
  • Eluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity.
  • the buffer solution can be exchanged into PBS, and the concentration can be determined by OD 280 using 1.43 extinction coefficient.
  • the monoclonal antibodies can be aliquoted and stored at ⁇ 80° C.
  • each antibody can be biotinylated using commercially available reagents (Pierce, Rockford, Ill.). Competition studies using unlabeled monoclonal antibodies and biotinylated monoclonal antibodies can be performed using PD-L1 coated-ELISA plates as described above. Biotinylated mAb binding can be detected with a strep-avidin-alkaline phosphatase probe.
  • isotype ELISAs can be performed using reagents specific for antibodies of a particular isotype. For example, to determine the isotype of a human monoclonal antibody, wells of microtiter plates can be coated with 1 ⁇ g/ml of anti-human immunoglobulin overnight at 4° C. After blocking with 1% BSA, the plates are reacted with 1 ⁇ g/ml or less of test monoclonal antibodies or purified isotype controls, at ambient temperature for one to two hours. The wells can then be reacted with either human IgG1 or human IgM-specific alkaline phosphatase-conjugated probes. Plates are developed and analyzed as described above.
  • Anti-PD-L1 human IgGs can be further tested for reactivity with PD-L1 antigen by Western blotting. Briefly, PD-L1 can be prepared and subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis. After electrophoresis, the separated antigens are transferred to nitrocellulose membranes, blocked with 10% fetal calf serum, and probed with the monoclonal antibodies to be tested. Human IgG binding can be detected using anti-human IgG alkaline phosphatase and developed with BCIP/NBT substrate tablets (Sigma Chem. Co., St. Louis, Mo.).
  • the antibodies of the present invention may be further characterized by the various physical properties of the anti-PD-L1 antibodies.
  • Various assays may be used to detect and/or differentiate different classes of antibodies based on these physical properties.
  • antibodies of the present invention may contain one or more glycosylation sites in either the light or heavy chain variable region.
  • the presence of one or more glycosylation sites in the variable region may result in increased immunogenicity of the antibody or an alteration of the pK of the antibody due to altered antigen binding (Marshall et al (1972) Annu Rev Biochem 41:673-702; Gala F A and Morrison S L (2004) J Immunol 172:5489-94; Wallick et al (1988) J Exp Med 168:1099-109; Spiro R G (2002) Glycobiology 12:43R-56R; Parekh et al (1985) Nature 316:452-7; Mimura et al.
  • variable region glycosylation may be tested using a Glycoblot assay, which cleaves the antibody to produce a Fab, and then tests for glycosylation using an assay that measures periodate oxidation and Schiff base formation.
  • variable region glycosylation may be tested using Dionex light chromatography (Dionex-LC), which cleaves saccharides from a Fab into monosaccharides and analyzes the individual saccharide content.
  • Dionex-LC Dionex light chromatography
  • the antibodies of the present invention do not contain asparagine isomerism sites.
  • a deamidation or isoaspartic acid effect may occur on N-G or D-G sequences, respectively.
  • the deamidation or isoaspartic acid effect results in the creation of isoaspartic acid which decreases the stability of an antibody by creating a kinked structure off a side chain carboxy terminus rather than the main chain.
  • the creation of isoaspartic acid can be measured using an iso-quant assay, which uses a reverse-phase HPLC to test for isoaspartic acid.
  • Each antibody will have a unique isoelectric point (pI), but generally antibodies will fall in the pH range of between 6 and 9.5.
  • the pI for an IgG1 antibody typically falls within the pH range of 7-9.5 and the pI for an IgG4 antibody typically falls within the pH range of 6-8.
  • Antibodies may have a pI that is outside this range. Although the effects are generally unknown, there is speculation that antibodies with a pI outside the normal range may have some unfolding and instability under in vivo conditions.
  • the isoelectric point may be tested using a capillary isoelectric focusing assay, which creates a pH gradient and may utilize laser focusing for increased accuracy (Janini et al (2002) Electrophoresis 23:1605-11; Ma et al.
  • an anti-PD-L1 antibody that contains a pI value that falls in the normal range. This can be achieved either by selecting antibodies with a pI in the normal range, or by mutating charged surface residues using standard techniques well known in the art.
  • each antibody will have a melting temperature that is indicative of thermal stability (Krishnamurthy R and Manning M C (2002) Curr Pharm Biotechnol 3:361-71). A higher thermal stability indicates greater overall antibody stability in vivo.
  • the melting point of an antibody may be measure using techniques such as differential scanning calorimetry (Chen et al (2003) Pharm Res 20:1952-60; Ghirlando et al (1999) Immunol Lett 68:47-52).
  • T M1 indicates the temperature of the initial unfolding of the antibody.
  • T M2 indicates the temperature of complete unfolding of the antibody.
  • the T M1 of an antibody of the present invention is greater than 60° C., preferably greater than 65° C., even more preferably greater than 70° C.
  • the thermal stability of an antibody may be measure using circular dichroism (Murray et al. (2002) J Chromatogr Sci 40:343-9).
  • Table 1 The thermal stability of anti-PD-L1 antibodies disclosed herein is summarized in Table
  • antibodies are selected that do not rapidly degrade. Fragmentation of an anti-PD-L1 antibody may be measured using capillary electrophoresis (CE) and MALDI-MS, as is well understood in the art (Alexander A J and Hughes D E (1995) Anal Chem 67:3626-32).
  • CE capillary electrophoresis
  • MALDI-MS MALDI-MS
  • antibodies are selected that have minimal aggregation effects. Aggregation may lead to triggering of an unwanted immune response and/or altered or unfavorable pharmacokinetic properties. Generally, antibodies are acceptable with aggregation of 25% or less, preferably 20% or less, even more preferably 15% or less, even more preferably 10% or less and even more preferably 5% or less. Aggregation may be measured by several techniques well known in the art, including size-exclusion column (SEC) high performance liquid chromatography (HPLC), and light scattering to identify monomers, dimers, trimers or multimers.
  • SEC size-exclusion column
  • HPLC high performance liquid chromatography
  • the present invention features an anti-PD-L1 antibody, or a fragment thereof, conjugated to a therapeutic moiety, such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radiotoxin.
  • a therapeutic moiety such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radiotoxin.
  • conjugates are referred to herein as “immunoconjugates”.
  • Immunoconjugates that include one or more cytotoxins are referred to as “immunotoxins.”
  • a cytotoxin or cytotoxic agent includes 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 also include, for example, 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., vin
  • An example of a calicheamicin antibody conjugate is commercially available (MylotargTM; Wyeth-Ayerst).
  • Cytotoxins can be conjugated to antibodies of the invention using linker technology available in the art.
  • linker types that have been used to conjugate a cytotoxin to an antibody include, but are not limited to, hydrazones, thioethers, esters, disulfides and peptide-containing linkers.
  • a linker can be chosen that is, for example, susceptible to cleavage by low pH within the lysosomal compartment or susceptible to cleavage by proteases, such as proteases preferentially expressed in tumor tissue such as cathepsins (e.g., cathepsins B, C, D).
  • Antibodies of the present invention also can be conjugated to a radioactive isotope to generate cytotoxic radiopharmaceuticals, also referred to as radioimmunoconjugates.
  • radioactive isotopes that can be conjugated to antibodies for use diagnostically or therapeutically include, but are not limited to, iodine 131 , indium 111 , yttrium 90 and lutetium 177 .
  • Method for preparing radioimmunconjugates are established in the art. Examples of radioimmunoconjugates are commercially available, including ZevalinTM (IDEC Pharmaceuticals) and BexxarTM (Corixa Pharmaceuticals), and similar methods can be used to prepare radioimmunoconjugates using the antibodies of the invention.
  • the antibody conjugates of the invention can be used to modify a given biological response, and the drug 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- ⁇ ; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.
  • IL-1 interleukin-1
  • IL-2 interleukin-2
  • IL-6 interleukin-6
  • the present invention features bispecific molecules comprising an anti-PD-L1 antibody, or a fragment thereof, of the invention.
  • An antibody of the invention, or antigen-binding portions thereof can be derivatized or linked to another functional molecule, e.g., another peptide or protein (e.g., another antibody or ligand for a receptor) to generate a bispecific molecule that binds to at least two different binding sites or target molecules.
  • the antibody of the invention may in fact be derivatized or linked to more than one other functional molecule to generate multispecific molecules that bind to more than two different binding sites and/or target molecules; such multispecific molecules are also intended to be encompassed by the term “bispecific molecule” as used herein.
  • an antibody of the invention can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other binding molecules, such as another antibody, antibody fragment, peptide or binding mimetic, such that a bispecific molecule results.
  • the present invention includes bispecific molecules comprising at least one first binding specificity for PD-L1 and a second binding specificity for a second target epitope.
  • the second target epitope is an Fc receptor, e.g., human Fc ⁇ RI (CD64) or a human Fc ⁇ receptor (CD89). Therefore, the invention includes bispecific molecules capable of binding both to Fc ⁇ R or Fc ⁇ R expressing effector cells (e.g., monocytes, macrophages or polymorphonuclear cells (PMNs)), and to target cells expressing PD-L1.
  • bispecific molecules target PD-L1 expressing cells to effector cell and trigger Fc receptor-mediated effector cell activities, such as phagocytosis of an PD-L1 expressing cells, antibody dependent cell-mediated cytotoxicity (ADCC), cytokine release, or generation of superoxide anion.
  • ADCC antibody dependent cell-mediated cytotoxicity
  • the molecule can further include a third binding specificity, in addition to an anti-Fc binding specificity and an anti-PD-L1 binding specificity.
  • the third binding specificity is an anti-enhancement factor (EF) portion, e.g., a molecule which binds to a surface protein involved in cytotoxic activity and thereby increases the immune response against the target cell.
  • EF anti-enhancement factor
  • the “anti-enhancement factor portion” can be an antibody, functional antibody fragment or a ligand that binds to a given molecule, e.g., an antigen or a receptor, and thereby results in an enhancement of the effect of the binding determinants for the F C receptor or target cell antigen.
  • the “anti-enhancement factor portion” can bind an F C receptor or a target cell antigen.
  • the anti-enhancement factor portion can bind to an entity that is different from the entity to which the first and second binding specificities bind.
  • the anti-enhancement factor portion can bind a cytotoxic T-cell (e.g. via CD2, CD3, CD8, CD28, CD4, CD40, ICAM-1 or other immune cell that results in an increased immune response against the target cell).
  • the bispecific molecules of the invention comprise as a binding specificity at least one antibody, or an antibody fragment thereof, including, e.g., an Fab, Fab′, F(ab′) 2 , Fv, or a single chain Fv.
  • the antibody may also be a light chain or heavy chain dimer, or any minimal fragment thereof such as a Fv or a single chain construct as described in Ladner et al. U.S. Pat. No. 4,946,778, the contents of which is expressly incorporated by reference.
  • the binding specificity for an Fc ⁇ receptor is provided by a monoclonal antibody, the binding of which is not blocked by human immunoglobulin G (IgG).
  • IgG receptor refers to any of the eight ⁇ -chain genes located on chromosome 1. These genes encode a total of twelve transmembrane or soluble receptor isoforms which are grouped into three Fc ⁇ receptor classes: Fc ⁇ RI (CD64), Fc ⁇ RII(CD32), and Fc ⁇ RIII (CD16).
  • the Fc ⁇ receptor a human high affinity Fc ⁇ RI.
  • the human Fc ⁇ RI is a 72 kDa molecule, which shows high affinity for monomeric IgG (10 8 -10 9 M ⁇ 1 ).
  • the hybridoma producing mAb 32 is available from the American Type Culture Collection, ATCC Accession No. HB9469.
  • the anti-Fc ⁇ receptor antibody is a humanized form of monoclonal antibody 22 (H22).
  • H22 monoclonal antibody 22
  • the production and characterization of the H22 antibody is described in Graziano, R. F. et al. (1995) J. Immunol 155 (10): 4996-5002 and PCT Publication WO 94/10332.
  • the H22 antibody producing cell line was deposited at the American Type Culture Collection under the designation HA022CL1 and has the accession no. CRL 11177.
  • the binding specificity for an Fc receptor is provided by an antibody that binds to a human IgA receptor, e.g., an Fc-alpha receptor (Fc ⁇ RI (CD89)), the binding of which is preferably not blocked by human immunoglobulin A (IgA).
  • IgA receptor is intended to include the gene product of one ⁇ -gene (Fc ⁇ RI) located on chromosome 19. This gene is known to encode several alternatively spliced transmembrane isoforms of 55 to 110 kDa.
  • Fc ⁇ RI (CD89) is constitutively expressed on monocytes/macrophages, eosinophilic and neutrophilic granulocytes, but not on non-effector cell populations.
  • Fc ⁇ RI has medium affinity ( ⁇ 5 ⁇ 10 7 M ⁇ 1 ) for both IgA1 and IgA2, which is increased upon exposure to cytokines such as G-CSF or GM-CSF (Morton, H. C. et al. (1996) Critical Reviews in Immunology 16:423-440).
  • cytokines such as G-CSF or GM-CSF
  • Fc ⁇ RI and Fc ⁇ RI are preferred trigger receptors for use in the bispecific molecules of the invention because they are (1) expressed primarily on immune effector cells, e.g., monocytes, PMNs, macrophages and dendritic cells; (2) expressed at high levels (e.g., 5,000-100,000 per cell); (3) mediators of cytotoxic activities (e.g., ADCC, phagocytosis); (4) mediate enhanced antigen presentation of antigens, including self-antigens, targeted to them.
  • immune effector cells e.g., monocytes, PMNs, macrophages and dendritic cells
  • mediators of cytotoxic activities e.g., ADCC, phagocytosis
  • human monoclonal antibodies are preferred, other antibodies which can be employed in the bispecific molecules of the invention are murine, chimeric and humanized monoclonal antibodies.
  • the bispecific molecules of the present invention can be prepared by conjugating the constituent binding specificities, e.g., the anti-FcR and anti-PD-L1 binding specificities, using methods known in the art. For example, each binding specificity of the bispecific molecule can be generated separately and then conjugated to one another. When the binding specificities are proteins or peptides, a variety of coupling or cross-linking agents can be used for covalent conjugation.
  • cross-linking agents examples include protein A, carbodiimide, N-succinimidyl-S-acetyl-thioacetate (SATA), 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), o-phenylenedimaleimide (oPDM), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), and sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohaxane-1-carboxylate (sulfo-SMCC) (see e.g., Karpovsky et al. (1984) J. Exp. Med.
  • Preferred conjugating agents are SATA and sulfo-SMCC, both available from Pierce Chemical Co. (Rockford, Ill.).
  • the binding specificities are antibodies, they can be conjugated via sulfhydryl bonding of the C-terminus hinge regions of the two heavy chains.
  • the hinge region is modified to contain an odd number of sulfhydryl residues, preferably one, prior to conjugation.
  • both binding specificities can be encoded in the same vector and expressed and assembled in the same host cell.
  • This method is particularly useful where the bispecific molecule is a mAb ⁇ mAb, mAb ⁇ Fab, Fab ⁇ F(ab′) 2 or ligand x Fab fusion protein.
  • a bispecific molecule of the invention can be a single chain molecule comprising one single chain antibody and a binding determinant, or a single chain bispecific molecule comprising two binding determinants. Bispecific molecules may comprise at least two single chain molecules. Methods for preparing bispecific molecules are described for example in U.S. Pat. No. 5,260,203; U.S. Pat. No. 5,455,030; U.S. Pat. No. 4,881,175; U.S.
  • Binding of the bispecific molecules to their specific targets can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, bioassay (e.g., growth inhibition), or Western Blot assay.
  • ELISA enzyme-linked immunosorbent assay
  • RIA radioimmunoassay
  • FACS fluorescence-activated cell sorting
  • bioassay e.g., growth inhibition
  • Western Blot assay Western Blot assay.
  • Each of these assays generally detects the presence of protein-antibody complexes of particular interest by employing a labeled reagent (e.g., an antibody) specific for the complex of interest.
  • a labeled reagent e.g., an antibody
  • the FcR-antibody complexes can be detected using e.g., an enzyme-linked antibody or antibody fragment which recognizes and specifically binds to the antibody-FcR complexes.
  • the antibody can be radioactively labeled and used in a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein).
  • RIA radioimmunoassay
  • the radioactive isotope can be detected by such means as the use of a ⁇ counter or a scintillation counter or by autoradiography.
  • the present invention provides a composition, e.g., a pharmaceutical composition, containing one or a combination of monoclonal antibodies, or antigen-binding portion(s) thereof, of the present invention, formulated together with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention can comprise a combination of antibodies (or immunoconjugates or bispecifics) that bind to different epitopes on the target antigen or that have complementary activities.
  • compositions of the invention also can be administered in combination therapy, i.e., combined with other agents.
  • the combination therapy can include an anti-PD-L1 antibody of the present invention combined with at least one other anti-inflammatory or immunosuppressant agent. Examples of therapeutic agents that can be used in combination therapy are described in greater detail below in the section on uses of the antibodies of 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, immunoconjuage, or bispecific molecule
  • the active compound i.e., antibody, immunoconjuage, or bispecific 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.
  • the pharmaceutical compounds of the invention may include one or more pharmaceutically acceptable salts.
  • 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 pharmaceutical composition of the invention also may include a pharmaceutically acceptable anti-oxidant.
  • pharmaceutically acceptable antioxidants 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
  • 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.
  • 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.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • 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.
  • the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • 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 0.01 percent to about ninety-nine percent of active ingredient, preferably from about 0.1 percent to about 70 percent, most preferably from about 1 percent to about 30 percent of active ingredient in combination with a pharmaceutically acceptable carrier.
  • 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. 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.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight.
  • dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg.
  • An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.
  • Preferred dosage regimens for an anti-PD-L1 antibody of the invention include 1 mg/kg body weight or 3 mg/kg body weight via intravenous administration, with the antibody being given using one of the following dosing schedules: (i) every four weeks for six dosages, then every three months; (ii) every three weeks; (iii) 3 mg/kg body weight once followed by 1 mg/kg body weight every three weeks.
  • two or more monoclonal antibodies with different binding specificities are administered simultaneously, in which case the dosage of each antibody administered falls within the ranges indicated.
  • Antibody is usually administered on multiple occasions. Intervals between single dosages can be, for example, weekly, monthly, every three months or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to the target antigen in the patient. In some methods, dosage is adjusted to achieve a plasma antibody concentration of about 1-1000 ⁇ g/ml and in some methods about 25-300 ⁇ g/ml.
  • antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the antibody in the patient. In general, human antibodies show the longest half life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regime.
  • Actual dosage levels of the active ingredients in the pharmaceutical 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 “therapeutically effective dosage” of an anti-PD-L1 antibody of the invention preferably results in a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • a “therapeutically effective dosage” preferably inhibits cell growth or tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects.
  • the ability of a compound to inhibit tumor growth can be evaluated in an animal model system predictive of efficacy in human tumors.
  • this property of a composition can be evaluated by examining the ability of the compound to inhibit, such inhibition in vitro by assays known to the skilled practitioner.
  • a therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in a subject.
  • One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.
  • a composition of the present invention can be administered via one or more routes of administration using one or more of a variety of methods known in the art.
  • routes and/or mode of administration will vary depending upon the desired results.
  • Preferred routes of administration for antibodies of the invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration 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 intrasternal injection and infusion.
  • an antibody of the invention can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • a non-parenteral route such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • 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.
  • 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.
  • 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
  • the human monoclonal antibodies of the invention can be formulated to ensure proper distribution in vivo.
  • the blood-brain barrier 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).
  • Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low et al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153:1038); antibodies (P. G. Bloeman et al. (1995) FEBS Lett. 357:140; M. Owais et al. (1995) Antimicrob. Agents Chemother. 39:180); surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol. 1233:134); p120 (Schreier et al. (1994) J. Biol. Chem. 269:9090); see also K. Keinanen; M. L. Laukkanen (1994) FEBS Lett. 346:123; J. J. Killion; I. J. Fidler (1994) Immunomethods 4:273.
  • the antibodies, antibody compositions and methods of the present invention have numerous in vitro and in vivo utilities involving, for example, detection of PD-L1 or enhancement of immune response by blockade of PD-L1.
  • the antibodies of the present invention are human antibodies.
  • these molecules can be administered to cells in culture, in vitro or ex vivo, or to human subjects, e.g., in vivo, to enhance immunity in a variety of situations.
  • the invention provides a method of modifying an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of the invention such that the immune response in the subject is modified.
  • the response is enhanced, stimulated or up-regulated.
  • the term “subject” is intended to include human and non-human animals.
  • Non-human animals includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cows and horses.
  • Preferred subjects include human patients in need of enhancement of an immune response.
  • the methods are particularly suitable for treating human patients having a disorder that can be treated by augmenting the T-cell mediated immune response.
  • the methods are particularly suitable for treatment of cancer cells in vivo.
  • the anti-PD-L1 antibodies can be administered together with an antigen of interest. When antibodies to PD-L1 are administered together with another agent, the two can be administered in either order or simultaneously.
  • the invention further provides methods for detecting the presence of human PD-L1 antigen in a sample, or measuring the amount of human PD-L1 antigen, comprising contacting the sample, and a control sample, with a human monoclonal antibody, or an antigen binding portion thereof, which specifically binds to human PD-L1, under conditions that allow for formation of a complex between the antibody or portion thereof and human PD-L1. The formation of a complex is then detected, wherein a difference complex formation between the sample compared to the control sample is indicative the presence of human PD-L1 antigen in the sample.
  • Blockade of PD-L1 by antibodies can enhance the immune response to cancerous cells in the patient.
  • PD-L1 is not expressed in normal human cells, but is abundant in a variety of human cancers (Dong et al. (2002) Nat Med 8:787-9).
  • the interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells (Dong et al. (2003) J Mol Med 81:281-7; Blank et al. (2004) Cancer Immunol. Immunother . [epub]; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100).
  • Immune suppression can be reversed by inhibiting the local interaction of PD-L1 to PD-1 and the effect is additive when the interaction of PD-L2 to PD-1 is blocked as well (Iwai et al. (2002) PNAS 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66).
  • An anti-PD-L1 antibody may be used alone to inhibit the growth of cancerous tumors.
  • an anti-PD-L1 antibody may be used in conjunction with other immunogenic agents, standard cancer treatments, or other antibodies, as described below.
  • the invention provides a method of inhibiting growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof.
  • the antibody is a human anti-PD-L1 antibody (such as any of the human anti-human PD-L1 antibodies described herein). Additionally or alternatively, the antibody may be a chimeric or humanized anti-PD-L1 antibody.
  • Preferred cancers whose growth may be inhibited using the antibodies of the invention include cancers typically responsive to immunotherapy.
  • preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer.
  • cancers examples include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid
  • antibodies to PD-L1 can be combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J Immunol. 173:4919-28).
  • an immunogenic agent such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J Immunol. 173:4919-28).
  • tumor vaccines include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MART1 and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF (discussed further below).
  • tumors have been shown to be immunogenic such as melanomas. It is anticipated that by raising the threshold of T cell activation by PD-L1 blockade, we may expect to activate tumor responses in the host.
  • PD-L1 blockade is likely to be most effective when combined with a vaccination protocol.
  • Many experimental strategies for vaccination against tumors have been devised (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C., 2000, ASCO Educational Book Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring: 414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; see also Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita, V. et al. (eds.), 1997, Cancer: Principles and Practice of Oncology. Fifth Edition).
  • a vaccine is prepared using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci U.S.A. 90: 3539-43).
  • tumor specific antigens are differentiation antigens expressed in the tumors and in the cell from which the tumor arose, for example melanocyte antigens gp100, MAGE antigens, and Trp-2. More importantly, many of these antigens can be shown to be the targets of tumor specific T cells found in the host.
  • PD-L1 blockade may be used in conjunction with a collection of recombinant proteins and/or peptides expressed in a tumor in order to generate an immune response to these proteins.
  • the tumor antigen may also include the protein telomerase, which is required for the synthesis of telomeres of chromosomes and which is expressed in more than 85% of human cancers and in only a limited number of somatic tissues (Kim, N et al. (1994) Science 266: 2011-2013). (These somatic tissues may be protected from immune attack by various means).
  • Tumor antigen may also be “neo-antigens” expressed in cancer cells because of somatic mutations that alter protein sequence or create fusion proteins between two unrelated sequences (i.e. bcr-abl in the Philadelphia chromosome), or idiotype from B cell tumors.
  • tumor vaccines may include the proteins from viruses implicated in human cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV).
  • HPV Human Papilloma Viruses
  • HBV Hepatitis Viruses
  • KHSV Kaposi's Herpes Sarcoma Virus
  • Another form of tumor specific antigen which may be used in conjunction with PD-L1 blockade is purified heat shock proteins (HSP) isolated from the tumor tissue itself. These heat shock proteins contain fragments of proteins from the tumor cells and these HSPs are highly efficient at delivery to antigen presenting cells for eliciting tumor immunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588; Tamura, Y. et al. (1997) Science 278:117-120).
  • HSP heat shock proteins
  • DC Dendritic cells
  • DC's can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DCs may also be transduced by genetic means to express these tumor antigens as well. DCs have also been fused directly to tumor cells for the purposes of immunization (Kugler, A. et al. (2000) Nature Medicine 6:332-336). As a method of vaccination, DC immunization may be effectively combined with PD-L1 blockade to activate more potent anti-tumor responses.
  • PD-L1 blockade may also be combined with standard cancer treatments. PD-L1 blockade may be effectively combined with chemotherapeutic regimes. In these instances, it may be possible to reduce the dose of chemotherapeutic reagent administered (Mokyr, M. et al. (1998) Cancer Research 58: 5301-5304).
  • An example of such a combination is an anti-PD-L1 antibody in combination with decarbazine for the treatment of melanoma.
  • Another example of such a combination is an anti-PD-L1 antibody in combination with interleukin-2 (IL-2) for the treatment of melanoma.
  • IL-2 interleukin-2
  • PD-L1 blockade The scientific rationale behind the combined use of PD-L1 blockade and chemotherapy is that cell death, that is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway.
  • Other combination therapies that may result in synergy with PD-L1 blockade through cell death are radiation, surgery, and hormone deprivation. Each of these protocols creates a source of tumor antigen in the host.
  • Angiogenesis inhibitors may also be combined with PD-L1 blockade. Inhibition of angiogenesis leads to tumor cell death which may feed tumor antigen into host antigen presentation pathways.
  • PD-L1 blocking antibodies can also be used in combination with bispecific antibodies that target Fc alpha or Fc ⁇ receptor-expressing effectors cells to tumor cells (see, e.g., U.S. Pat. Nos. 5,922,845 and 5,837,243).
  • Bispecific antibodies can be used to target two separate antigens.
  • anti-Fc receptor/anti tumor antigen e.g., Her-2/neu
  • bispecific antibodies have been used to target macrophages to sites of tumor. This targeting may more effectively activate tumor specific responses.
  • the T cell arm of these responses would by augmented by the use of PD-L1 blockade.
  • antigen may be delivered directly to DCs by the use of bispecific antibodies which bind to tumor antigen and a dendritic cell specific cell surface marker.
  • Tumors evade host immune surveillance by a large variety of mechanisms. Many of these mechanisms may be overcome by the inactivation of proteins which are expressed by the tumors and which are immunosuppressive. These include among others TGF-beta (Kehrl, J. et al. (1986) J. Exp. Med. 163: 1037-1050), IL-10 (Howard, M. & O'Garra, A. (1992) Immunology Today 13: 198-200), and Fas ligand (Hahne, M. et al. (1996) Science 274: 1363-1365). Antibodies to each of these entities may be used in combination with anti-PD-L1 to counteract the effects of the immunosuppressive agent and favor tumor immune responses by the host.
  • Anti-CD40 antibodies are able to substitute effectively for T cell helper activity (Ridge, J. et al. (1998) Nature 393: 474-478) and can be used in conjunction with PD-L1 antibodies (Ito, N. et al. (2000) Immunobiology 201 (5) 527-40).
  • Activating antibodies to T cell costimulatory molecules such as OX-40 (Weinberg, A. et al. (2000) Immunol 164: 2160-2169), 4-1BB (Melero, I. et al.
  • Bone marrow transplantation is currently being used to treat a variety of tumors of hematopoietic origin. While graft versus host disease is a consequence of this treatment, therapeutic benefit may be obtained from graft vs. tumor responses.
  • PD-L1 blockade can be used to increase the effectiveness of the donor engrafted tumor specific T cells.
  • another aspect of the invention provides a method of treating an infectious disease in a subject comprising administering to the subject an anti-PD-L1 antibody, or antigen-binding portion thereof, such that the subject is treated for the infectious disease.
  • the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein).
  • the antibody can be a chimeric or humanized antibody.
  • antibody mediated PD-L1 blockade can be used alone, or as an adjuvant, in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens.
  • pathogens for which this therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa .
  • PD-L1 blockade is particularly useful against established infections by agents such as HIV that present altered antigens over the course of the infections. These novel epitopes are recognized as foreign at the time of anti-human PD-L1 administration, thus provoking a strong T cell response that is not dampened by negative signals through PD-L1.
  • pathogenic viruses causing infections treatable by methods of the invention include HIV, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • herpes virus e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus
  • adenovirus e.g., influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie
  • pathogenic bacteria causing infections treatable by methods of the invention include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella , bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • pathogenic fungi causing infections treatable by methods of the invention include Candida ( albicans, krusei, glabrata, tropicalis , etc.), Cryptococcus neoformans, Aspergillus ( fumigatus, niger , etc.), Genus Mucorales ( mucor, absidia, rhizophus ), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • pathogenic parasites causing infections treatable by methods of the invention include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis.
  • PD-L1 blockade can be combined with other forms of immunotherapy such as cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), or bispecific antibody therapy, which provides for enhanced presentation of tumor antigens (see, e.g., Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak (1994) Structure 2:1121-1123).
  • cytokine treatment e.g., interferons, GM-CSF, G-CSF, IL-2
  • bispecific antibody therapy which provides for enhanced presentation of tumor antigens
  • Anti-PD-L1 antibodies may provoke and amplify autoimmune responses. Indeed, induction of anti-tumor responses using tumor cell and peptide vaccines reveals that many anti-tumor responses involve anti-self reactivities (depigmentation observed in anti-CTLA-4+GM-CSF-modified B16 melanoma in van Elsas et al. supra; depigmentation in Trp-2 vaccinated mice (Overwijk, W. et al. (1999) Proc. Natl. Acad. Sci. U.S.A. 96: 2982-2987); autoimmune prostatitis evoked by TRAMP tumor cell vaccines (Hurwitz, A. (2000) supra), melanoma peptide antigen vaccination and vitilago observed in human clinical trials (Rosenberg, S A and White, D E (1996) J. Immunother Emphasis Tumor Immunol 19 (1): 81-4).
  • anti-PD-L1 blockade in conjunction with various self proteins in order to devise vaccination protocols to efficiently generate immune responses against these self proteins for disease treatment.
  • Alzheimer's disease involves inappropriate accumulation of A ⁇ peptide in amyloid deposits in the brain; antibody responses against amyloid are able to clear these amyloid deposits (Schenk et al., (1999) Nature 400: 173-177).
  • Analogous methods as described above for the use of anti-PD-L1 antibody can be used for induction of therapeutic autoimmune responses to treat patients having an inappropriate accumulation of other self-antigens, such as amyloid deposits, including A ⁇ in Alzheimer's disease, cytokines such as TNF ⁇ , and IgE.
  • Anti-PD-L1 antibodies may be used to stimulate antigen-specific immune responses by coadministration of an anti-PD-L1 antibody with an antigen of interest (e.g., a vaccine). Accordingly, in another aspect the invention provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) an anti-PD-L1 antibody, or antigen-binding portion thereof, such that an immune response to the antigen in the subject is enhanced.
  • the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • the antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen.
  • antigens include those discussed in the sections above, such as the tumor antigens (or tumor vaccines) discussed above, or antigens from the viruses, bacteria or other pathogens described above.
  • Anti-PD-L1 antibodies may also be used to abrogate secondary effects associated with diseases such as T cell suppressed wasting disease with colitis (Kanai et al. (2003) J. Immunol. 171:4156-63). Accordingly, in another aspect the invention provides a method of abrogating leukocyte infiltration, decreasing production of IFN- ⁇ , IL-2, and IFN- ⁇ by T cells.
  • the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • Anti-PD-L1 antibodies may also be used to treat diseases such as chronic inflammatory diseases, such as lichen planus, a T-cell mediated chronic inflammatory mucocutaneous disease (Youngnak-Piboonratanakit et al. (2004) Immunol Letters 94:215-22). Accordingly, in another aspect the invention provides a method of abrogating chronic inflammatory disease by T cells.
  • the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • Suitable routes of administering the antibody compositions e.g., human monoclonal antibodies, multispecific and bispecific molecules and immunoconjugates
  • the antibody compositions can be administered by injection (e.g., intravenous or subcutaneous).
  • Suitable dosages of the molecules used will depend on the age and weight of the subject and the concentration and/or formulation of the antibody composition.
  • human anti-PD-L1 antibodies of the invention can be co-administered with one or other more therapeutic agents, e.g., a cytotoxic agent, a radiotoxic agent or an immunosuppressive agent.
  • the antibody can be linked to the agent (as an immunocomplex) or can be administered separate from the agent. In the latter case (separate administration), the antibody can be administered before, after or concurrently with the agent or can be co-administered with other known therapies, e.g., an anti-cancer therapy, e.g., radiation.
  • Such therapeutic agents include, among others, anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient.
  • anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient.
  • Cisplatin is intravenously administered as a 100 mg/dose once every four weeks and adriamycin is intravenously administered as a 60-75 mg/ml dose once every 21 days.
  • Co-administration of the human anti-PD-L1 antibodies, or antigen binding fragments thereof, of the present invention with chemotherapeutic agents provides two anti-cancer agents which operate via different mechanisms which yield a cytotoxic effect to human tumor cells. Such co-administration can solve problems due to development of resistance to drugs or a change in the antigenicity of the tumor cells which would render them unreactive with the antibody.
  • kits comprising the antibody compositions of the invention (e.g., human antibodies, bispecific or multispecific molecules, or immunoconjugates) and instructions for use.
  • the kit can further contain a least one additional reagent, or one or more additional human antibodies of the invention (e.g., a human antibody having a complementary activity which binds to an epitope in PD-L1 antigen distinct from the first human antibody).
  • Kits typically include a label indicating the intended use of the contents of the kit.
  • the term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
  • Immunization protocols utilized as antigen both (i) a recombinant fusion protein comprising the extracellular portion of PD-L1, and (ii) membrane bound full-length PD-L1. Both antigens were generated by recombinant transfection methods in a CHO cell line.
  • Fully human monoclonal antibodies to PD-L1 were prepared using the KM strain of transgenic transchromosomic mice, which expresses human antibody genes.
  • the endogenous mouse kappa light chain gene has been homozygously disrupted as described in Chen et al. (1993) EMBO J. 12:811-820 and the endogenous mouse heavy chain gene has been homozygously disrupted as described in Example 1 of PCT Publication WO 01/09187.
  • this mouse strain carries a human kappa light chain transgene, KCo5, as described in Fishwild et al. (1996) Nature Biotechnology 14:845-851, and a SC20 transchromosome as described in PCT Publication WO 02/43478.
  • mice of the KM-Mouse® strain were immunized with purified recombinant PD-L1-Ig and PD-L1-transfected CHO cells as antigen.
  • General immunization schemes for HuMab mice are described in Lonberg, N. et al (1994) Nature 368(6474): 856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851 and PCT Publication WO 98/24884.
  • the mice were 6-16 weeks of age upon the first infusion of antigen.
  • a purified recombinant preparation (5-50 ⁇ g) of PD-L1-Ig antigen and 5-10 ⁇ 10 6 cells were used to immunize the HuMab mice intraperitonealy (IP), subcutaneously (Sc) or via footpad injection.
  • mice were immunized twice with antigen in complete Freund's adjuvant or Ribi adjuvant IP, followed by 3-21 days IP (up to a total of 11 immunizations) with the antigen in incomplete Freund's or Ribi adjuvant.
  • the immune response was monitored by retroorbital bleeds.
  • the plasma was screened by ELISA (as described below), and mice with sufficient titers of anti-PD-L1 human immunogolobulin were used for fusions.
  • Mice were boosted intravenously with antigen 3 days before sacrifice and removal of the spleen. Typically, 10-35 fusions for each antigen were performed. Several dozen mice were immunized for each antigen.
  • mice producing antibodies that bound PD-L1 sera from immunized mice were tested by ELISA as described by Fishwild, D. et al. (1996). Briefly, microtiter plates were coated with purified recombinant PD-L1 fusion protein from transfected CHO cells at 1-2 ⁇ g/ml in PBS, 100 ⁇ l/wells incubated 4° C. overnight then blocked with 200 ⁇ l/well of 5% fetal bovine serum in PBS/Tween (0.05%). Dilutions of sera from PD-L1-immunized mice were added to each well and incubated for 1-2 hours at ambient temperature.
  • the plates were washed with PBS/Tween and then incubated with a goat-anti-human IgG polyclonal antibody conjugated with horseradish peroxidase (HRP) for 1 hour at room temperature. After washing, the plates were developed with ABTS substrate (Sigma, A-1888, 0.22 mg/ml) and analyzed by spectrophotometer at OD 415-495. Mice that developed the highest titers of anti-PD-L1 antibodies were used for fusions. Fusions were performed as described below and hybridoma supernatants were tested for anti-PD-L1 activity by ELISA.
  • HRP horseradish peroxidase
  • mice The mouse splenocytes, isolated from a KM mouse, were fused with PEG to a mouse myeloma cell line based upon standard protocols. The resulting hybridomas were then screened for the production of antigen-specific antibodies. Single cell suspensions of splenocytes from immunized mice were fused to one-fourth the number of SP2/0 nonsecreting mouse myeloma cells (ATCC, CRL 1581) with 50% PEG (Sigma).
  • Cells were plated at approximately 1 ⁇ 10 5 /well in flat bottom microtiter plate, followed by about two week incubation in selective medium containing 10% fetal bovine serum, 10% P388D1 (ATCC, CRL TIB-63) conditioned medium, 3-5% origen (IGEN) in DMEM (Mediatech, CRL 10013, with high glucose, L-glutamine and sodium pyruvate) plus 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 mg/ml gentamycin and 1 ⁇ HAT (Sigma, CRL P-7185). After 1-2 weeks, cells were cultured in medium in which the HAT was replaced with HT.
  • selective medium containing 10% fetal bovine serum, 10% P388D1 (ATCC, CRL TIB-63) conditioned medium, 3-5% origen (IGEN) in DMEM (Mediatech, CRL 10013, with high glucose, L-glutamine and sodium pyruvate) plus 5 mM HEPES, 0.05
  • Hybridoma clones 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 were selected for further analysis.
  • the cDNA sequences encoding the heavy and light chain variable regions of the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 monoclonal antibodies were obtained from the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 hybridomas, respectively, using standard PCR techniques and were sequenced using standard DNA sequencing techniques.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 3G10 are shown in FIG. 1A and in SEQ ID NO:81 and 1, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 3G10 are shown in FIG. 1B and in SEQ ID NO:91 and 11, respectively.
  • Further analysis of the 3G10 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 1A and 11 , and in SEQ ID NOs:21, 31 and 41, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 12A4 are shown in FIG. 2A and in SEQ ID NO:82 and 2, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 12A4 are shown in FIG. 2B and in SEQ ID NO:92 and 12, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 10A5 are shown in FIG. 3A and in SEQ ID NO:83 and 3, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 10A5 are shown in FIG. 3B and in SEQ ID NO:93 and 13, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 5F8 are shown in FIG. 4A and in SEQ ID NO:84 and 4, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 5F8 are shown in FIG. 4B and in SEQ ID NO:94 and 14, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 10H10 are shown in FIG. 5A and in SEQ ID NO:85 and 5, respectively.
  • nucleotide and amino acid sequences of the light chain variable region of 10H10 are shown in FIG. 5B and in SEQ ID NO:95 and 15, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 1B12 are shown in FIG. 6A and in SEQ ID NO:86 and 6, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 1B12 are shown in FIG. 6B and in SEQ ID NO:96 and 16, respectively.
  • the alignment of the 1B12 VH sequence to the germline VII 1-69 sequence is shown in FIG. 16 .
  • Further analysis of the 1B12 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 6A and 16 , and in SEQ ID NOs:26, 36, and 46, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 7H1 are shown in FIG. 7A and in SEQ ID NO:87 and 7, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 7H1 are shown in FIG. 7B and in SEQ ID NO:97 and 17, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 11E6 are shown in FIG. 4A and in SEQ ID NO:84 and 4, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 11E6 are shown in FIG. 4B and in SEQ ID NO:94 and 14, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 12B7 are shown in FIG. 9A and in SEQ ID NO:89 and 9, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 12B7 are shown in FIG. 9B and in SEQ ID NO:99 and 19, respectively.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 13G4 are shown in FIG. 10A and in SEQ ID NO:90 and 10, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 13G4 are shown in FIG. 10B and in SEQ ID NO:100 and 20, respectively.
  • binding affinity and binding kinetics of anti-PD-L1 antibodies were examined by Biacore analysis. Binding specificity, and cross-competition were examined by flow cytometry.
  • Anti-PD-L1 antibodies were characterized for affinities and binding kinetics by Biacore analysis (Biacore AB, Uppsala, Sweden). Purified recombinant human PD-L1 fusion protein was covalently linked to a CMS chip (carboxy methyl dextran coated chip) via primary amines, using standard amine coupling chemistry and kit provided by Biacore, to a density of 562 RUs. Binding was measured by flowing the antibodies in HBS EP buffer (provided by Biacore AB) at a concentration of 133 nM at a flow rate of 50 ⁇ l/min. The antigen-antibody association kinetics was followed for 1 minute and the dissociation kinetics was followed for 1 minute.
  • association and dissociation curves were fit to a 1:1 Langmuir binding model using BIAevaluation software (Biacore AB). To minimize the effects of avidity in the estimation of the binding constants, only the initial segment of data corresponding to association and dissociation phases were used for fitting.
  • the K D , k on and k off values that were determined are shown in Table 2.
  • CHO cell lines that express recombinant human PD-L1 at the cell surface were developed and used to determine the specificity of PD-L1 human monoclonal antibodies by flow cytometry.
  • CHO cells were transfected with expression plasmids containing full length cDNA encoding transmembrane forms of PD-L1. Binding of the 3G10, 10A5, and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the transfected cells with the anti-PD-L1 human monoclonal antibody. The cells were washed and binding was detected with a FITC-labeled anti-human IgG Ab.
  • FIG. 32A Human 3G10
  • 32 B HumanMAb 10A5
  • 32 C HumanMAb 12A4
  • Binding was also tested using varying concentrations of an anti-PD-L1 antibody.
  • FIG. 33 The anti-PD-L1 human monoclonal antibodies 3G10, 10A5, and 12A4 bound to the CHO cells transfected with PD-L1 in a concentration dependent manner.
  • the specificity of the anti-PD-L1 monoclonal antibodies was determined using a standard ELISA assay for binding to a human PD-L1 fusion to an immunoglobulin Fc region.
  • An Fc-fusion protein of human PD-L1 was tested for binding against the anti-PD-L1 human monoclonal antibodies 3G10, 12A4, and 10A5. Standard ELISA procedures were performed. The anti-PD-L1 human monoclonal antibodies were added at different concentrations. Goat-anti-human IgG (kappa chain-specific) polyclonal antibody conjugated with horseradish peroxidase (HRP) was used as secondary antibody. The results are shown in FIG. 34 . Each of the anti-PD-L1 human monoclonal antibodies 3G10, 12A4, and 10A5 bound with high specificity to PD-L1.
  • Anti-PD-L1 antibodies were tested by flow cytometry for binding to activated human or cynomolgus monkey T cells expressing PD-L1 on their surface.
  • Human or monkey T cells were activated by anti-CD3 antibody to induce PD-L1 expression prior to binding with a human anti-PD-L1 monoclonal antibody. Binding of the 3G10, 1B12, 13G4, and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the activated cells with serial dilutions of the anti-PD-L1 human monoclonal antibodies. An isotype control antibody was used as a negative control. The cells were washed and binding was detected with a FITC-labeled anti-human Ig-kappa light chain Ab. Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.).
  • the results are shown in FIGS. 35 and 36 .
  • Anti-PD-L1 antibodies were tested for binding to activated human T cells expressing PD-L1 on their cell surface by flow cytometry.
  • Human T cells were activated by anti-CD3 antibody to induce PD-L1 expression on T cells prior to binding with a human anti-PD-L1 monoclonal antibody. Binding of the 3G10, 10A5 and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the activated T cells with the anti-PD-L1 human monoclonal antibodies at a concentration of 20 ⁇ g/ml. An isotype control antibody was used as a negative control. The cells were washed and binding was detected with a FITC-labeled anti-human IgG Ab. Flow cytometric analyses were performed using a FACScalibur flow cytometry (Becton Dickinson, San Jose, Calif.). The results are shown in FIG.
  • the ES-2 human ovarian carcinoma cell line that expresses human PD-L1 at the cell surface was used to determine the specificity of PD-L1 human monoclonal antibodies by flow cytometry.
  • ES-2 cells were treated overnight with 500 IU/mL of recombinant hIFN- ⁇ to increase PD-L1 expression over the basal level.
  • Binding of the 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 anti-PD-L1 human monoclonal antibodies was assessed by incubating the induced cells with serial dilutions of the anti-PD-L1 human monoclonal antibody.
  • the cells were washed and binding was detected with a PE-labeled anti-human IgG Ab.
  • Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The binding was compared to isotype control antibody. The results are shown in FIG. 38 .
  • the anti-PD-L1 human monoclonal antibodies 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 bound to the hIFN- ⁇ -induced ES-2 cells in a concentration dependent manner.
  • a mixed lymphocyte reaction was employed to demonstrate the effect of blocking the PD-L1/PD-1 pathway to lymphocyte effector cells.
  • T cells in the assay were tested for proliferation, IFN- ⁇ secretion and IL-2 secretion in the presence or absence of an anti-PD-L1 human monoclonal antibody.
  • Human CD4+ T-cells were purified from PBMC using a CD4+ positive selection kit (Dynal Biotech).
  • Dendritic cells were derived from purified monocytes cultured with 1000 U/ml of IL-4 and 500 U/ml of GM-CSF (R&D Biosystems) for seven days.
  • Monocytes were prepared using a monocyte negative selection kig (Mitenyi Biotech).
  • Each culture contained 10 5 purified T-cells and 10 4 allogeneic dendritic cells in a total volume of 200 ⁇ l.
  • Anti-PD-L1 monoclonal antibody 10A5, 12A4, or 3G10 was added to each culture at different antibody concentrations. Either no antibody or an isotype control antibody was used as a negative control.
  • the cells were cultured for 5 days at 37° C. After day 5, 100 ⁇ I of medium was taken from each culture for cytokine measurement. The levels of IFN- ⁇ and IL-2 were measured using OptEIA ELISA kits (BD Biosciences). The cells were labeled with 3 H-thymidine, cultured for another 18 hours, and analyzed for cell proliferation. The results are shown in FIG. 39A (T cell proliferation), 39 B (IFN- ⁇ secretion using HuMAb 10A5), 39 C (IFN- ⁇ secretion using HuMAb 12A4 or 3G10) and 39 D (IL-2 secretion).
  • T cell proliferation T cell proliferation
  • 39 B IFN- ⁇ secretion using HuMAb 10A5
  • 39 C IFN- ⁇ secretion using HuMAb 12A4 or 3G10
  • 39 D IL-2 secretion
  • the anti-PD-L1 human monoclonal antibody 10A5 promotes T-cell proliferation, IFN- ⁇ secretion and IL-2 secretion in a concentration dependent manner.
  • the anti-PD-L1 human monoclonal antibodies 12A4 and 3G10 also showed an increase in IFN- ⁇ secretion.
  • cultures containing the control antibody did not show an increase in T cell proliferation, IFN- ⁇ or IL-2 secretion.
  • an allogeneic mixed lymphocyte reaction was employed to demonstrate the effect of blocking the PD-L1/PD-1 pathway in lymphocyte effector cells.
  • T cells in the assay were tested for proliferation and IFN- ⁇ secretion in the presence or absence of an anti-PD-L1 human monoclonal antibody or isotype control antibody.
  • Human CD4+ T-cells were purified from PBMC using a CD4+ negative selection kit (Miltenyi). Monocytes were prepared using a monocyte negative selection kit (Mitenyi Biotech). Dendritic cells were derived from purified monocytes cultured with 1000 U/ml of IL-4 and 500 U/ml of GM-CSF (R&D Biosystems) for seven days. Each MLR culture contained 10 5 purified T-cells and 10 4 allogeneic dendritic cells in a total volume of 200 ⁇ l. Anti-PD-L1 monoclonal antibody 12A4, 11E6, 3G10, 13G4, 1B12, 10A5, and 12B7 were added to each culture at different antibody concentrations.
  • Either no antibody or an isotype control antibody was used as a negative control.
  • the cells were cultured for 5 days at 37° C. On day 5, 50 ⁇ I of medium was taken from each culture for cytokine measurement and replaced with an equal volume of culture medium containing 1 ⁇ Ci of 3 H-thymidine.
  • the cells were cultured for another 18 hours, harvested, and analyzed for cell proliferation.
  • the levels of IFN- ⁇ in the culture fluid were measured using an OptEIA hIFN- ⁇ ELISA kit (BD Biosciences). The results are shown in FIG. 40 .
  • the anti-PD-L1 human monoclonal antibodies promote T-cell proliferation and IFN- ⁇ secretion in a concentration-dependent manner. In contrast, cultures containing the control antibody did not show an increase in T cell proliferation or IFN- ⁇ secretion.
  • T regulatory cells are lymphocytes that suppress the immune response. The effect of the addition of T regulatory cells on proliferation and IFN- ⁇ secretion in the allogeneic dendritic cell and T cell MLR in the presence or absence of an anti-PD-L1 human monoclonal antibody was tested.
  • T regulatory cells were purified from PBMC using a CD4+CD25+ regulatory T cell isolation kit (Miltenyi Biotec). T regulatory cells were added into a mixed lymphocyte reaction (see above) containing purified CD4+CD25 ⁇ T cells and allogeneic dendritic cells in a 2:1 ratio of CD4+CD25 ⁇ to T regulatory cells.
  • Anti-PD-L1 monoclonal antibody 10A5 was added to each culture at a concentration of 10 ⁇ g/ml. Either no antibody or an isotype control antibody was used as a negative control. The cells were cultured for 5 days at 37° C. at which time the supernatants were analyzed for IFN- ⁇ secretion using a Beadlyte cytokine detection system (Upstate).
  • the cells were labeled with 3 H-thymidine, cultured for another 18 hours, and analyzed for cell proliferation. The results are shown in FIG. 41A (T cell proliferation) and 41 B (IFN- ⁇ secretion).
  • the addition of anti-PD-L1 human monoclonal antibody 10A5 promotes both T cell proliferation and IFN- ⁇ secretion in cell cultures of allogeneic dendritic cells, T cells and T regulatory cells, indicating that anti-PD-L1 antibodies can reverse the effect of T regulatory cells in the allogeneic DC-T cell-MLR
  • human anti-PD-L1 antibodies 12A4 and 13G4, and a control antibody 1D12 were tested in the MLR assay with T regulatory cells. The results are shown in FIG. 42 (T cell proliferation) and 43 (IFN- ⁇ secretion).
  • the addition of anti-PD-L1 human monoclonal antibodies 12A4 or 13G4 partially reverses the suppression of both T cell proliferation and IFN- ⁇ secretion in cell cultures of allogeneic dendritic cells and T cells containing T-regulatory cells, indicating that anti-PD-L1 antibodies may have an effect on T-regulatory cells.
  • CMV antigen-responsive human PBMC (Astarte Biologics, Redmond, Wash.) were cultured at 2e5 cells/well in flat bottom TC-treated 96 well plates, in the presence of 0.5 ug/ml CMV lysate (Astarte Biologics)+/ ⁇ titrated anti-PD-L1 antibodies.
  • AIM-V medium Invitrogen
  • FBS heat-inactivated FBS
  • the results are shown in FIG. 44 .
  • the anti-PD-L1 human monoclonal antibodies promote IFN- ⁇ secretion by CMV-specific T-cells in a dose-dependent manner.
  • the most robust response was generated by antibodies 13G4, 1B12, and 12A4 compared to isotype control.
  • Anti-PD-L1 human monoclonal antibodies were tested for the ability to block binding of the ligand PD-L1 to PD-1 expressed on transfected CHO cells by using a cell cytometry assay.
  • PD-1 expressing CHO cells were suspended in FACS buffer (PBS with 4% fetal calf serum).
  • FACS buffer PBS with 4% fetal calf serum.
  • Various concentrations of the anti-PD-L1 HuMAbs 3G10, 10A5 or 12A4 was added to the cell suspension tubes at 4° C. for 30 minutes, followed by addition FITC-labeled PD-L1 fused to an immunoglobulin Fc-region.
  • Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The results are depicted in FIG. 45 .
  • the anti-PD-L1 monoclonal antibodies 3G10, 10A5, and 12A4 blocked binding of PD-L1 to CHO cells transfected with human PD-1, as measured by the mean fluorescent intensity (MFI) of staining.
  • MFI mean fluorescent intensity
  • Example 11 Inhibition of the Binding of Soluble PD-1 to Cell-Surface PD-L1 by Human Anti-PD-L1 Antibodies
  • Anti-PD-L1 human monoclonal antibodies were tested for the ability to block binding of a soluble dimeric version of the PD-1 receptor (PD-1-hFc) to PD-L1 expressed on hIFN- ⁇ -induced ES-2 human ovarian carcinoma cells using a flow cytometry assay. The blocking was compared to isotype control antibody.
  • PD-1-hFc soluble dimeric version of the PD-1 receptor
  • ES-2 cells were induced overnight with 500 IU/mL of hIFN- ⁇ to upregulate hPD-L1 cell surface expression. Induced cells were suspended in FACS buffer. Serial dilutions of the anti-PD-L1 HuMAbs 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 were added to the cell suspension tubes at 4° C. for 30 minutes, followed by two washes to remove unbound antibody. Next PD-1-hFc protein was added at a constant 2 ug/mL to all wells at 4° C. for 30 minutes, followed by two washes to remove unbound PD-1-hFc.
  • the anti-PD-L1 monoclonal antibodies 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 blocked binding of PD-1 to ES-2 cells that express human PD-L1, as measured by the geometric mean fluorescent intensity (GMFI) of staining.
  • GMFI geometric mean fluorescent intensity
  • mice implanted with a cancerous tumor are treated in vivo with anti-PD-L1 antibodies to examine the in vivo effect of the antibodies on tumor growth.
  • Female AJ mice between 6-8 weeks of age are randomized by weight into 6 groups.
  • the mice are implanted subcutaneously in the right flank with 2 ⁇ 10 6 SA1/N fibrosarcoma cells dissolved in 200 ⁇ l of DMEM media on day 0.
  • the mice are treated with PBS vehicle, or anti-PD-L1 antibodies at 10 mg/kg.
  • the animals are dosed by intraperitoneal injection with approximately 200 ⁇ l of PBS containing antibody or vehicle on days 1, 4, 8 and 11.
  • Each group contains 10 animals and the groups consist of: (i) a vehicle group, (ii) control mouse IgG, and (iii) an anti-PD-L1 antibody.
  • the mice are monitored twice weekly for tumor growth for approximately 6 weeks. Using an electronic caliper, the tumors are measured three dimensionally (height ⁇ width ⁇ length) and tumor volume is calculated. Mice are euthanized when the tumors reached tumor end point (1500 mm 3 ) or show greater than 15% weight loss.
  • Example 13 In Vivo Efficacy of Combination Therapy (Anti-CTLA-4 and Anti-PD-L1 Antibodies) on Tumor Establishment and Growth
  • MC38 colorectal cancer cells (available from Dr. N. Restifo, National Cancer Institute, Bethesda, Md.; or Jeffrey Schlom, National Institutes of Health, Bethesda, Md.) were implanted in C57BL/6 mice (2 ⁇ 10 6 cells/mouse) and selected for treatment when tumors reached a size of 100-200 mm 3 ).
  • each of four groups of 10 mice each was injected intraperitoneally (IP) with one of the following: (1) 10 mg/kg mouse IgG and 10 mg/kg of rat IgG (control), (2) 10 mg/kg anti-CTLA-4 monoclonal antibody 9D9 (mouse anti-mouse CTLA-4, obtained from J.
  • IP intraperitoneally
  • Snap frozen and OCT embedded normal and tumor tissues were purchased from Cooperative Human Tissue Network (Philadelphia, Pa.) or National Disease Research Institute (Philadelphia, Pa.). Cryostat sections at 5 ⁇ m were fixed with acetone for 10 min at room temperature, and stored at ⁇ 80° C. until use. A Medarex developed immunohistochemistry protocol was performed using unmodified HuMab anti-PD-L1 by pre-complex of the primary antibodies (12A4, 13G4, 3G10 and 12B7) and secondary antibody (FITC conjugated Fab fragment of goat anti-Hu-IgG. Jackson ImmunoResearch Laboratories. West Grove, Pa.) before applying onto the sections.
  • HuMabs There was overall less intense staining by HuMabs, especially for the staining in the germinal centers. In spleen, diffuse weak immunoreactivity in red pulp was slightly above the background staining. In addition, weak to moderate staining was displayed in Kupffer-like cells in liver and scattered cells in Peyer's patch, as well as in scattered macrophage-like cells and fibroblasts mainly in focal region of the muscularis externa of small intestine.
  • VH CDR2 a.a. 12A4 33 VH CDR2 a.a. 10A5 34 VH CDR2 a.a. 5F8 35 VH CDR2 a.a. 10H10 36 VH CDR2 a.a. 1B12 37 VH CDR2 a.a. 7H1 38 VH CDR2 a.a. 11E6 39 VH CDR2 a.a. 12B7 40 VH CDR2 a.a. 13G4 41 VH CDR3 a.a. 3G10 42 VH CDR3 a.a. 12A4 43 VH CDR3 a.a. 10A5 44 VH CDR3 a.a.
  • VK n.t. 13G4 101 VH 1-18 germline a.a. 102 VH 1-69 germline a.a. 103 VH 1-3 germline a.a. 104 VH 3-9 germline a.a. 105 VK L6 germline a.a. 106 VK L15 germline a.a. 107 VK A27 germline a.a. 108 VK L18 germline a.a. 109 VK a.a. 11E6a

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Abstract

The present disclosure provides isolated monoclonal antibodies, particularly human monoclonal antibodies that specifically bind to PD-L1 with high affinity. Nucleic acid molecules encoding the antibodies of this disclosure, expression vectors, host cells and methods for expressing the antibodies of this disclosure are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The disclosure also provides methods for detecting PD-L1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-L1 antibodies.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a divisional of U.S. application Ser. No. 15/188,860, filed Jun. 21, 2016, which is a divisional of U.S. application Ser. No. 14/807,522, filed Jul. 23, 2015, which is a divisional of U.S. application Ser. No. 13/746,773, filed Jan. 22, 2013, now U.S. Pat. No. 9,102,725, which is a divisional application of U.S. application Ser. No. 13/091,936, filed Apr. 21, 2011, now U.S. Pat. No. 8,383,796, which is a divisional application of U.S. application Ser. No. 11/917,727, having a 371(c) date of Jun. 9, 2008, now U.S. Pat. No. 7,943,743, which is a national phase of PCT Appl. No. PCT/US2006/026046, filed Jun. 30, 2006, which claims the benefit of U.S. Provisional Patent Application No. 60/696,426, filed Jul. 1, 2005, each of which is incorporated herein by reference in its entirety.
    • REFERENCE TO A SEQUENCE LISTING
  • The instant application contains a Sequence Listing, which has been submitted in ASCII text file format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jan. 23, 2017, is named “3338_0370007_SeqListing.txt”, and is 77,719 bytes in size.
    • BACKGROUND
  • Programmed death 1 (PD-1) is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA. The initial members of the family, CD28 and ICOS, were discovered by functional effect on augmenting T cell proliferation following the addition of monoclonal antibodies (Hutloff et al. (1999) Nature 397:263-266; Hansen et al. (1980) Immunogenics 10:247-260). Two cell surface glycoprotein ligands for PD-1 have been identified, PD-L1 and PD-L2, and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1 (Freeman et al. (2000) J Exp Med 192:1027-34; Latchman et al. (2001) Nat Immunol 2:261-8; Carter et al. (2002) Eur J Immunol 32:634-43; Ohigashi et al. (2005) Clin Cancer Res 11:2947-53). Both PD-L1 (B7-H1) and PD-L2 (B7-DC) are B7 homologs that bind to PD-1, but do not bind to other CD28 family members (Blank et al. (2004). Expression of PD-L1 on the cell surface has also been shown to be upregulated through IFN-γ stimulation.
  • PD-L1 expression has been found in several murine and human cancers, including human lung, ovarian and colon carcinoma and various myelomas (Iwai et al. (2002) PNAS 99:12293-7; Ohigashi et al. (2005) Clin Cancer Res 11:2947-53). PD-L1 has been suggested to play a role in tumor immunity by increasing apoptosis of antigen-specific T-cell clones (Dong et al. (2002) Nat Med 8:793-800). It has also been suggested that PD-L1 might be involved in intestinal mucosal inflammation and inhibition of PD-L1 suppresses wasting disease associated with colitis (Kanai et al. (2003) J Immunol 171:4156-63).
    • SUMMARY
  • The present invention provides isolated monoclonal antibodies, in particular human monoclonal antibodies that bind to PD-L1 and exhibit numerous desirable properties. These properties include high affinity binding to human PD-L1. Still further, antibodies of the invention have been shown to increase T-cell proliferation, IFN-γ secretion, and IL-2 secretion in a mixed lymphocyte reaction.
  • In one aspect, the invention pertains to an isolated monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody exhibits at least one of the following properties:
      • (a) binds to human PD-L1 with a KD of 1×10−7 M or less;
      • (b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
      • (c) increases interferon-γ production in an MLR assay;
      • (d) increases IL-2 secretion in an MLR assay;
      • (e) stimulates antibody responses; or
      • (f) reverses the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
        Preferably the antibody is a human antibody, although in alternative embodiments the antibody can be, for example, a murine antibody, a chimeric antibody or humanized antibody.
  • In particular embodiments, the antibody binds to human PD-L1 with a KD of 5×10−8 M or less, binds to human PD-L1 with a KD of 1×10−8 M or less, binds to human PD-L1 with a KD of 5×10−9M or less, binds to human PD-L1 with a KD of 5×10−9 M or less, or binds to human PD-L1 with a KD of between 1×10−8M and 1×10−10M.
  • In another embodiment, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, wherein the antibody cross-competes for binding to PD-L1 with a reference antibody comprising:
      • (a) the human heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and
      • (b) the human light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
        In various embodiments, the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:11;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:12;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:13;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:14;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:5; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:15;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:16;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:17;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:18;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:19;
        or the reference antibody comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:20.
  • In another aspect, the invention pertains to an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-18 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-69 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-3 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 3-9 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L6 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L15 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK A27 gene, wherein the antibody specifically binds PD-L1. The invention further provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L18 gene, wherein the antibody specifically binds PD-L1.
  • In a particularly preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 1-18 gene; and
      • (b) a light chain variable region of a human VK L6 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 1-69 gene; and
      • (b) a light chain variable region of a human VK L6 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 1-3 gene; and
      • (b) a light chain variable region of a human VK L15 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 1-69 gene; and
      • (b) a light chain variable region of a human VK A27 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 3-9 gene; and
      • (b) a light chain variable region of a human VK L15 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
      • (a) a heavy chain variable region of a human VH 3-9 gene; and
      • (b) a light chain variable region of a human VK L18 gene;
      • wherein the antibody specifically binds to PD-L1.
  • In another aspect, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising:
      • a heavy chain variable region that comprises CDR1, CDR2, and CDR3 sequences;
      • and a light chain variable region that comprises CDR1, CDR2, and CDR3 sequences, wherein:
      • (a) the heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, and conservative modifications thereof;
      • (b) the light chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, and conservative modifications thereof; and
      • (c) the antibody specifically binds to human PD-L1.
  • Preferably, the heavy chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and conservative modifications thereof; and the light chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and conservative modifications thereof. Preferably, the heavy chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, and conservative modifications thereof; and the light chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, and conservative modifications thereof.
  • In yet another aspect, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
      • (a) the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
      • (b) the light chain variable region comprises an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; and
      • (c) the antibody binds to human PD-L1 with a KD of 1×10−7 M or less.
  • In a preferred embodiment, the antibodies additionally comprise at least one of the following properties:
      • (a) the antibody increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
      • (b) the antibody increases interferon-γ production in an MLR assay; or
      • (c) the antibody increases IL-2 secretion in an MLR assay.
  • In preferred embodiments, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising:
      • (a) a heavy chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30;
      • (b) a heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40;
      • (c) a heavy chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50;
      • (d) a light chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60;
      • (e) a light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and
      • (f) a light chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;
      • wherein the antibody specifically binds PD-L1.
        A preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:21;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:31;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:41;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:51;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:61; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:71.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:22;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:32;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:42;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:52;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:62; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:72.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:23;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:33;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:43;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:53;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:63; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:73.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:24;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:34;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:44;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:54;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:64; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:74.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:25;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:35;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:45;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:55;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:65; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:75.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:26;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:36;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:46;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:56;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:66; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:76.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:27;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:37;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:47;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:57;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:67; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:77.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:28;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:38;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:48;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:58;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:68; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:78.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:29;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:39;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:49;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:59;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:69; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:79.
        Another preferred combination comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:30;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:40;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:50;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:60;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:70; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:80.
        Other preferred antibodies of the invention, or antigen binding portions thereof comprise:
      • (a) a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and
      • (b) a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; wherein the antibody specifically binds PD-L1.
        A preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:11.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:12.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:13.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:14.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:5; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:15.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:16.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:17.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:18.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:19.
        Another preferred combination comprises:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10; and
      • (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:20.
  • In another aspect of the instant disclosure, antibodies, or antigen-binding portions thereof, are provided that compete for binding to PD-L1 with any of the aforementioned antibodies.
  • The antibodies of the instant disclosure can be, for example, full-length antibodies, for example of an IgG1 or IgG4 isotype. Alternatively, the antibodies can be antibody fragments, such as Fab or Fab′2 fragments, or single chain antibodies.
  • The instant disclosure also provides an immunoconjugate comprising an antibody of the invention, or antigen-binding portion thereof, linked to a therapeutic agent, such as a cytotoxin or a radioactive isotope. The invention also provides a bispecific molecule comprising an antibody, or antigen-binding portion thereof, of the invention, linked to a second functional moiety having a different binding specificity than said antibody, or antigen binding portion thereof.
  • Compositions comprising an antibody, or antigen-binding portion thereof, or immunoconjugate or bispecific molecule of the instant disclosure and a pharmaceutically acceptable carrier are also provided.
  • Nucleic acid molecules encoding the antibodies, or antigen-binding portions thereof, of the invention are also encompassed by the invention, as well as expression vectors comprising such nucleic acids and host cells comprising such expression vectors. Moreover, the invention provides a transgenic mouse comprising human immunoglobulin heavy and light chain transgenes, wherein the mouse expresses an antibody of the invention, as well as hybridomas prepared from such a mouse, wherein the hybridoma produces the antibody of the invention.
  • In yet another aspect, the invention provides a method of modulating an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of the invention such that the immune response in the subject is modulated. Preferably, the antibody of the invention enhances, stimulates or increases the immune response in the subject.
  • In a further aspect, the invention provides a method of inhibiting growth of tumor cells in a subject, comprising administering to a subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof. The antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention). For example, a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of inhibiting tumor growth.
  • In a further aspect, the invention provides a method of treating an infectious disease in a subject, comprising administering to a subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof. The antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention). For example, a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of treating an infectious disease.
  • Still further, the invention provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) an anti-PD-L1 antibody, or antigen-binding portion thereof, such that an immune response to the antigen in the subject is enhanced. The antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen. The antibodies of the invention are preferred for use in the method although other anti-PD-L1 antibodies can be used instead (or in combination with an anti-PD-L1 antibody of the invention). For example, a chimeric, humanized or fully human anti-PD-L1 antibody can be used in the method of enhancing an immune response to an antigen in a subject.
  • The invention also provides methods for making “second generation” anti-PD-L1 antibodies based on the sequences of the anti-PD-L1 antibodies provided herein. For example, the invention provides a method for preparing an anti-PD-L1 antibody comprising:
  • (a) providing: (i) a heavy chain variable region antibody sequence comprising a CDR1 sequence that is selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, a CDR2 sequence that is selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40; and a CDR3 sequence that is selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; or (ii) a light chain variable region antibody sequence comprising a CDR1 sequence that is selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, a CDR2 sequence that is selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and a CDR3 sequence that is selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;
  • (b) altering at least one amino acid residue within at least one variable region antibody sequence, said sequence being selected from the heavy chain variable region antibody sequence and the light chain variable region antibody sequence, to create at least one altered antibody sequence; and
  • (c) expressing the altered antibody sequence as a protein.
  • Other features and advantages of the instant invention will be apparent from the following detailed description and examples which should not be construed as limiting. The contents of all references, Genbank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1A shows the nucleotide sequence (SEQ ID NO:81) and amino acid sequence (SEQ ID NO:1) of the heavy chain variable region of the 3G10 human monoclonal antibody. The CDR1 (SEQ ID NO:21), CDR2 (SEQ ID NO:31) and CDR3 (SEQ ID NO:41) regions are delineated and the V, D and J germline derivations are indicated.
  • FIG. 1B shows the nucleotide sequence (SEQ ID NO:91) and amino acid sequence (SEQ ID NO:11) of the light chain variable region of the 3G10 human monoclonal antibody. The CDR1 (SEQ ID NO:51), CDR2 (SEQ ID NO:61) and CDR3 (SEQ ID NO:71) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 2A shows the nucleotide sequence (SEQ ID NO:82) and amino acid sequence (SEQ ID NO:2) of the heavy chain variable region of the 12A4 human monoclonal antibody. The CDR1 (SEQ ID NO:22), CDR2 (SEQ ID NO:32) and CDR3 (SEQ ID NO:42) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 2B shows the nucleotide sequence (SEQ ID NO:92) and amino acid sequence (SEQ ID NO:12) of the light chain variable region of the 12A4 human monoclonal antibody. The CDR1 (SEQ ID NO:52), CDR2 (SEQ ID NO:62) and CDR3 (SEQ ID NO:72) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 3A shows the nucleotide sequence (SEQ ID NO:83) and amino acid sequence (SEQ ID NO:3) of the heavy chain variable region of the 10A5 human monoclonal antibody. The CDR1 (SEQ ID NO:23), CDR2 (SEQ ID NO:33) and CDR3 (SEQ ID NO:43) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 3B shows the nucleotide sequence (SEQ ID NO:93) and amino acid sequence (SEQ ID NO:13) of the light chain variable region of the 10A5 human monoclonal antibody. The CDR1 (SEQ ID NO:53), CDR2 (SEQ ID NO:63) and CDR3 (SEQ ID NO:73) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 4A shows the nucleotide sequence (SEQ ID NO:84) and amino acid sequence (SEQ ID NO:4) of the heavy chain variable region of the 5F8 human monoclonal antibody. The CDR1 (SEQ ID NO:24), CDR2 (SEQ ID NO:34) and CDR3 (SEQ ID NO:44) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 4B shows the nucleotide sequence (SEQ ID NO:94) and amino acid sequence (SEQ ID NO:14) of the light chain variable region of the 5F8 human monoclonal antibody. The CDR1 (SEQ ID NO:54), CDR2 (SEQ ID NO:64) and CDR3 (SEQ ID NO:74) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 5A shows the nucleotide sequence (SEQ ID NO:85) and amino acid sequence (SEQ ID NO:5) of the heavy chain variable region of the 10H10 human monoclonal antibody. The CDR1 (SEQ ID NO:25), CDR2 (SEQ ID NO:35) and CDR3 (SEQ ID NO:45) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 5B shows the nucleotide sequence (SEQ ID NO:95) and amino acid sequence (SEQ ID NO:15) of the light chain variable region of the 10H10 human monoclonal antibody. The CDR1 (SEQ ID NO:55), CDR2 (SEQ ID NO:65) and CDR3 (SEQ ID NO:75) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 6A shows the nucleotide sequence (SEQ ID NO:86) and amino acid sequence (SEQ ID NO:6) of the heavy chain variable region of the 1B12 human monoclonal antibody. The CDR1 (SEQ ID NO:26), CDR2 (SEQ ID NO:36) and CDR3 (SEQ ID NO:46) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 6B shows the nucleotide sequence (SEQ ID NO:96) and amino acid sequence (SEQ ID NO:16) of the light chain variable region of the 1B12 human monoclonal antibody. The CDR1 (SEQ ID NO:56), CDR2 (SEQ ID NO:66) and CDR3 (SEQ ID NO:76) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 7A shows the nucleotide sequence (SEQ ID NO:87) and amino acid sequence (SEQ ID NO:7) of the heavy chain variable region of the 7H1 human monoclonal antibody. The CDR1 (SEQ ID NO:27), CDR2 (SEQ ID NO:37) and CDR3 (SEQ ID NO:47) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 7B shows the nucleotide sequence (SEQ ID NO:97) and amino acid sequence (SEQ ID NO:17) of the light chain variable region of the 7H1 human monoclonal antibody. The CDR1 (SEQ ID NO:57), CDR2 (SEQ ID NO:67) and CDR3 (SEQ ID NO:77) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 8A shows the nucleotide sequence (SEQ ID NO:88) and amino acid sequence (SEQ ID NO: 8) of the heavy chain variable region of the 11E6 human monoclonal antibody. The CDR1 (SEQ ID NO:28), CDR2 (SEQ ID NO:38) and CDR3 (SEQ ID NO:48) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 8B shows the nucleotide sequence (SEQ ID NO:98) and amino acid sequence (SEQ ID NO:18) of the light chain variable region of the 11E6 human monoclonal antibody. The CDR1 (SEQ ID NO:58), CDR2 (SEQ ID NO:68) and CDR3 (SEQ ID NO:78) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 9A shows the nucleotide sequence (SEQ ID NO:89) and amino acid sequence (SEQ ID NO:9) of the heavy chain variable region of the 12B7 human monoclonal antibody. The CDR1 (SEQ ID NO:29), CDR2 (SEQ ID NO:39) and CDR3 (SEQ ID NO:49) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 9B shows the nucleotide sequence (SEQ ID NO:99) and amino acid sequence (SEQ ID NO:19) of the light chain variable region of the 12B7 human monoclonal antibody. The CDR1 (SEQ ID NO:59), CDR2 (SEQ ID NO:69) and CDR3 (SEQ ID NO:79) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 10A shows the nucleotide sequence (SEQ ID NO:90) and amino acid sequence (SEQ ID NO:10) of the heavy chain variable region of the 13G4 human monoclonal antibody. The CDR1 (SEQ ID NO:30), CDR2 (SEQ ID NO:40) and CDR3 (SEQ ID NO:50) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 10B shows the nucleotide sequence (SEQ ID NO:100) and amino acid sequence (SEQ ID NO:20) of the light chain variable region of the 13G4 human monoclonal antibody. The CDR1 (SEQ ID NO:60), CDR2 (SEQ ID NO:70) and CDR3 (SEQ ID NO:80) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 11 shows the alignment of the amino acid sequence of the heavy chain variable region of 3G10 with the human germline VH 1-18 amino acid sequence (SEQ ID NO:101).
  • FIG. 12 shows the alignment of the amino acid sequence of the heavy chain variable region of 12A4 with the human germline VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 13 shows the alignment of the amino acid sequence of the heavy chain variable region of 10A5 with the human germline VH 1-3 amino acid sequence (SEQ ID NO:103).
  • FIG. 14 shows the alignment of the amino acid sequence of the heavy chain variable region of 5F8 with the human germline VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 15 shows the alignment of the amino acid sequence of the heavy chain variable region of 10H10 with the human germline VH 3-9 amino acid sequence (SEQ ID NO:104).
  • FIG. 16 shows the alignment of the amino acid sequence of the heavy chain variable region of 1B12 with the human germline VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 17 shows the alignment of the amino acid sequence of the heavy chain variable region of 7H1 with the human germline VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 18 shows the alignment of the amino acid sequence of the heavy chain variable region of 11E6 with the human germline VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 19 shows the alignment of the amino acid sequence of the heavy chain variable region of 12B7 with the human germline VH 1-69 amino acid sequence (SEQ ID NO:102).
  • FIG. 20 shows the alignment of the amino acid sequence of the heavy chain variable region of 13G4 with the human germline VH 3-9 amino acid sequence (SEQ ID NO:104).
  • FIG. 21 shows the alignment of the amino acid sequence of the light chain variable region of 3G10 with the human germline Vk L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 22 shows the alignment of the amino acid sequence of the light chain variable region of 12A4 with the human germline Vk L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 23 shows the alignment of the amino acid sequence of the light chain variable region of 10A5 with the human germline Vk L15 amino acid sequence (SEQ ID NO:106).
  • FIG. 24 shows the alignment of the amino acid sequence of the light chain variable region of 5F8 with the human germline Vk A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 25 shows the alignment of the amino acid sequence of the light chain variable region of 10H10 with the human germline Vk L15 amino acid sequence (SEQ ID NO:106).
  • FIG. 26 shows the alignment of the amino acid sequence of the light chain variable region of 1B12 with the human germline Vk L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 27 shows the alignment of the amino acid sequence of the light chain variable region of 7H1 with the human germline Vk L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 28 shows the alignment of the amino acid sequence of the light chain variable region of 11E6 with the human germline Vk A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 29 shows the alignment of the amino acid sequence of the light chain variable region of 11E6a (SEQ ID NO:109) with the human germline Vk A27 amino acid sequence (SEQ ID NO:107).
  • FIG. 30 shows the alignment of the amino acid sequence of the light chain variable region of 12B7 with the human germline Vk L6 amino acid sequence (SEQ ID NO:105).
  • FIG. 31 shows the alignment of the amino acid sequence of the light chain variable region of 13G4 with the human germline Vk L18 amino acid sequence (SEQ ID NO:108).
  • FIGS. 32A-32C show the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds the cell surface of CHO cells transfected with full-length human PD-L1. FIG. 32A is a Flow cytometry plot for 3G10, FIG. 32B is a Flow cytometry plot for 10A5, and FIG. 32C is a Flow cytometry plot for 12A4.
  • FIG. 33 shows the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds the cell surface of CHO cells transfected with full-length human PD-L1 in a concentration dependent manner.
  • FIG. 34 shows the results of ELISA experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds to PD-L1-Fc fusion protein.
  • FIG. 35 shows the results of experiments demonstrating HuMab titration on stimulated human CD4+ T cells.
  • FIG. 36 shows the results of experiments demonstrating HuMab titration on stimulated cynomolgus PBMC.
  • FIGS. 37A-37C show the results of flow cytometry experiments demonstrating that the human monoclonal antibodies 3G10, 10A5, and 12A4, directed against human PD-L1, binds to PD-L1 on the cell surface of activated T cells. FIG. 37A is a Flow cytometry plot for 3G10, FIG. 37B is a Flow cytometry plot for 10A5, and FIG. 37C is a Flow cytometry plot for 12A4.
  • FIG. 38 demonstrates binding of HuMabs to ES-2 cells.
  • FIGS. 39A-39D show the results of experiments demonstrating that human monoclonal antibodies against human PD-L1 promote T-cell proliferation, IFN-γ secretion and IL-2 secretion in a mixed lymphocyte reaction assay. FIG. 39A is a bar graph showing concentration dependent T-cell proliferation using HuMAb 10A5; FIG. 39B is a bar graph showing concentration dependent IFN-γ secretion using HuMAb 10A5; FIG. 39C is a bar graph showing IFN-γ secretion using HuMAbs 3G10 and 12A4; FIG. 39D is a bar graph showing concentration dependent IL-2 secretion using HuMAb 10A5.
  • FIG. 40 demonstrates the effect of human anti-PD-L1 antibody on proliferation and IFN-γ secretion in the MLR using allogeneic dendritic cells and T cells (CD4+ effector T cells) Dendritic Cells.
  • FIGS. 41A and 41B show the results of experiments demonstrating that human monoclonal antibodies against human PD-L1 promote T-cell proliferation and IFN-γ secretion in MLR containing T regulatory cells. FIG. 41A is a bar graph showing concentration dependent T-cell proliferation using HuMAb 10A5; FIG. 41B is a bar graph showing concentration dependent IFN-γ secretion using HuMAb 10A5.
  • FIG. 42 demonstrates the results of anti-PD-L1 antibodies on cell proliferation in a Mixed Lymphocyte Reaction in the presence of regulatory T cells.
  • FIG. 43 demonstrates the results of anti-PD-L1 antibodies on cytokine production in a Mixed Lymphocyte Reaction in the presence of regulatory T cells.
  • FIG. 44 demonstrates the results of anti-PD-L1 antibodies on CMV lysate stimulated human PBMC IFN-γ secretion.
  • FIG. 45 shows the results of flow cytometry experiments demonstrating that human monoclonal antibodies against human PD-L1 block the binding of PD-L1 to CHO transfected cells expressing PD-1.
  • FIG. 46 shows that anti-PD-L1 antibodies block binding of PD-1 to IFNγ treated ES-2 cells.
  • FIG. 47 shows the effect of anti-PD-L1 antibodies on tumor growth in vivo.
    •  DETAILED DESCRIPTION
  • In one aspect, the present disclosure relates to isolated monoclonal antibodies, particularly human monoclonal antibodies that bind specifically to PD-L1. In certain embodiments, the antibodies of the invention exhibit one or more desirable functional properties, such as high affinity binding to PD-L1, the ability to augment T cell proliferation, IFN-γ and/or IL-2 secretion in mixed lymphocyte reactions, the ability to inhibit binding of PD-L1 to the PD-1 receptor, the ability to stimulate antibody responses and/or the ability to reverse the suppressive function of T regulatory cells. Additionally or alternatively, the antibodies of the invention are derived from particular heavy and light chain germline sequences and/or comprise particular structural features such as CDR regions comprising particular amino acid sequences.
  • The instant disclosure provides, for example, isolated antibodies, methods of making such antibodies, immunoconjugates and bispecific molecules comprising such antibodies and pharmaceutical compositions containing the antibodies, immunconjugates or bispecific molecules of the invention.
  • In another aspect, the disclosure pertains to methods of inhibiting growth of tumor cells in a subject using anti-PD-L1 antibodies. The invention also relates to methods of using the antibodies to modify an immune response, as well as to treat diseases such as cancer or infectious disease, or to stimulate a protective autoimmune response or to stimulate antigen-specific immune responses (e.g., by coadministration of anti-PD-L1 with an antigen of interest).
  • In order that the present disclosure may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.
  • The term “immune response” refers to the action of, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by the above cells or the liver (including antibodies, cytokines, and complement) that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
  • A “signal transduction pathway” refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of a cell. As used herein, the phrase “cell surface receptor” includes, for example, molecules and complexes of molecules capable of receiving a signal and the transmission of such a signal across the plasma membrane of a cell. An example of a “cell surface receptor” of the present invention is the PD-L1 receptor.
  • The term “antibody” as referred to herein includes whole antibodies and any antigen binding fragment (i.e., “antigen-binding portion”) or single chains 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 VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • The term “antigen-binding portion” of an antibody (or simply “antibody portion”), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., PD-L1). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 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 VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, 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 VL and VH 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). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.
  • An “isolated antibody,” as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds PD-L1 is substantially free of antibodies that specifically bind antigens other than PD-L1). An isolated antibody that specifically binds PD-L1 may, however, have cross-reactivity to other antigens, such as PD-L1 molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • The terms “monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
  • The term “human antibody,” as used herein, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody,” as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • The term “human monoclonal antibody” refers to antibodies displaying a single binding specificity which have variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. In one embodiment, the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman 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.
  • The term “recombinant human antibody,” as used herein, 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 below), (b) antibodies isolated from a host cell transformed to express the human 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 regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. In certain embodiments, however, 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 VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • As used herein, “isotype” refers to the antibody class (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes.
  • The phrases “an antibody recognizing an antigen” and “an antibody specific for an antigen” are used interchangeably herein with the term “an antibody which binds specifically to an antigen.”
  • The term “human antibody derivatives” refers to any modified form of the human antibody, e.g., a conjugate of the antibody and another agent or antibody.
  • The term “humanized antibody” is intended to refer to antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Additional framework region modifications may be made within the human framework sequences.
  • The term “chimeric antibody” is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.
  • As used herein, an antibody that “specifically binds to human PD-L1” is intended to refer to an antibody that binds to human PD-L1 with a KD of 1×10−7 M or less, more preferably 5×10−8 M or less, more preferably 1×10−8 M or less, more preferably 5×10−9 M or less, even more preferably between 1×10−8 M and 1×10−10 M or less.
  • The term “Kassoc” or “Ka,” as used herein, is intended to refer to the association rate of a particular antibody-antigen interaction, whereas the term “Kdis” or “Kd,” as used herein, is intended to refer to the dissociation rate of a particular antibody-antigen interaction. The term “KD,” as used herein, is intended to refer to the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e., Kd/Ka) and is expressed as a molar concentration (M). KD values for antibodies can be determined using methods well established in the art. A preferred method for determining the KD of an antibody is by using surface plasmon resonance, preferably using a biosensor system such as a Biacore® system.
  • As used herein, the term “high affinity” for an IgG antibody refers to an antibody having a KD of 10−8 M or less, more preferably 10−9M or less and even more preferably 10−10 M or less for a target antigen. However, “high affinity” binding can vary for other antibody isotypes. For example, “high affinity” binding for an IgM isotype refers to an antibody having a KD of 10−7 M or less, more preferably 10−8 M or less, even more preferably 10−9 M or less.
  • As used herein, the term “subject” includes any human or nonhuman animal. The term “nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • Various aspects of the disclosure are described in further detail in the following subsections.
    • Anti-PD-L1 Antibodies
  • The antibodies of the invention are characterized by particular functional features or properties of the antibodies. For example, the antibodies bind specifically to human PD-L1. Preferably, an antibody of the invention binds to PD-L1 with high affinity, for example with a KD of 1×10−7M or less. The anti-PD-L1 antibodies of the invention preferably exhibit one or more of the following characteristics:
      • (a) binds to human PD-L1 with a KD of 1×10−7M or less;
      • (b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
      • (c) increases interferon-γ production in an MLR assay;
      • (d) increases IL-2 secretion in an MLR assay
      • (e) stimulates antibody responses; and/or
      • (f) reverses the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
  • Preferably, the antibody binds to human PD-L1 with a KD of 5×10−8 M or less, binds to human PD-L1 with a KD of 1×10−8 M or less, binds to human PD-L1 with a KD of 5×10−9 M or less, binds to human PD-L1 with a KD of 4×10−9 M or less, binds to human PD-L1 with a KD of 2×10−9 M or less, or binds to human PD-L1 with a KD of between 1×10−9 M and 1×10−10 M or less.
  • Standard assays to evaluate the binding ability of the antibodies toward PD-L1 are known in the art, including for example, ELISAs, Western blots and RIAs. Suitable assays are described in detail in the Examples. The binding kinetics (e.g., binding affinity) of the antibodies also can be assessed by standard assays known in the art, such as by Biacore® analysis.
    • Monoclonal Antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4.
  • Preferred antibodies of the invention are the human monoclonal antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, isolated and structurally characterized as described in Examples 1 and 2. The VH amino acid sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, respectively. The VL amino acid sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, respectively.
  • Given that each of these antibodies can bind to PD-L1, the VH and VL sequences can be “mixed and matched” to create other anti-PD-L1 binding molecules of the invention. PD-L1 binding of such “mixed and matched” antibodies can be tested using the binding assays described above and in the Examples (e.g., ELISAs). Preferably, when VH and VL chains are mixed and matched, a VH sequence from a particular VH/VL pairing is replaced with a structurally similar VH sequence. Likewise, preferably a VL sequence from a particular VH/VL pairing is replaced with a structurally similar VL sequence.
  • Accordingly, in one aspect, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof comprising:
  • (a) a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and
  • (b) a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20;
  • wherein the antibody specifically binds PD-L1, preferably human PD-L1. Preferred heavy and light chain combinations include:
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:11; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:12; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:13; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:14; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:5; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:15; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:16; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:17; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:18; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:19; or
      • (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:20.
  • In another aspect, the invention provides antibodies that comprise the heavy chain and light chain CDR1s, CDR2s and CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, or combinations thereof. The amino acid sequences of the VH CDR1s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, respectively. The amino acid sequences of the VH CDR2s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, respectively. The amino acid sequences of the VH CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, respectively. The amino acid sequences of the Vk CDR1s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, respectively. The amino acid sequences of the Vk CDR2s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, respectively. The amino acid sequences of the Vk CDR3s of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 are shown in SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, respectively. The CDR regions are delineated using the Kabat system (Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • Given that each of these antibodies can bind to PD-L1 and that antigen-binding specificity is provided primarily by the CDR1, CDR2, and CDR3 regions, the VH CDR1, CDR2, and CDR3 sequences and Vk CDR1, CDR2, and CDR3 sequences can be “mixed and matched” (i.e., CDRs from different antibodies can be mixed and match, although each antibody must contain a VH CDR1, CDR2, and CDR3 and a Vk CDR1, CDR2, and CDR3) to create other anti-PD-L1 binding molecules of the invention. PD-L1 binding of such “mixed and matched” antibodies can be tested using the binding assays described above and in the Examples (e.g., ELISAs, Biacore analysis). Preferably, when VH CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular VH sequence is replaced with a structurally similar CDR sequence(s). Likewise, when Vk CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular Vk sequence preferably is replaced with a structurally similar CDR sequence(s). It will be readily apparent to the ordinarily skilled artisan that novel VH and VL sequences can be created by substituting one or more VH and/or VL CDR region sequences with structurally similar sequences from the CDR sequences disclosed herein for monoclonal antibodies antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4.
  • Accordingly, in another aspect, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof comprising:
      • (a) a heavy chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30;
      • (b) a heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40;
      • (c) a heavy chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50;
      • (d) a light chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60;
      • (e) a light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and
      • (f) a light chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;
  • wherein the antibody specifically binds PD-L1, preferably human PD-L1.
  • In a preferred embodiment, the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:21;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:31;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:41;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:51;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:61; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:71.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:22;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:32;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:42;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:52;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:62; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:72.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:23;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:33;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:43;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:53;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:63; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:73.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:24;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:34;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:44;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:54;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:64; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:74.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:25;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:35;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:45;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:55;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:65; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:75.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:26;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:36;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:46;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:56;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:66; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:76.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:27;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:37;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:47;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:57;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:67; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:77.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:28;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:38;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:48;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:58;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:68; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:78.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:29;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:39;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:49;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:59;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:69; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:79.
        In another preferred embodiment the antibody comprises:
      • (a) a heavy chain variable region CDR1 comprising SEQ ID NO:30;
      • (b) a heavy chain variable region CDR2 comprising SEQ ID NO:40;
      • (c) a heavy chain variable region CDR3 comprising SEQ ID NO:50;
      • (d) a light chain variable region CDR1 comprising SEQ ID NO:60;
      • (e) a light chain variable region CDR2 comprising SEQ ID NO:70; and
      • (f) a light chain variable region CDR3 comprising SEQ ID NO:80.
  • It is well known in the art that the CDR3 domain, independently from the CDR1 and/or CDR2 domain(s), alone can determine the binding specificity of an antibody for a cognate antigen and that multiple antibodies can predictably be generated having the same binding specificity based on a common CDR3 sequence. See, for example, Klimka et al., British J. of Cancer 83(2):252-260 (2000) (describing the production of a humanized anti-CD30 antibody using only the heavy chain variable domain CDR3 of murine anti-CD30 antibody Ki-4); Beiboer et al., J. Mol. Biol. 296:833-849 (2000) (describing recombinant epithelial glycoprotein-2 (EGP-2) antibodies using only the heavy chain CDR3 sequence of the parental murine MOC-31 anti-EGP-2 antibody); Rader et al., Proc. Natl. Acad. Sci. U.S.A. 95:8910-8915 (1998) (describing a panel of humanized anti-integrin αvβ3 antibodies using a heavy and light chain variable CDR3 domain of a murine anti-integrin αvβ3 antibody LM609 wherein each member antibody comprises a distinct sequence outside the CDR3 domain and capable of binding the same epitope as the parent muring antibody with affinities as high or higher than the parent murine antibody); Barbas et al., J. Am. Chem. Soc. 116:2161-2162 (1994) (disclosing that the CDR3 domain provides the most significant contribution to antigen binding); Barbas et al., Proc. Natl. Acad. Sci. U.S.A. 92:2529-2533 (1995) (describing the grafting of heavy chain CDR3 seqeunces of three Fabs (SI-1, SI-40, and SI-32) against human placental DNA onto the heavy chain of an anti-tetanus toxoid Fab thereby replacing the existing heavy chain CDR3 and demonstrating that the CDR3 domain alone conferred binding specificity); and Ditzel et al., J. Immunol. 157:739-749 (1996) (describing grafting studies wherein transfer of only the heavy chain CDR3 of a parent polyspecific Fab LNA3 to a heavy chain of a monospecific IgG tetanus toxoid-binding Fab p313 antibody was sufficient to retain binding specificity of the parent Fab). Each of these references is hereby incorporated by reference in its entirety.
  • Accordingly, within certain aspects, the present invention provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domain from a non-human antibody, such as a mouse or rat antibody, wherein the monoclonal antibody is capable of specifically binding to PD-L1. Within some embodiments, such inventive antibodies comprising one or more heavy and/or light chain CDR3 domain from a non-human antibody (a) are capable of competing for binding with; (b) retain the functional characteristics; (c) bind to the same epitope; and/or (d) have a similar binding affinity as the corresponding parental non-human antibody.
  • Within other aspects, the present invention provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domain from a first human antibody, such as, for example, a human antibody obtained from a non-human animal, wherein the first human antibody is capable of specifically binding to PD-L1 and wherein the CDR3 domain from the first human antibody replaces a CDR3 domain in a human antibody that is lacking binding specificity for PD-L1 to generate a second human antibody that is capable of specifically binding to PD-L1. Within some embodiments, antibodies of the instant disclosure comprising one or more heavy and/or light chain CDR3 domain from the first human antibody (a) are capable of competing for binding with; (b) retain the functional characteristics; (c) bind to the same epitope; and/or (d) have a similar binding affinity as the corresponding parental first human antibody.
    • Antibodies Having Particular Germline Sequences
  • In certain embodiments, an antibody of the invention comprises a heavy chain variable region from a particular germline heavy chain immunoglobulin gene and/or a light chain variable region from a particular germline light chain immunoglobulin gene.
  • For example, in a preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-18 gene, wherein the antibody specifically binds PD-L1. In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-69 gene, wherein the antibody specifically binds PD-L1. In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 1-3 gene, wherein the antibody specifically binds PD-L1. In another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human VH 3-9 gene, wherein the antibody specifically binds PD-L1. In yet another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L6 gene, wherein the antibody specifically binds PD-L1. In yet another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L15 gene, wherein the antibody specifically binds PD-L1. In yet another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK A27 gene, wherein the antibody specifically binds PD-L1. In yet another preferred embodiment, the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human VK L18 gene, wherein the antibody specifically binds PD-L1. In yet another preferred embodiment, the invention provides an isolated monoclonal antibody, or antigen-binding portion thereof, wherein the antibody:
  • (a) comprises a heavy chain variable region that is the product of or derived from a human VH 1-18, 1-69, 1-3 or 3-9 gene (which encodes the amino acid sequences set forth in SEQ ID NOs:101, 102, 103 and 104, respectively);
  • (b) comprises a light chain variable region that is the product of or derived from a human VK L6, L15, A27 or L18 gene (which encodes the amino acid sequences set forth in SEQ ID NOs:105, 106, 107 and 108, respectively); and
  • (c) specifically binds to PD-L1, preferably human PD-L1.
  • An example of an antibody having VH and VK of VH 1-18 and VK L6, respectively, is 3G10. Examples of antibodies having VH and VK of VH 1-69 and VK L6, respectively, 12A4, 1B12, 7H1, and 12B7. An example of an antibody having VH and VK of VH 1-3 and VK L15, respectively, is 10A5. Examples of antibodies having VH and VK of VH 1-69 and VK A27, respectively, are 5F8, 11E6 and 11E6a. An example of an antibody having VH and VK of VH 3-9 and VK L15, respectively, is 10H10. An example of an antibody having VH and VK of VH 1-3 and VK L15, respectively, is 10A5. An example of an antibody having VH and VK of VH 3-9 and VK L18, respectively, is 13G4.
  • As used herein, a human antibody comprises heavy or light chain variable regions that is “the product of” or “derived from” a particular germline sequence if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin genes. Such systems include immunizing a transgenic mouse carrying human immunoglobulin genes with the antigen of interest or screening a human immunoglobulin gene library displayed on phage with the antigen of interest. A human antibody that is “the product of” or “derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequences of human germline immunoglobulins and selecting the human germline immunoglobulin sequence that is closest in sequence (i.e., greatest % identity) to the sequence of the human antibody. A human antibody that is “the product of” or “derived from” a particular human germline immunoglobulin sequence may contain amino acid differences as compared to the germline sequence, due to, for example, naturally-occurring somatic mutations or intentional introduction of site-directed mutation. However, a selected human antibody is generally at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences). In certain cases, a human antibody may be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene. In certain embodiments, a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene. In certain other embodiments, the human antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene.
    • Homologous Antibodies
  • In yet another embodiment, an antibody of the invention comprises heavy and light chain variable regions comprising amino acid sequences that are homologous to the amino acid sequences of the preferred antibodies described herein, and wherein the antibodies retain the desired functional properties of the anti-PD-L1 antibodies of the invention.
  • For example, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
      • (a) the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
      • (b) the light chain variable region comprises an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20;
      • (c) the antibody binds to human PD-L1 with a KD of 1×10−7 M or less;
      • (d) the antibody increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
      • (e) the antibody increases interferon-γ production in an MLR assay;
      • (f) the antibody increases IL-2 secretion in an MLR assay,
      • (g) the antibody stimulates antibody responses; and
      • (h) reverses the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
  • In other embodiments, the VH and/or VL amino acid sequences may be 85%, 90%, 95%, 96%, 97%, 98% or 99% homologous to the sequences set forth above. An antibody having VH and VL regions having high (i.e., 80% or greater) homology to the VH and VL regions of the sequences set forth above, can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of nucleic acid molecules encoding SEQ ID NOs:25, 26, 27, 28, 29, and 30, followed by testing of the encoded altered antibody for retained function (i.e., the functions set forth in (c) through (h) above) using the functional assays described herein.
  • As used herein, the percent homology between two amino acid sequences is equivalent to the percent identity between the two sequences. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology=# of identical positions/total # of positions×100), 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 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 amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4:11-17 (1988)) 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. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. 48:444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossum 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.
  • In certain instances, the protein sequences of the present disclosure can be further 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 XBLAST program (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the antibody molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See www.ncbi.nlm.nih.gov.
  • Antibodies with Conservative Modifications
  • In certain embodiments, an antibody of the invention comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences, wherein one or more of these CDR sequences comprise specified amino acid sequences based on the preferred antibodies described herein (e.g., 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4), or conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the anti-PD-L1 antibodies of the invention. Accordingly, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein:
  • (a) the heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, and conservative modifications thereof;
  • (b) the light chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequence of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, and conservative modifications thereof;
  • (c) the antibody binds to human PD-L1 with a KD of 1×10−7 M or less;
  • (d) the antibody increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
  • (e) the antibody increases interferon-γ production in an MLR assay;
  • (f) the antibody increases IL-2 secretion in an MLR assay
  • (g) the antibody stimulates antibody responses; and
  • (h) reverses the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
  • In a preferred embodiment, the heavy chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and conservative modifications thereof; and the light chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and conservative modifications thereof. In another preferred embodiment, the heavy chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, and conservative modifications thereof; and the light chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, and conservative modifications thereof.
  • As used herein, the term “conservative sequence modifications” is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are 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). Thus, one or more amino acid residues within the CDR regions of an antibody of the invention can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for retained function (i.e., the functions set forth in (c) through (h) above) using the functional assays described herein.
  • Antibodies that Bind to the Same Epitope as Anti-PD-L1 Antibodies of the Invention
  • In another embodiment, the invention provides antibodies that bind to the same epitope on human PD-L1 as any of the PD-L1 monoclonal antibodies of the invention (i.e., antibodies that have the ability to cross-compete for binding to PD-L1 with any of the monoclonal antibodies of the invention). In preferred embodiments, the reference antibody for cross-competition studies can be the monoclonal antibody 3G10 (having VH and VL sequences as shown in SEQ ID NOs:1 and 11, respectively), or the monoclonal antibody 12A4 (having VH and VL sequences as shown in SEQ ID NOs:2 and 12, respectively), or the monoclonal antibody 10A5 (having VH and VL sequences as shown in SEQ ID NOs:3 and 13, respectively), or the monoclonal antibody 10A5 (having VH and VL sequences as shown in SEQ ID NOs:3 and 13, respectively), or the monoclonal antibody 5F8 (having VH and VL sequences as shown in SEQ ID NOs:4 and 14, respectively), or the monoclonal antibody 10H10 (having VH and VL sequences as shown in SEQ ID NOs:5 and 15, respectively), or the monoclonal antibody 1B12 (having VH and VL sequences as shown in SEQ ID NOs:6 and 16, respectively), or the monoclonal antibody 7H1 (having VH and VL sequences as shown in SEQ ID NOs:7 and 17, respectively), or the monoclonal antibody 11E6 (having VH and VL sequences as shown in SEQ ID NOs:8 and 18, respectively), or the monoclonal antibody 12B7 (having VH and VL sequences as shown in SEQ ID NOs:9 and 19, respectively), or the monoclonal antibody 13G4 (having VH and VL sequences as shown in SEQ ID NOs:10 and 20, respectively). Such cross-competing antibodies can be identified based on their ability to cross-compete with 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 in standard PD-L1 binding assays. For example, BIAcore analysis, ELISA assays or flow cytometry may be used to demonstrate cross-competition with the antibodies of the current invention. The ability of a test antibody to inhibit the binding of, for example, 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4, to human PD-L1 demonstrates that the test antibody can compete with 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 for binding to human PD-L1 and thus binds to the same epitope on human PD-L1 as 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4. In a preferred embodiment, the antibody that binds to the same epitope on human PD-L1 as 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 is a human monoclonal antibody. Such human monoclonal antibodies can be prepared and isolated as described in the Examples.
    • Engineered and Modified Antibodies
  • An antibody of the invention further can be prepared using an antibody having one or more of the VH and/or VL sequences disclosed herein as starting material to engineer a modified antibody, which modified antibody may have altered properties from the starting antibody. An antibody can be engineered by modifying one or more residues within one or both variable regions (i.e., VH and/or VL), for example within one or more CDR regions and/or within one or more framework regions. Additionally or alternatively, an antibody can be engineered by modifying residues within the constant region(s), for example to alter the effector function(s) of the antibody.
  • One type of variable region engineering that can be performed is CDR grafting. 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; Queen, C. et al. (1989) Proc. Natl. Acad. See. U.S.A. 86:10029-10033; U.S. Pat. No. 5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.)
  • Accordingly, another embodiment of the invention pertains to an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, respectively. Thus, such antibodies contain the VH and VL CDR sequences of monoclonal antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 yet may contain different framework sequences from these antibodies.
  • Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, germline DNA sequences for human heavy and light chain variable region genes can be found in the “VBase” human germline sequence database (available on the Internet at www.mrc-cpe.cam.ac.uk/vbase), as well as in Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Tomlinson, I. M., et al. (1992) “The Repertoire of Human Germline VH Sequences Reveals about Fifty Groups of VH Segments with Different Hypervariable Loops” J. Mol. Biol. 227:776-798; and Cox, J. P. L. et al. (1994) “A Directory of Human Germ-line VH Segments Reveals a Strong Bias in their Usage” Eur. J. Immunol. 24:827-836; the contents of each of which are expressly incorporated herein by reference.
  • Antibody protein sequences are compared against a compiled protein sequence database using one of the sequence similarity searching methods called the Gapped BLAST (Altschul et al. (1997) Nucleic Acids Research 25:3389-3402), which is well known to those skilled in the art. BLAST is a heuristic algorithm in that a statistically significant alignment between the antibody sequence and the database sequence is likely to contain high-scoring segment pairs (HSP) of aligned words. Segment pairs whose scores cannot be improved by extension or trimming is called a hit. Briefly, the nucleotide sequences of VBASE origin (vbase.mrc-cpe.cam.ac.uk/vbase1/list2.php) are translated and the region between and including FR1 through FR3 framework region is retained. The database sequences have an average length of 98 residues. Duplicate sequences which are exact matches over the entire length of the protein are removed. A BLAST search for proteins using the program blastp with default, standard parameters except the low complexity filter which is turned off and the substitution matrix of BLOSUM62, filters for top 5 hits yielding sequence matches. The nucleotide sequences are translated in all six frames and the frame with no stop codons in the matching segment of the database sequence is considered the potential hit. This is in turn confirmed using the BLAST program tblastx. This translates the antibody sequence in all six frames and compares those translations to the VBASE nucleotide sequences dynamically translated in all six frames.
  • The identities are exact amino acid matches between the antibody sequence and the protein database over the entire length of the sequence. The positives (identities+substitution match) are not identical but amino acid substitutions guided by the BLOSUM62 substitution matrix. If the antibody sequence matches two of the database sequences with same identity, the hit with most positives would be decided to be the matching sequence hit.
  • Preferred framework sequences for use in the antibodies of the invention are those that are structurally similar to the framework sequences used by selected antibodies of the invention, e.g., similar to the VH 1-18 framework sequences (SEQ ID NO:101) and/or the VH 1-69 framework sequences (SEQ ID NO:102) and/or the VH 1-3 framework sequences (SEQ ID NO:103) and/or the VH 3-9 framework sequences (SEQ ID NO:104) and/or the VK L6 framework sequences (SEQ ID NO:105) and/or the VK L15 framework sequences (SEQ ID NO:106) and/or the VK A27 framework sequences (SEQ ID NO:107) and/or the VK L18 framework sequences (SEQ ID NO:107) used by preferred monoclonal antibodies of the invention. The VH CDR1, CDR2, and CDR3 sequences, and the VK CDR1, CDR2, and CDR3 sequences, can be grafted onto framework regions that have the identical sequence as that found in the germline immunoglobulin gene from which the framework sequence derive, or the CDR sequences can be grafted onto framework regions that contain one or more mutations as compared to the germline sequences. For example, it has been found that in certain instances it is beneficial to mutate residues within the framework regions to maintain or enhance the antigen binding ability of the antibody (see e.g., U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al).
  • Another type of variable region modification is to mutate amino acid residues within the VH and/or VK CDR1, CDR2 and/or CDR3 regions to thereby improve one or more binding properties (e.g., affinity) of the antibody of interest. Site-directed mutagenesis or PCR-mediated mutagenesis can be performed to introduce the mutation(s) and the effect on antibody binding, or other functional property of interest, can be evaluated in in vitro or in vivo assays as described herein and provided in the Examples. Preferably conservative modifications (as discussed above) are introduced. The mutations may be amino acid substitutions, additions or deletions, but are preferably substitutions. Moreover, typically no more than one, two, three, four or five residues within a CDR region are altered.
  • Accordingly, in another embodiment, the invention provides isolated anti-PD-L1 monoclonal antibodies, or antigen binding portions thereof, comprising a heavy chain variable region comprising: (a) a VH CDR1 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30; (b) a VH CDR2 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40; (c) a VH CDR3 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; (d) a VK CDR1 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60; (e) a VK CDR2 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and (f) a VK CDR3 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80.
  • Engineered antibodies of the invention include those in which modifications have been made to framework residues within VH and/or VK, e.g. to improve the properties of the antibody. Typically such framework modifications are made to decrease the immunogenicity of the antibody. For example, one approach is to “backmutate” one or more framework residues to the corresponding germline sequence. More specifically, an antibody that has undergone somatic mutation may contain framework residues that differ from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the antibody framework sequences to the germline sequences from which the antibody is derived. For example, as described below, a number of amino acid changes in the framework regions of the anti-PD-L1 antibodies 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 and 13G4 that differ from the parent germline sequence. To return the framework region sequences to their germline configuration, the somatic mutations can be “backmutated” to the germline sequence by, for example, site-directed mutagenesis or PCR-mediated mutagenesis. The alignment of the VH region for 3G10 against the parent germline VH 1-18 sequence is shown in FIG. 11. The alignment of the VH region for 12A4 against the parent germline VH 1-69 sequence is shown in FIG. 12. The alignment of the VH region for 10A5 against the parent germline VH 1-3 sequence is shown in FIG. 13. The alignment of the VH region for 5F8 against the parent germline VH 1-69 sequence is shown in FIG. 14. The alignment of the VH region for 10H10 against the parent germline VH 3-9 sequence is shown in FIG. 15. The alignment of the VH region for 1B12 against the parent germline VH 1-69 sequence is shown in FIG. 16. The alignment of the VH region for 7H1 against the parent germline VH 1-69 sequence is shown in FIG. 17. The alignment of the VH region for 11E6 against the parent germline VH 1-69 sequence is shown in FIG. 18. The alignment of the VH region for 12B7 against the parent germline VH 1-69 sequence is shown in FIG. 19. The alignment of the VH region for 13G4 against the parent germline VH 3-9 sequence is shown in FIG. 20.
  • For example, for 3G10, amino acid residue #79 (within FR3) of VH is a valine whereas this residue in the corresponding VH 1-18 germline sequence is an alanine. To return the framework region sequences to their germline configuration, the somatic mutations can be “backmutated” to the germline sequence by, for example, site-directed mutagenesis or PCR-mediated mutagenesis (e.g., residue #79 (residue #13 of FR3) of the VH of 3G10 can be “backmutated” from valine to alanine).
  • As another example, for 12A4, amino acid residue #24 (within FR1) of VH is a threonine whereas this residue in the corresponding VH 1-69 germline sequence is an alanine. To return the framework region sequences to their germline configuration, for example, residue #24 of the VH of 12A4 can be “backmutated” from threonine to alanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12A4, amino acid residue #27 (within FR1) of VH is an aspartic acid whereas this residue in the corresponding VH 1-69 germline sequence is a glycine. To return the framework region sequences to their germline configuration, for example, residue #27 of the VH of 12A4 can be “backmutated” from aspartic acid to glycine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12A4, amino acid residue #95 (within FR3) of VH is a phenylalanine whereas this residue in the corresponding VH 1-69 germline sequence is a tyrosine. To return the framework region sequences to their germline configuration, for example, residue #95 (residue #29 of FR3) of the VH of 12A4 can be “backmutated” from phenylalanine to tyrosine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 5F8, amino acid residue #24 (within FR1) is a valine whereas this residue in the corresponding VH 1-69 germline sequence is an alanine. To return the framework region sequences to their germline configuration, for example, residue #24 of the VH of 5F8 can be “backmutated” from valine to alanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 5F8, amino acid residue #28 (within FR1) is an isoleucine whereas this residue in the corresponding VH 1-69 germline sequence is an threonine. To return the framework region sequences to their germline configuration, for example, residue #28 of the VH of 5F8 can be “backmutated” from isoleucine to threonine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 10H10, amino acid residue #24 (within FR1) is a valine whereas this residue in the corresponding VH 3-9 germline sequence is an alanine. To return the framework region sequences to their germline configuration, for example, residue #24 of the VH of 10H10 can be “backmutated” from valine to alanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 10H10, an amino acid can be inserted following amino acid residue #97 (within FR3). This amino acid is a valine. To return the framework region sequences to their germline configuration, for example, the inserted amino acid following residue #97 of the VH of 10H10 can be “backmutated” to delete this valine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 1B12, amino acid residue #24 (within FR1) is a threonine whereas this residue in the corresponding VH 1-69 germline sequence is an alanine. To return the framework region sequences to their germline configuration, for example, residue #24 of the VH of 1B12 can be “backmutated” from threonine to alanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 1B12, amino acid residue #27 (within FR1) is an aspartic acid whereas this residue in the corresponding VH 1-69 germline sequence is an glycine. To return the framework region sequences to their germline configuration, for example, residue #27 of the VH of 1B12 can be “backmutated” from aspartic acid to glycine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 1B12, amino acid residue #95 (within FR3) is a phenylalanine whereas this residue in the corresponding VH 1-69 germline sequence is an tyrosine. To return the framework region sequences to their germline configuration, for example, residue #95 (residue #29 of FR3) of the VH of 1B12 can be “backmutated” from phenylalanine to tyrosine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 7H1, amino acid residue #24 (within FR1) is a threonine whereas this residue in the corresponding VH 1-69 germline sequence is an alanine. To return the framework region sequences to their germline configuration, for example, residue #24 of the VH of 7H1 can be “backmutated” from threonine to alanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 7H1, amino acid residue #77 (within FR3) is a threonine whereas this residue in the corresponding VH 1-69 germline sequence is a serine. To return the framework region sequences to their germline configuration, for example, residue #72 (residue #11 of FR3) of the VH of 7H1 can be “backmutated” from threonine to serine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 11E6, amino acid residue #78 (within FR3) is an alanine whereas this residue in the corresponding VH 1-69 germline sequence is a threonine. To return the framework region sequences to their germline configuration, for example, residue #78 (residue 12 of FR3) of the VH of 11E6 can be “backmutated” from alanine to threonine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12B7, amino acid residue #13 (within FR1) is a glutamic acid whereas this residue in the corresponding VH 1-69 germline sequence is an lysine. To return the framework region sequences to their germline configuration, for example, residue #13 of the VH of 12B7 can be “backmutated” glutamic acid to lysine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12B7, amino acid residue #30 (within FR1) is an asparagine whereas this residue in the corresponding VH 1-69 germline sequence is an serine. To return the framework region sequences to their germline configuration, for example, residue #30 of the VH of 12B7 can be “backmutated” from asparagine to serine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12B7, amino acid residue #77 (within FR3) is an asparagine whereas this residue in the corresponding VH 1-69 germline sequence is an serine. To return the framework region sequences to their germline configuration, for example, residue #377 (residue 11 of FR3) of the VH of 12B7 can be “backmutated” from asparagine to serine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 12B7, amino acid residue #82 (within FR3) is an aspartic acid whereas this residue in the corresponding VH 1-69 germline sequence is a glutamic acid. To return the framework region sequences to their germline configuration, for example, residue #82 (residue #16 of FR3) of the VH of 12B7 can be “backmutated” from aspartic acid to glutamic acid. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • As another example, for 13G4, amino acid residue #27 (within FR1) is an isoleucine whereas this residue in the corresponding VH 1-69 germline sequence is an phenylalanine. To return the framework region sequences to their germline configuration, for example, residue #27 of the VH of 12B7 can be “backmutated” from isoleucine to phenylalanine. Such “backmutated” antibodies are also intended to be encompassed by the invention.
  • Another type of framework modification involves mutating one or more residues within the framework region, or even within one or more CDR regions, to remove T cell epitopes to thereby reduce the potential immunogenicity of the antibody. This approach is also referred to as “deimmunization” and is described in further detail in U.S. Patent Publication No. 20030153043 by Carr et al.
  • In addition or alternative to modifications made within the framework or CDR regions, antibodies of the invention may be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity. Furthermore, an antibody of the invention may be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its glycosylation, again to alter one or more functional properties of the antibody. Each of these embodiments is described in further detail below. The numbering of residues in the Fc region is that of the EU index of Kabat.
  • In one embodiment, the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased. This approach is described further in U.S. Pat. No. 5,677,425 by Bodmer et al. The number of cysteine residues in the hinge region of CH1 is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.
  • In another embodiment, the Fc hinge region of an antibody is mutated to decrease the biological half life of the antibody. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has impaired Staphylococcyl protein A (SpA) binding relative to native Fc-hinge domain SpA binding. This approach is described in further detail in U.S. Pat. No. 6,165,745 by Ward et al.
  • In another embodiment, the antibody is modified to increase its biological half life. Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375 to Ward. Alternatively, to increase the biological half life, the antibody can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Pat. Nos. 5,869,046 and 6,121,022 by Presta et al.
  • In yet other embodiments, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector function(s) of the antibody. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320 and 322 can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.
  • In another example, one or more amino acids selected from amino acid residues 329, 331 and 322 can be replaced with a different amino acid residue such that the antibody has altered C1q binding and/or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Pat. No. 6,194,551 by Idusogie et al.
  • In another example, one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94/29351 by Bodmer et al.
  • In yet another example, the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or to increase the affinity of the antibody for an Fcγ receptor by modifying one or more amino acids at the following positions: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438 or 439. This approach is described further in PCT Publication WO 00/42072 by Presta. Moreover, the binding sites on human IgG1 for FcγR1, FcγRII, FcγRIII and FcRn have been mapped and variants with improved binding have been described (see Shields, R. L. et al. (2001) J. Biol. Chem. 276:6591-6604). Specific mutations at positions 256, 290, 298, 333, 334 and 339 were shown to improve binding to FcγRIII. Additionally, the following combination mutants were shown to improve FcγRIII binding: T256A/S298A, S298A/E333A, S298A/K224A and S298A/E333A/K334A.
  • In still another embodiment, the glycosylation of an antibody is modified. For example, an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen. Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation may increase the affinity of the antibody for antigen. Such an approach is described in further detail in U.S. Pat. Nos. 5,714,350 and 6,350,861 by Co et al.
  • In certain other embodiments, an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation. For example, the cell lines Ms704, Ms705, and Ms709 lack the fucosyltransferase gene, FUT8 (alpha (1,6) fucosyltransferase), such that antibodies expressed in the Ms704, Ms705, and Ms709 cell lines lack fucose on their carbohydrates. The Ms704, Ms705, and Ms709 FUT8−/− cell lines were created by the targeted disruption of the FUT8 gene in CHO/DG44 cells using two replacement vectors (see U.S. Patent Publication No. 20040110704 by Yamane et al. and Yamane-Ohnuki et al. (2004) Biotechnol Bioeng 87:614-22). As another example, EP 1,176,195 by Hanai et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation by reducing or eliminating the alpha 1,6 bond-related enzyme. Hanai et al. also describe cell lines which have a low enzyme activity for adding fucose to the N-acetylglucosamine that binds to the Fc region of the antibody or does not have the enzyme activity, for example the rat myeloma cell line YB2/0 (ATCC CRL 1662). PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Lec13 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields, R. L. et al. (2002) J. Biol. Chem. 277:26733-26740). PCT Publication WO 99/54342 by Umana et al. describes cell lines engineered to express glycoprotein-modifying glycosyl transferases (e.g., beta(1,4)-N-acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al. (1999) Nat. Biotech. 17:176-180). Alternatively, the fucose residues of the antibody may be cleaved off using a fucosidase enzyme. For example, the fucosidase alpha-L-fucosidase removes fucosyl residues from antibodies (Tarentino, A. L. et al. (1975) Biochem. 14:5516-23).
  • Another modification of the antibodies herein that is contemplated by the invention is pegylation. An antibody can be pegylated to, for example, increase the biological (e.g., serum) half life of the antibody. To pegylate an antibody, the antibody, or fragment thereof, typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment. Preferably, the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). As used herein, the term “polyethylene glycol” is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (C1-C10) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certain embodiments, the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies of the invention. See for example, EP 0 154 316 by Nishimura et al. and EP 0 401 384 by Ishikawa et al.
    • Methods of Engineering Antibodies
  • As discussed above, the anti-PD-L1 antibodies having VH and VK sequences disclosed herein can be used to create new anti-PD-L1 antibodies by modifying the VH and/or VK sequences, or the constant region(s) attached thereto. Thus, in another aspect of the invention, the structural features of an anti-PD-L1 antibody of the invention, e.g. 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, or 13G4, are used to create structurally related anti-PD-L1 antibodies that retain at least one functional property of the antibodies of the invention, such as binding to human PD-L1. For example, one or more CDR regions of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, or 13G4 or mutations thereof, can be combined recombinantly with known framework regions and/or other CDRs to create additional, recombinantly-engineered, anti-PD-L1 antibodies of the invention, as discussed above. Other types of modifications include those described in the previous section. The starting material for the engineering method is one or more of the VH and/or VK sequences provided herein, or one or more CDR regions thereof. To create the engineered antibody, it is not necessary to actually prepare (i.e., express as a protein) an antibody having one or more of the VH and/or VK sequences provided herein, or one or more CDR regions thereof. Rather, the information contained in the sequence(s) is used as the starting material to create a “second generation” sequence(s) derived from the original sequence(s) and then the “second generation” sequence(s) is prepared and expressed as a protein.
  • Accordingly, in another embodiment, the invention provides a method for preparing an anti-PD-L1 antibody comprising:
  • (a) providing: (i) a heavy chain variable region antibody sequence comprising a CDR1 sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, a CDR2 sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and/or a CDR3 sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; and/or (ii) a light chain variable region antibody sequence comprising a CDR1 sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, a CDR2 sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, and/or a CDR3 sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;
  • (b) altering at least one amino acid residue within the heavy chain variable region antibody sequence and/or the light chain variable region antibody sequence to create at least one altered antibody sequence; and
  • (c) expressing the altered antibody sequence as a protein.
  • Standard molecular biology techniques can be used to prepare and express the altered antibody sequence.
  • Preferably, the antibody encoded by the altered antibody sequence(s) is one that retains one, some or all of the functional properties of the anti-PD-L1 antibodies described herein, which functional properties include, but are not limited to:
      • (i) binds to human PD-L1 with a KD of 1×10−7 M or less;
      • (ii) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;
      • (iii) increases interferon-γ production in an MLR assay;
      • (iv) increases IL-2 secretion in an MLR assay;
      • (v) stimulates antibody responses; and/or
      • (vi) reverses the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
  • The functional properties of the altered antibodies can be assessed using standard assays available in the art and/or described herein, such as those set forth in the Examples (e.g., flow cytometry, binding assays).
  • In certain embodiments of the methods of engineering antibodies of the invention, mutations can be introduced randomly or selectively along all or part of an anti-PD-L1 antibody coding sequence and the resulting modified anti-PD-L1 antibodies can be screened for binding activity and/or other functional properties as described herein. Mutational methods have been described in the art. For example, PCT Publication WO 02/092780 by Short describes methods for creating and screening antibody mutations using saturation mutagenesis, synthetic ligation assembly, or a combination thereof. Alternatively, PCT Publication WO 03/074679 by Lazar et al. describes methods of using computational screening methods to optimize physiochemical properties of antibodies.
    • Nucleic Acid Molecules Encoding Antibodies of the Disclosure
  • Another aspect of the disclosure pertains to nucleic acid molecules that encode the antibodies of the invention. 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. (1987) Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York. A nucleic acid of the invention can be, for example, DNA or RNA and may or may not contain intronic sequences. In a preferred embodiment, the nucleic acid is a cDNA molecule.
  • Nucleic acids of the invention can be obtained using standard molecular biology techniques. For antibodies expressed by hybridomas (e.g., hybridomas prepared from transgenic mice carrying human immunoglobulin genes as described further below), cDNAs encoding the light and heavy chains of the antibody made by the hybridoma can be obtained by standard PCR amplification or cDNA cloning techniques. For antibodies obtained from an immunoglobulin gene library (e.g., using phage display techniques), nucleic acid encoding the antibody can be recovered from the library.
  • Preferred nucleic acids molecules of the invention are those encoding the VH and VL sequences of the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, monoclonal antibodies. DNA sequences encoding the VH sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, are shown in SEQ ID NOs:81, 82, 83, 84, 85, 86, 87, 88, 89 and 90, respectively. DNA sequences encoding the VL sequences of 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, are shown in SEQ ID NOs:91, 92, 93, 94, 95, 96, 97, 98, 99 and 100, respectively.
  • Once DNA fragments encoding VH and VL segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene. In these manipulations, a VL- or VH-encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker. The term “operatively linked,” as used in this context, is intended to mean that the two DNA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
  • The isolated DNA encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding DNA to another DNA molecule encoding heavy chain constant regions (CH1, CH2 and CH3). The sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat, E. A., el al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most preferably is an IgG1 or IgG4 constant region. For a Fab fragment heavy chain gene, the VH-encoding DNA can be operatively linked to another DNA molecule encoding only the heavy chain CH1 constant region.
  • The isolated DNA encoding the VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL. The sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The light chain constant region can be a kappa or lambda constant region, but most preferably is a kappa constant region.
  • To create a scFv gene, the VH- and VL-encoding DNA fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly4-Ser)3, such that the VH and VL sequences can be expressed as a contiguous single-chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., (1990) Nature 348:552-554).
    • Production of Monoclonal Antibodies of the Invention
  • Monoclonal antibodies (mAbs) of the present invention can be produced by a variety of techniques, including conventional monoclonal antibody methodology e.g., the standard somatic cell hybridization technique of Kohler and Milstein (1975) Nature 256: 495. Although somatic cell hybridization procedures are preferred, in principle, other techniques for producing monoclonal antibody can be employed e.g., viral or oncogenic transformation of B lymphocytes.
  • The preferred animal system for preparing hybridomas is the murine system. Hybridoma production in the mouse is a very well-established procedure. Immunization protocols and techniques for isolation of immunized splenocytes for fusion are known in the art. Fusion partners (e.g., murine myeloma cells) and fusion procedures are also known.
  • Chimeric or humanized antibodies of the present invention can be prepared based on the sequence of a murine monoclonal antibody prepared as described above. DNA encoding the heavy and light chain immunoglobulins can be obtained from the murine hybridoma of interest and engineered to contain non-murine (e.g., human) immunoglobulin sequences using standard molecular biology techniques. For example, to create a chimeric antibody, the murine variable regions can be linked to human constant regions using methods known in the art (see e.g., U.S. Pat. No. 4,816,567 to Cabilly et al.). To create a humanized antibody, the murine CDR regions can be inserted into a human framework using methods known in the art (see e.g., U.S. Pat. No. 5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.).
  • In a preferred embodiment, the antibodies of the invention are human monoclonal antibodies. Such human monoclonal antibodies directed against PD-L1 can be generated using transgenic or transchromosomic mice carrying parts of the human immune system rather than the mouse system. These transgenic and transchromosomic mice include mice referred to herein as HuMAb mice and KM Mice™, respectively, and are collectively referred to herein as “human Ig mice.”
  • The HuMAb Mouse® (Medarex, Inc.) contains human immunoglobulin gene miniloci that encode unrearranged human heavy (μ and γ) and κ light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous μ and κ chain loci (see e.g., Lonberg, et al. (1994) Nature 368(6474): 856-859). Accordingly, the mice exhibit reduced expression of mouse IgM or κ, and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgGκ monoclonal (Lonberg, N. et al. (1994), supra; reviewed in Lonberg, N. (1994) Handbook of Experimental Pharmacology 113:49-101; Lonberg, N. and Huszar, D. (1995) Intern. Rev. Immunol. 13: 65-93, and Harding, F. and Lonberg, N. (1995) Ann. N.Y. Acad. Sci. 764:536-546). The preparation and use of HuMab mice, and the genomic modifications carried by such mice, is further described in Taylor, L. et al. (1992) Nucleic Acids Research 20:6287-6295; Chen, J. et al. (1993) International Immunology 5: 647-656; Tuaillon et al. (1993) Proc. Natl. Acad. Sci. USA 90:3720-3724; Choi et al. (1993) Nature Genetics 4:117-123; Chen, J. et al. (1993) EMBO J. 12: 821-830; Tuaillon et al. (1994) J. Immunol. 152:2912-2920; Taylor, L. et al. (1994) International Immunology 6: 579-591; and Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851, the contents of all of which are hereby specifically incorporated by reference in their entirety. See further, U.S. Pat. Nos. 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,789,650; 5,877,397; 5,661,016; 5,814,318; 5,874,299; and 5,770,429; all to Lonberg and Kay; U.S. Pat. No. 5,545,807 to Surani et al.; PCT Publication Nos. WO 92/03918, WO 93/12227, WO 94/25585, WO 97/13852, WO 98/24884 and WO 99/45962, all to Lonberg and Kay; and PCT Publication No. WO 01/14424 to Korman et al.
  • In another embodiment, human antibodies of the invention can be raised using a mouse that carries human immunoglobulin sequences on transgenes and transchomosomes, such as a mouse that carries a human heavy chain transgene and a human light chain transchromosome. Such mice, referred to herein as “KM Mice™,” are described in detail in PCT Publication WO 02/43478 to Ishida et al.
  • Still further, alternative transgenic animal systems expressing human immunoglobulin genes are available in the art and can be used to raise anti-PD-L1 antibodies of the invention. For example, an alternative transgenic system referred to as the Xenomouse (Abgenix, Inc.) can be used; such mice are described in, for example, U.S. Pat. Nos. 5,939,598; 6,075,181; 6,114,598; 6,150,584 and 6,162,963 to Kucherlapati et al.
  • Moreover, alternative transchromosomic animal systems expressing human immunoglobulin genes are available in the art and can be used to raise anti-PD-L1 antibodies of the invention. For example, mice carrying both a human heavy chain transchromosome and a human light chain tranchromosome, referred to as “TC mice” can be used; such mice are described in Tomizuka et al. (2000) Proc. Natl. Acad. Sci. USA 97:722-727. Furthermore, cows carrying human heavy and light chain transchromosomes have been described in the art (Kuroiwa et al. (2002) Nature Biotechnology 20:889-894) and can be used to raise anti-PD-L1 antibodies of the invention.
  • Human monoclonal antibodies of the invention can also be prepared using phage display methods for screening libraries of human immunoglobulin genes. Such phage display methods for isolating human antibodies are established in the art. See for example: U.S. Pat. Nos. 5,223,409; 5,403,484; and U.S. Pat. No. 5,571,698 to Ladner et al.; U.S. Pat. Nos. 5,427,908 and 5,580,717 to Dower et al.; U.S. Pat. Nos. 5,969,108 and 6,172,197 to McCafferty et al.; and U.S. Pat. Nos. 5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915 and 6,593,081 to Griffiths et al.
  • Human monoclonal antibodies of the invention can also be prepared using SCID mice into which human immune cells have been reconstituted such that a human antibody response can be generated upon immunization. Such mice are described in, for example, U.S. Pat. Nos. 5,476,996 and 5,698,767 to Wilson et al.
    • Immunization of Human Ig Mice
  • When human Ig mice are used to raise human antibodies of the invention, such mice can be immunized with a purified or enriched preparation of PD-L1 antigen and/or recombinant PD-L1, or an PD-L1 fusion protein, as described by Lonberg, N. et al. (1994) Nature 368(6474): 856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851; and PCT Publication WO 98/24884 and WO 01/14424. Preferably, the mice will be 6-16 weeks of age upon the first infusion. For example, a purified or recombinant preparation (5-50 μg) of PD-L1 antigen can be used to immunize the human Ig mice intraperitoneally.
  • Detailed procedures to generate fully human monoclonal antibodies to PD-L1 are described in Example 1 below. Cumulative experience with various antigens has shown that the transgenic mice respond when initially immunized intraperitoneally (IP) with antigen in complete Freund's adjuvant, followed by every other week IP immunizations (up to a total of 6) with antigen in incomplete Freund's adjuvant. However, adjuvants other than Freund's are also found to be effective. In addition, whole cells in the absence of adjuvant are found to be highly immunogenic. The immune response can be monitored over the course of the immunization protocol with plasma samples being obtained by retroorbital bleeds. The plasma can be screened by ELISA (as described below), and mice with sufficient titers of anti-PD-L1 human immunoglobulin can be used for fusions. Mice can be boosted intravenously with antigen 3 days before sacrifice and removal of the spleen. It is expected that 2-3 fusions for each immunization may need to be performed. Between 6 and 24 mice are typically immunized for each antigen. Usually both HCo7 and HCo12 strains are used. In addition, both HCo7 and HCo12 transgene can be bred together into a single mouse having two different human heavy chain transgenes (HCo7/HCo12). Alternatively or additionally, the KM Mouse™ strain can be used, as described in Example 1.
    • Generation of Hybridomas Producing Human Monoclonal Antibodies of the Disclosure
  • To generate hybridomas producing human monoclonal antibodies of the invention, splenocytes and/or lymph node cells from immunized mice can be isolated and fused to an appropriate immortalized cell line, such as a mouse myeloma cell line. The resulting hybridomas can be screened for the production of antigen-specific antibodies. For example, single cell suspensions of splenic lymphocytes from immunized mice can be fused to one-sixth the number of P3X63-Ag8.653 nonsecreting mouse myeloma cells (ATCC, CRL 1580) with 50% PEG. Cells are plated at approximately 2×105 in flat bottom microtiter plate, followed by a two week incubation in selective medium containing 20% fetal Clone Serum, 18% “653” conditioned media, 5% origen (IGEN), 4 mM L-glutamine, 1 mM sodium pyruvate, 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 units/ml penicillin, 50 mg/ml streptomycin, 50 mg/ml gentamycin and 1×HAT (Sigma; the HAT is added 24 hours after the fusion). After approximately two weeks, cells can be cultured in medium in which the HAT is replaced with HT. Individual wells can then be screened by ELISA for human monoclonal IgM and IgG antibodies. Once extensive hybridoma growth occurs, medium can be observed usually after 10-14 days. The antibody secreting hybridomas can be re-plated, screened again, and if still positive for human IgG, the monoclonal antibodies can be subcloned at least twice by limiting dilution. The stable subclones can then be cultured in vitro to generate small amounts of antibody in tissue culture medium for characterization.
  • To purify human monoclonal antibodies, selected hybridomas can be grown in two-liter spinner-flasks for monoclonal antibody purification. Supernatants can be filtered and concentrated before affinity chromatography with protein A-sepharose (Pharmacia, Piscataway, N.J.). Eluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity. The buffer solution can be exchanged into PBS, and the concentration can be determined by OD280 using 1.43 extinction coefficient. The monoclonal antibodies can be aliquoted and stored at −80° C.
    • Generation of Transfectomas Producing Monoclonal Antibodies of the Disclosure
  • Antibodies of the invention also can be produced in a host cell transfectoma using, for example, a combination of recombinant DNA techniques and gene transfection methods as is well known in the art (e.g., Morrison, S. (1985) Science 229:1202).
  • For example, to express the antibodies, or antibody fragments thereof, DNAs encoding partial or full-length light and heavy chains, can be obtained by standard molecular biology techniques (e.g., PCR amplification or cDNA cloning using a hybridoma that expresses the antibody of interest) and the DNAs can be inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences. In this context, the term “operatively linked” is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene. The expression vector and expression control sequences are chosen to be compatible with the expression host cell used. The antibody light chain gene and the antibody heavy chain gene can be inserted into separate vector or, more typically, both genes are inserted into the same expression vector. The antibody genes are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present). The light and heavy chain variable regions of the antibodies described herein can be used to create full-length antibody genes of any antibody isotype by inserting them into expression vectors already encoding heavy chain constant and light chain constant regions of the desired isotype such that the VH segment is operatively linked to the CH segment(s) within the vector and the VK segment is operatively linked to the CL segment within the vector. Additionally or alternatively, the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell. The antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
  • In addition to the antibody chain genes, the recombinant expression vectors of the invention carry regulatory sequences that control the expression of the antibody chain genes in a host cell. The term “regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes. Such regulatory sequences are described, for example, in Goeddel (Gene Expression Technology. Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990)). It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences, may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV), Simian Virus 40 (SV40), adenovirus, (e.g., the adenovirus major late promoter (AdMLP) and polyoma. Alternatively, nonviral regulatory sequences may be used, such as the ubiquitin promoter or β-globin promoter. Still further, regulatory elements composed of sequences from different sources, such as the SRα promoter system, which contains sequences from the SV40 early promoter and the long terminal repeat of human T cell leukemia virus type 1 (Takebe, Y. et al. (1988) Mol. Cell. Biol. 8:466-472).
  • In addition to the antibody chain genes and regulatory sequences, the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes. The selectable marker gene facilitates selection of host cells into which the vector has been introduced (see, e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al.). For example, typically the selectable marker gene confers resistance to drugs, such as G418, hygromycin or methotrexate, on a host cell into which the vector has been introduced. Preferred selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr-host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
  • For expression of the light and heavy chains, the expression vector(s) encoding the heavy and light chains is transfected into a host cell by standard techniques. The various forms of the term “transfection” are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like. Although it is theoretically possible to express the antibodies of the invention in either prokaryotic or eukaryotic host cells, expression of antibodies in eukaryotic cells, and most preferably mammalian host cells, is the most preferred because such eukaryotic cells, and in particular mammalian cells, are more likely than prokaryotic cells to assemble and secrete a properly folded and immunologically active antibody. Prokaryotic expression of antibody genes has been reported to be ineffective for production of high yields of active antibody (Boss, M. A. and Wood, C. R. (1985) Immunology Today 6:12-13).
  • Preferred mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr-CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R. J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621), NSO myeloma cells, COS cells and SP2 cells. In particular, for use with NSO myeloma cells, another preferred expression system is the GS gene expression system disclosed in WO 87/04462, WO 89/01036 and EP 338,841. When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.
    • Characterization of Antibody Binding to Antigen
  • Antibodies of the invention can be tested for binding to PD-L1 by, for example, standard ELISA. Briefly, microtiter plates are coated with purified PD-L1 at 0.25 μg/ml in PBS, and then blocked with 5% bovine serum albumin in PBS. Dilutions of antibody (e.g., dilutions of plasma from PD-L1-immunized mice) are added to each well and incubated for 1-2 hours at 37° C. The plates are washed with PBS/Tween and then incubated with secondary reagent (e.g., for human antibodies, a goat-anti-human IgG Fc-specific polyclonal reagent) conjugated to alkaline phosphatase for 1 hour at 37° C. After washing, the plates are developed with pNPP substrate (1 mg/ml), and analyzed at OD of 405-650. Preferably, mice which develop the highest titers will be used for fusions.
  • An ELISA assay as described above can also be used to screen for hybridomas that show positive reactivity with PD-L1 immunogen. Hybridomas that bind with high avidity to PD-L1 are subcloned and further characterized. One clone from each hybridoma, which retains the reactivity of the parent cells (by ELISA), can be chosen for making a 5-10 vial cell bank stored at −140° C., and for antibody purification.
  • To purify anti-PD-L1 antibodies, selected hybridomas can be grown in two-liter spinner-flasks for monoclonal antibody purification. Supernatants can be filtered and concentrated before affinity chromatography with protein A-sepharose (Pharmacia, Piscataway, N.J.). Eluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity. The buffer solution can be exchanged into PBS, and the concentration can be determined by OD280 using 1.43 extinction coefficient. The monoclonal antibodies can be aliquoted and stored at −80° C.
  • To determine if the selected anti-PD-L1 monoclonal antibodies bind to unique epitopes, each antibody can be biotinylated using commercially available reagents (Pierce, Rockford, Ill.). Competition studies using unlabeled monoclonal antibodies and biotinylated monoclonal antibodies can be performed using PD-L1 coated-ELISA plates as described above. Biotinylated mAb binding can be detected with a strep-avidin-alkaline phosphatase probe.
  • To determine the isotype of purified antibodies, isotype ELISAs can be performed using reagents specific for antibodies of a particular isotype. For example, to determine the isotype of a human monoclonal antibody, wells of microtiter plates can be coated with 1 μg/ml of anti-human immunoglobulin overnight at 4° C. After blocking with 1% BSA, the plates are reacted with 1 μg/ml or less of test monoclonal antibodies or purified isotype controls, at ambient temperature for one to two hours. The wells can then be reacted with either human IgG1 or human IgM-specific alkaline phosphatase-conjugated probes. Plates are developed and analyzed as described above.
  • Anti-PD-L1 human IgGs can be further tested for reactivity with PD-L1 antigen by Western blotting. Briefly, PD-L1 can be prepared and subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis. After electrophoresis, the separated antigens are transferred to nitrocellulose membranes, blocked with 10% fetal calf serum, and probed with the monoclonal antibodies to be tested. Human IgG binding can be detected using anti-human IgG alkaline phosphatase and developed with BCIP/NBT substrate tablets (Sigma Chem. Co., St. Louis, Mo.).
    • Antibody Physical Properties
  • The antibodies of the present invention may be further characterized by the various physical properties of the anti-PD-L1 antibodies. Various assays may be used to detect and/or differentiate different classes of antibodies based on these physical properties.
  • In some embodiments, antibodies of the present invention may contain one or more glycosylation sites in either the light or heavy chain variable region. The presence of one or more glycosylation sites in the variable region may result in increased immunogenicity of the antibody or an alteration of the pK of the antibody due to altered antigen binding (Marshall et al (1972) Annu Rev Biochem 41:673-702; Gala F A and Morrison S L (2004) J Immunol 172:5489-94; Wallick et al (1988) J Exp Med 168:1099-109; Spiro R G (2002) Glycobiology 12:43R-56R; Parekh et al (1985) Nature 316:452-7; Mimura et al. (2000) Mol Immunol 37:697-706). Glycosylation has been known to occur at motifs containing an N—X—S/T sequence. Variable region glycosylation may be tested using a Glycoblot assay, which cleaves the antibody to produce a Fab, and then tests for glycosylation using an assay that measures periodate oxidation and Schiff base formation. Alternatively, variable region glycosylation may be tested using Dionex light chromatography (Dionex-LC), which cleaves saccharides from a Fab into monosaccharides and analyzes the individual saccharide content. In some instances, it is preferred to have an anti-PD-L1 antibody that does not contain variable region glycosylation. This can be achieved either by selecting antibodies that do not contain the glycosylation motif in the variable region or by mutating residues within the glycosylation motif using standard techniques well known in the art.
  • In a preferred embodiment, the antibodies of the present invention do not contain asparagine isomerism sites. A deamidation or isoaspartic acid effect may occur on N-G or D-G sequences, respectively. The deamidation or isoaspartic acid effect results in the creation of isoaspartic acid which decreases the stability of an antibody by creating a kinked structure off a side chain carboxy terminus rather than the main chain. The creation of isoaspartic acid can be measured using an iso-quant assay, which uses a reverse-phase HPLC to test for isoaspartic acid.
  • Each antibody will have a unique isoelectric point (pI), but generally antibodies will fall in the pH range of between 6 and 9.5. The pI for an IgG1 antibody typically falls within the pH range of 7-9.5 and the pI for an IgG4 antibody typically falls within the pH range of 6-8. Antibodies may have a pI that is outside this range. Although the effects are generally unknown, there is speculation that antibodies with a pI outside the normal range may have some unfolding and instability under in vivo conditions. The isoelectric point may be tested using a capillary isoelectric focusing assay, which creates a pH gradient and may utilize laser focusing for increased accuracy (Janini et al (2002) Electrophoresis 23:1605-11; Ma et al. (2001) Chromatographia 53:S75-89; Hunt et al (1998) J Chromatogr A 800:355-67). In some instances, it is preferred to have an anti-PD-L1 antibody that contains a pI value that falls in the normal range. This can be achieved either by selecting antibodies with a pI in the normal range, or by mutating charged surface residues using standard techniques well known in the art.
  • Each antibody will have a melting temperature that is indicative of thermal stability (Krishnamurthy R and Manning M C (2002) Curr Pharm Biotechnol 3:361-71). A higher thermal stability indicates greater overall antibody stability in vivo. The melting point of an antibody may be measure using techniques such as differential scanning calorimetry (Chen et al (2003) Pharm Res 20:1952-60; Ghirlando et al (1999) Immunol Lett 68:47-52). TM1 indicates the temperature of the initial unfolding of the antibody. TM2 indicates the temperature of complete unfolding of the antibody. Generally, it is preferred that the TM1 of an antibody of the present invention is greater than 60° C., preferably greater than 65° C., even more preferably greater than 70° C. Alternatively, the thermal stability of an antibody may be measure using circular dichroism (Murray et al. (2002) J Chromatogr Sci 40:343-9). The thermal stability of anti-PD-L1 antibodies disclosed herein is summarized in Table 1.
  • TABLE 1
    mAb Tm1 (° C.) Tm2 (° C.)
    3G10 70 75
    5F8 72 74
    11E6 64 73
    1B12 69 72
    12A4 68 72
    10A5 71
    12B7 70
    13G4 66 69
    10H10 69
  • In a preferred embodiment, antibodies are selected that do not rapidly degrade. Fragmentation of an anti-PD-L1 antibody may be measured using capillary electrophoresis (CE) and MALDI-MS, as is well understood in the art (Alexander A J and Hughes D E (1995) Anal Chem 67:3626-32).
  • In another preferred embodiment, antibodies are selected that have minimal aggregation effects. Aggregation may lead to triggering of an unwanted immune response and/or altered or unfavorable pharmacokinetic properties. Generally, antibodies are acceptable with aggregation of 25% or less, preferably 20% or less, even more preferably 15% or less, even more preferably 10% or less and even more preferably 5% or less. Aggregation may be measured by several techniques well known in the art, including size-exclusion column (SEC) high performance liquid chromatography (HPLC), and light scattering to identify monomers, dimers, trimers or multimers.
    • Immunoconjugates
  • In another aspect, the present invention features an anti-PD-L1 antibody, or a fragment thereof, conjugated to a therapeutic moiety, such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radiotoxin. Such conjugates are referred to herein as “immunoconjugates”. Immunoconjugates that include one or more cytotoxins are referred to as “immunotoxins.” A cytotoxin or cytotoxic agent includes 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 also include, for example, 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., vincristine and vinblastine).
  • Other preferred examples of therapeutic cytotoxins that can be conjugated to an antibody of the invention include duocarmycins, calicheamicins, maytansines and auristatins, and derivatives thereof. An example of a calicheamicin antibody conjugate is commercially available (Mylotarg™; Wyeth-Ayerst).
  • Cytotoxins can be conjugated to antibodies of the invention using linker technology available in the art. Examples of linker types that have been used to conjugate a cytotoxin to an antibody include, but are not limited to, hydrazones, thioethers, esters, disulfides and peptide-containing linkers. A linker can be chosen that is, for example, susceptible to cleavage by low pH within the lysosomal compartment or susceptible to cleavage by proteases, such as proteases preferentially expressed in tumor tissue such as cathepsins (e.g., cathepsins B, C, D).
  • For further discussion of types of cytotoxins, linkers and methods for conjugating therapeutic agents to antibodies, see also Saito, G. et al. (2003) Adv. Drug Deliv. Rev. 55:199-215; Trail, P. A. et al. (2003) Cancer Immunol. Immunother. 52:328-337; Payne, G. (2003) Cancer Cell 3:207-212; Allen, T. M. (2002) Nat. Rev. Cancer 2:750-763; Pastan, I. and Kreitman, R. J. (2002) Curr. Opin. Investig. Drugs 3:1089-1091; Senter, P. D. and Springer, C. J. (2001) Adv. Drug Deliv. Rev. 53:247-264.
  • Antibodies of the present invention also can be conjugated to a radioactive isotope to generate cytotoxic radiopharmaceuticals, also referred to as radioimmunoconjugates. Examples of radioactive isotopes that can be conjugated to antibodies for use diagnostically or therapeutically include, but are not limited to, iodine131, indium111, yttrium90 and lutetium177. Method for preparing radioimmunconjugates are established in the art. Examples of radioimmunoconjugates are commercially available, including Zevalin™ (IDEC Pharmaceuticals) and Bexxar™ (Corixa Pharmaceuticals), and similar methods can be used to prepare radioimmunoconjugates using the antibodies of the invention.
  • The antibody conjugates of the invention can be used to modify a given biological response, and the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such 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-γ; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.
  • 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. Liss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery,” in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review,” in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); “Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy,” in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., “The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates,” Immunol. Rev., 62:119-58 (1982).
    • Bispecific Molecules
  • In another aspect, the present invention features bispecific molecules comprising an anti-PD-L1 antibody, or a fragment thereof, of the invention. An antibody of the invention, or antigen-binding portions thereof, can be derivatized or linked to another functional molecule, e.g., another peptide or protein (e.g., another antibody or ligand for a receptor) to generate a bispecific molecule that binds to at least two different binding sites or target molecules. The antibody of the invention may in fact be derivatized or linked to more than one other functional molecule to generate multispecific molecules that bind to more than two different binding sites and/or target molecules; such multispecific molecules are also intended to be encompassed by the term “bispecific molecule” as used herein. To create a bispecific molecule of the invention, an antibody of the invention can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other binding molecules, such as another antibody, antibody fragment, peptide or binding mimetic, such that a bispecific molecule results.
  • Accordingly, the present invention includes bispecific molecules comprising at least one first binding specificity for PD-L1 and a second binding specificity for a second target epitope. In a particular embodiment of the invention, the second target epitope is an Fc receptor, e.g., human FcγRI (CD64) or a human Fcα receptor (CD89). Therefore, the invention includes bispecific molecules capable of binding both to FcγR or FcαR expressing effector cells (e.g., monocytes, macrophages or polymorphonuclear cells (PMNs)), and to target cells expressing PD-L1. These bispecific molecules target PD-L1 expressing cells to effector cell and trigger Fc receptor-mediated effector cell activities, such as phagocytosis of an PD-L1 expressing cells, antibody dependent cell-mediated cytotoxicity (ADCC), cytokine release, or generation of superoxide anion.
  • In an embodiment of the invention in which the bispecific molecule is multispecific, the molecule can further include a third binding specificity, in addition to an anti-Fc binding specificity and an anti-PD-L1 binding specificity. In one embodiment, the third binding specificity is an anti-enhancement factor (EF) portion, e.g., a molecule which binds to a surface protein involved in cytotoxic activity and thereby increases the immune response against the target cell. The “anti-enhancement factor portion” can be an antibody, functional antibody fragment or a ligand that binds to a given molecule, e.g., an antigen or a receptor, and thereby results in an enhancement of the effect of the binding determinants for the FC receptor or target cell antigen. The “anti-enhancement factor portion” can bind an FC receptor or a target cell antigen. Alternatively, the anti-enhancement factor portion can bind to an entity that is different from the entity to which the first and second binding specificities bind. For example, the anti-enhancement factor portion can bind a cytotoxic T-cell (e.g. via CD2, CD3, CD8, CD28, CD4, CD40, ICAM-1 or other immune cell that results in an increased immune response against the target cell).
  • In one embodiment, the bispecific molecules of the invention comprise as a binding specificity at least one antibody, or an antibody fragment thereof, including, e.g., an Fab, Fab′, F(ab′)2, Fv, or a single chain Fv. The antibody may also be a light chain or heavy chain dimer, or any minimal fragment thereof such as a Fv or a single chain construct as described in Ladner et al. U.S. Pat. No. 4,946,778, the contents of which is expressly incorporated by reference.
  • In one embodiment, the binding specificity for an Fcγ receptor is provided by a monoclonal antibody, the binding of which is not blocked by human immunoglobulin G (IgG). As used herein, the term “IgG receptor” refers to any of the eight γ-chain genes located on chromosome 1. These genes encode a total of twelve transmembrane or soluble receptor isoforms which are grouped into three Fcγ receptor classes: FcγRI (CD64), FcγRII(CD32), and FcγRIII (CD16). In one preferred embodiment, the Fcγ receptor a human high affinity FcγRI. The human FcγRI is a 72 kDa molecule, which shows high affinity for monomeric IgG (108-109M−1).
  • The production and characterization of certain preferred anti-Fcγ monoclonal antibodies are described by Fanger et al. in PCT Publication WO 88/00052 and in U.S. Pat. No. 4,954,617, the teachings of which are fully incorporated by reference herein. These antibodies bind to an epitope of FcγRI, FcγRII or FcγRIII at a site which is distinct from the Fcγ binding site of the receptor and, thus, their binding is not blocked substantially by physiological levels of IgG. Specific anti-FcγRI antibodies useful in this invention are mAb 22, mAb 32, mAb 44, mAb 62 and mAb 197. The hybridoma producing mAb 32 is available from the American Type Culture Collection, ATCC Accession No. HB9469. In other embodiments, the anti-Fcγ receptor antibody is a humanized form of monoclonal antibody 22 (H22). The production and characterization of the H22 antibody is described in Graziano, R. F. et al. (1995) J. Immunol 155 (10): 4996-5002 and PCT Publication WO 94/10332. The H22 antibody producing cell line was deposited at the American Type Culture Collection under the designation HA022CL1 and has the accession no. CRL 11177.
  • In still other preferred embodiments, the binding specificity for an Fc receptor is provided by an antibody that binds to a human IgA receptor, e.g., an Fc-alpha receptor (FcαRI (CD89)), the binding of which is preferably not blocked by human immunoglobulin A (IgA). The term “IgA receptor” is intended to include the gene product of one α-gene (FcαRI) located on chromosome 19. This gene is known to encode several alternatively spliced transmembrane isoforms of 55 to 110 kDa. FcαRI (CD89) is constitutively expressed on monocytes/macrophages, eosinophilic and neutrophilic granulocytes, but not on non-effector cell populations. FcαRI has medium affinity (≈5×107M−1) for both IgA1 and IgA2, which is increased upon exposure to cytokines such as G-CSF or GM-CSF (Morton, H. C. et al. (1996) Critical Reviews in Immunology 16:423-440). Four FcαRI-specific monoclonal antibodies, identified as A3, A59, A62 and A77, which bind FcαRI outside the IgA ligand binding domain, have been described (Monteiro, R. C. et al. (1992) J. Immunol. 148:1764).
  • FcαRI and FcγRI are preferred trigger receptors for use in the bispecific molecules of the invention because they are (1) expressed primarily on immune effector cells, e.g., monocytes, PMNs, macrophages and dendritic cells; (2) expressed at high levels (e.g., 5,000-100,000 per cell); (3) mediators of cytotoxic activities (e.g., ADCC, phagocytosis); (4) mediate enhanced antigen presentation of antigens, including self-antigens, targeted to them.
  • While human monoclonal antibodies are preferred, other antibodies which can be employed in the bispecific molecules of the invention are murine, chimeric and humanized monoclonal antibodies.
  • The bispecific molecules of the present invention can be prepared by conjugating the constituent binding specificities, e.g., the anti-FcR and anti-PD-L1 binding specificities, using methods known in the art. For example, each binding specificity of the bispecific molecule can be generated separately and then conjugated to one another. When the binding specificities are proteins or peptides, a variety of coupling or cross-linking agents can be used for covalent conjugation. Examples of cross-linking agents include protein A, carbodiimide, N-succinimidyl-S-acetyl-thioacetate (SATA), 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), o-phenylenedimaleimide (oPDM), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), and sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohaxane-1-carboxylate (sulfo-SMCC) (see e.g., Karpovsky et al. (1984) J. Exp. Med. 160:1686; Liu, M A et al. (1985) Proc. Natl. Acad. Sci. USA 82:8648). Other methods include those described in Paulus (1985) Behring Ins. Mitt. No. 78, 118-132; Brennan et al. (1985) Science 229:81-83), and Glennie et al. (1987) J. Immunol. 139: 2367-2375). Preferred conjugating agents are SATA and sulfo-SMCC, both available from Pierce Chemical Co. (Rockford, Ill.).
  • When the binding specificities are antibodies, they can be conjugated via sulfhydryl bonding of the C-terminus hinge regions of the two heavy chains. In a particularly preferred embodiment, the hinge region is modified to contain an odd number of sulfhydryl residues, preferably one, prior to conjugation.
  • Alternatively, both binding specificities can be encoded in the same vector and expressed and assembled in the same host cell. This method is particularly useful where the bispecific molecule is a mAb×mAb, mAb×Fab, Fab×F(ab′)2 or ligand x Fab fusion protein. A bispecific molecule of the invention can be a single chain molecule comprising one single chain antibody and a binding determinant, or a single chain bispecific molecule comprising two binding determinants. Bispecific molecules may comprise at least two single chain molecules. Methods for preparing bispecific molecules are described for example in U.S. Pat. No. 5,260,203; U.S. Pat. No. 5,455,030; U.S. Pat. No. 4,881,175; U.S. Pat. No. 5,132,405; U.S. Pat. No. 5,091,513; U.S. Pat. No. 5,476,786; U.S. Pat. No. 5,013,653; U.S. Pat. No. 5,258,498; and U.S. Pat. No. 5,482,858.
  • Binding of the bispecific molecules to their specific targets can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, bioassay (e.g., growth inhibition), or Western Blot assay. Each of these assays generally detects the presence of protein-antibody complexes of particular interest by employing a labeled reagent (e.g., an antibody) specific for the complex of interest. For example, the FcR-antibody complexes can be detected using e.g., an enzyme-linked antibody or antibody fragment which recognizes and specifically binds to the antibody-FcR complexes. Alternatively, the complexes can be detected using any of a variety of other immunoassays. For example, the antibody can be radioactively labeled and used in a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein). The radioactive isotope can be detected by such means as the use of a γ counter or a scintillation counter or by autoradiography.
    • Pharmaceutical Compositions
  • In another aspect, the present invention provides a composition, e.g., a pharmaceutical composition, containing one or a combination of monoclonal antibodies, or antigen-binding portion(s) thereof, of the present invention, formulated together with a pharmaceutically acceptable carrier. Such compositions may include one or a combination of (e.g., two or more different) antibodies, or immunoconjugates or bispecific molecules of the invention. For example, a pharmaceutical composition of the invention can comprise a combination of antibodies (or immunoconjugates or bispecifics) that bind to different epitopes on the target antigen or that have complementary activities.
  • Pharmaceutical compositions of the invention also can be administered in combination therapy, i.e., combined with other agents. For example, the combination therapy can include an anti-PD-L1 antibody of the present invention combined with at least one other anti-inflammatory or immunosuppressant agent. Examples of therapeutic agents that can be used in combination therapy are described in greater detail below in the section on uses of the antibodies of the invention.
  • As used herein, “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. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound, i.e., antibody, immunoconjuage, or bispecific 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.
  • The pharmaceutical compounds of the invention may include one or more pharmaceutically acceptable salts. 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. 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 pharmaceutical composition of the invention also may include a pharmaceutically acceptable anti-oxidant. Examples of pharmaceutically acceptable antioxidants 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.
  • Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention 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. 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.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • Therapeutic 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. In many cases, it will be preferable to include 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. Generally, 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. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • 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 0.01 percent to about ninety-nine percent of active ingredient, preferably from about 0.1 percent to about 70 percent, most preferably from about 1 percent to about 30 percent of active ingredient in combination with a pharmaceutically acceptable carrier.
  • 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. 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. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • For administration of the antibody, the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight. For example dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg. An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months. Preferred dosage regimens for an anti-PD-L1 antibody of the invention include 1 mg/kg body weight or 3 mg/kg body weight via intravenous administration, with the antibody being given using one of the following dosing schedules: (i) every four weeks for six dosages, then every three months; (ii) every three weeks; (iii) 3 mg/kg body weight once followed by 1 mg/kg body weight every three weeks.
  • In some methods, two or more monoclonal antibodies with different binding specificities are administered simultaneously, in which case the dosage of each antibody administered falls within the ranges indicated. Antibody is usually administered on multiple occasions. Intervals between single dosages can be, for example, weekly, monthly, every three months or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to the target antigen in the patient. In some methods, dosage is adjusted to achieve a plasma antibody concentration of about 1-1000 μg/ml and in some methods about 25-300 μg/ml.
  • Alternatively, antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the antibody in the patient. In general, human antibodies show the longest half life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regime.
  • Actual dosage levels of the active ingredients in the pharmaceutical 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 “therapeutically effective dosage” of an anti-PD-L1 antibody of the invention preferably results in a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. For example, for the treatment of PD-L1+ tumors, a “therapeutically effective dosage” preferably inhibits cell growth or tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. The ability of a compound to inhibit tumor growth can be evaluated in an animal model system predictive of efficacy in human tumors. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit, such inhibition in vitro by assays known to the skilled practitioner. A therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in a subject. One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.
  • A composition of the present invention can be administered via one or more routes of administration using one or more of 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. Preferred routes of administration for antibodies of the invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” 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 intrasternal injection and infusion.
  • Alternatively, an antibody of the invention can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • 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.
  • Therapeutic compositions can be administered with medical devices known in the art. For example, in a preferred embodiment, 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. 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. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Pat. No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Pat. No. 4,475,196, which discloses an osmotic drug delivery system. These patents are incorporated herein by reference. Many other such implants, delivery systems, and modules are known to those skilled in the art.
  • In certain embodiments, the human monoclonal antibodies of the invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the therapeutic compounds of the invention cross the BBB (if desired), they can be formulated, for example, in 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). Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low et al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153:1038); antibodies (P. G. Bloeman et al. (1995) FEBS Lett. 357:140; M. Owais et al. (1995) Antimicrob. Agents Chemother. 39:180); surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol. 1233:134); p120 (Schreier et al. (1994) J. Biol. Chem. 269:9090); see also K. Keinanen; M. L. Laukkanen (1994) FEBS Lett. 346:123; J. J. Killion; I. J. Fidler (1994) Immunomethods 4:273.
    • Uses and Methods of the Invention
  • The antibodies, antibody compositions and methods of the present invention have numerous in vitro and in vivo utilities involving, for example, detection of PD-L1 or enhancement of immune response by blockade of PD-L1. In a preferred embodiment, the antibodies of the present invention are human antibodies. For example, these molecules can be administered to cells in culture, in vitro or ex vivo, or to human subjects, e.g., in vivo, to enhance immunity in a variety of situations. Accordingly, in one aspect, the invention provides a method of modifying an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of the invention such that the immune response in the subject is modified. Preferably, the response is enhanced, stimulated or up-regulated.
  • As used herein, the term “subject” is intended to include human and non-human animals. Non-human animals includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cows and horses. Preferred subjects include human patients in need of enhancement of an immune response. The methods are particularly suitable for treating human patients having a disorder that can be treated by augmenting the T-cell mediated immune response. In a particular embodiment, the methods are particularly suitable for treatment of cancer cells in vivo. To achieve antigen-specific enhancement of immunity, the anti-PD-L1 antibodies can be administered together with an antigen of interest. When antibodies to PD-L1 are administered together with another agent, the two can be administered in either order or simultaneously.
  • The invention further provides methods for detecting the presence of human PD-L1 antigen in a sample, or measuring the amount of human PD-L1 antigen, comprising contacting the sample, and a control sample, with a human monoclonal antibody, or an antigen binding portion thereof, which specifically binds to human PD-L1, under conditions that allow for formation of a complex between the antibody or portion thereof and human PD-L1. The formation of a complex is then detected, wherein a difference complex formation between the sample compared to the control sample is indicative the presence of human PD-L1 antigen in the sample.
    • Cancer
  • Blockade of PD-L1 by antibodies can enhance the immune response to cancerous cells in the patient. PD-L1 is not expressed in normal human cells, but is abundant in a variety of human cancers (Dong et al. (2002) Nat Med 8:787-9). The interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells (Dong et al. (2003) J Mol Med 81:281-7; Blank et al. (2004) Cancer Immunol. Immunother. [epub]; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100). Immune suppression can be reversed by inhibiting the local interaction of PD-L1 to PD-1 and the effect is additive when the interaction of PD-L2 to PD-1 is blocked as well (Iwai et al. (2002) PNAS 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66). An anti-PD-L1 antibody may be used alone to inhibit the growth of cancerous tumors. Alternatively, an anti-PD-L1 antibody may be used in conjunction with other immunogenic agents, standard cancer treatments, or other antibodies, as described below.
  • Accordingly, in one embodiment, the invention provides a method of inhibiting growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof. Preferably, the antibody is a human anti-PD-L1 antibody (such as any of the human anti-human PD-L1 antibodies described herein). Additionally or alternatively, the antibody may be a chimeric or humanized anti-PD-L1 antibody.
  • Preferred cancers whose growth may be inhibited using the antibodies of the invention include cancers typically responsive to immunotherapy. Non-limiting examples of preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer. Examples of other cancers that may be treated using the methods of the invention include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. The present invention is also useful for treatment of metastatic cancers, especially metastatic cancers that express PD-L1 (Iwai et al. (2005) Int. Immunol. 17:133-144).
  • Optionally, antibodies to PD-L1 can be combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J Immunol. 173:4919-28). Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MART1 and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF (discussed further below).
  • In humans, some tumors have been shown to be immunogenic such as melanomas. It is anticipated that by raising the threshold of T cell activation by PD-L1 blockade, we may expect to activate tumor responses in the host.
  • PD-L1 blockade is likely to be most effective when combined with a vaccination protocol. Many experimental strategies for vaccination against tumors have been devised (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C., 2000, ASCO Educational Book Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring: 414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; see also Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita, V. et al. (eds.), 1997, Cancer: Principles and Practice of Oncology. Fifth Edition). In one of these strategies, a vaccine is prepared using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci U.S.A. 90: 3539-43).
  • The study of gene expression and large scale gene expression patterns in various tumors has led to the definition of so-called tumor specific antigens (Rosenberg, S A (1999) Immunity 10: 281-7). In many cases, these tumor specific antigens are differentiation antigens expressed in the tumors and in the cell from which the tumor arose, for example melanocyte antigens gp100, MAGE antigens, and Trp-2. More importantly, many of these antigens can be shown to be the targets of tumor specific T cells found in the host. PD-L1 blockade may be used in conjunction with a collection of recombinant proteins and/or peptides expressed in a tumor in order to generate an immune response to these proteins. These proteins are normally viewed by the immune system as self antigens and are therefore tolerant to them. The tumor antigen may also include the protein telomerase, which is required for the synthesis of telomeres of chromosomes and which is expressed in more than 85% of human cancers and in only a limited number of somatic tissues (Kim, N et al. (1994) Science 266: 2011-2013). (These somatic tissues may be protected from immune attack by various means). Tumor antigen may also be “neo-antigens” expressed in cancer cells because of somatic mutations that alter protein sequence or create fusion proteins between two unrelated sequences (i.e. bcr-abl in the Philadelphia chromosome), or idiotype from B cell tumors.
  • Other tumor vaccines may include the proteins from viruses implicated in human cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). Another form of tumor specific antigen which may be used in conjunction with PD-L1 blockade is purified heat shock proteins (HSP) isolated from the tumor tissue itself. These heat shock proteins contain fragments of proteins from the tumor cells and these HSPs are highly efficient at delivery to antigen presenting cells for eliciting tumor immunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588; Tamura, Y. et al. (1997) Science 278:117-120).
  • Dendritic cells (DC) are potent antigen presenting cells that can be used to prime antigen-specific responses. DC's can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DCs may also be transduced by genetic means to express these tumor antigens as well. DCs have also been fused directly to tumor cells for the purposes of immunization (Kugler, A. et al. (2000) Nature Medicine 6:332-336). As a method of vaccination, DC immunization may be effectively combined with PD-L1 blockade to activate more potent anti-tumor responses.
  • PD-L1 blockade may also be combined with standard cancer treatments. PD-L1 blockade may be effectively combined with chemotherapeutic regimes. In these instances, it may be possible to reduce the dose of chemotherapeutic reagent administered (Mokyr, M. et al. (1998) Cancer Research 58: 5301-5304). An example of such a combination is an anti-PD-L1 antibody in combination with decarbazine for the treatment of melanoma. Another example of such a combination is an anti-PD-L1 antibody in combination with interleukin-2 (IL-2) for the treatment of melanoma. The scientific rationale behind the combined use of PD-L1 blockade and chemotherapy is that cell death, that is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway. Other combination therapies that may result in synergy with PD-L1 blockade through cell death are radiation, surgery, and hormone deprivation. Each of these protocols creates a source of tumor antigen in the host. Angiogenesis inhibitors may also be combined with PD-L1 blockade. Inhibition of angiogenesis leads to tumor cell death which may feed tumor antigen into host antigen presentation pathways.
  • PD-L1 blocking antibodies can also be used in combination with bispecific antibodies that target Fc alpha or Fc γ receptor-expressing effectors cells to tumor cells (see, e.g., U.S. Pat. Nos. 5,922,845 and 5,837,243). Bispecific antibodies can be used to target two separate antigens. For example anti-Fc receptor/anti tumor antigen (e.g., Her-2/neu) bispecific antibodies have been used to target macrophages to sites of tumor. This targeting may more effectively activate tumor specific responses. The T cell arm of these responses would by augmented by the use of PD-L1 blockade. Alternatively, antigen may be delivered directly to DCs by the use of bispecific antibodies which bind to tumor antigen and a dendritic cell specific cell surface marker.
  • Tumors evade host immune surveillance by a large variety of mechanisms. Many of these mechanisms may be overcome by the inactivation of proteins which are expressed by the tumors and which are immunosuppressive. These include among others TGF-beta (Kehrl, J. et al. (1986) J. Exp. Med. 163: 1037-1050), IL-10 (Howard, M. & O'Garra, A. (1992) Immunology Today 13: 198-200), and Fas ligand (Hahne, M. et al. (1996) Science 274: 1363-1365). Antibodies to each of these entities may be used in combination with anti-PD-L1 to counteract the effects of the immunosuppressive agent and favor tumor immune responses by the host.
  • Other antibodies which may be used to activate host immune responsiveness can be used in combination with anti-PD-L1. These include molecules on the surface of dendritic cells which activate DC function and antigen presentation. Anti-CD40 antibodies are able to substitute effectively for T cell helper activity (Ridge, J. et al. (1998) Nature 393: 474-478) and can be used in conjunction with PD-L1 antibodies (Ito, N. et al. (2000) Immunobiology 201 (5) 527-40). Activating antibodies to T cell costimulatory molecules such as OX-40 (Weinberg, A. et al. (2000) Immunol 164: 2160-2169), 4-1BB (Melero, I. et al. (1997) Nature Medicine 3: 682-685 (1997), and ICOS (Hutloff, A. et al. (1999) Nature 397: 262-266) as well as antibodies which block the activity of negative costimulatory molecules such as CTLA-4 (e.g., U.S. Pat. No. 5,811,097) or BTLA (Watanabe, N. et al. (2003) Nat Immunol 4:670-9), B7-H4 (Sica, G L et al. (2003) Immunity 18:849-61) may also provide for increased levels of T cell activation.
  • Bone marrow transplantation is currently being used to treat a variety of tumors of hematopoietic origin. While graft versus host disease is a consequence of this treatment, therapeutic benefit may be obtained from graft vs. tumor responses. PD-L1 blockade can be used to increase the effectiveness of the donor engrafted tumor specific T cells.
  • There are also several experimental treatment protocols that involve ex vivo activation and expansion of antigen specific T cells and adoptive transfer of these cells into recipients in order to antigen-specific T cells against tumor (Greenberg, R. & Riddell, S. (1999) Science 285: 546-51). These methods may also be used to activate T cell responses to infectious agents such as CMV. Ex vivo activation in the presence of anti-PD-L1 antibodies may be expected to increase the frequency and activity of the adoptively transferred T cells.
    • Infectious Diseases
  • Other methods of the invention are used to treat patients that have been exposed to particular toxins or pathogens. Accordingly, another aspect of the invention provides a method of treating an infectious disease in a subject comprising administering to the subject an anti-PD-L1 antibody, or antigen-binding portion thereof, such that the subject is treated for the infectious disease. Preferably, the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • Similar to its application to tumors as discussed above, antibody mediated PD-L1 blockade can be used alone, or as an adjuvant, in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful, include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa. PD-L1 blockade is particularly useful against established infections by agents such as HIV that present altered antigens over the course of the infections. These novel epitopes are recognized as foreign at the time of anti-human PD-L1 administration, thus provoking a strong T cell response that is not dampened by negative signals through PD-L1.
  • Some examples of pathogenic viruses causing infections treatable by methods of the invention include HIV, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • Some examples of pathogenic bacteria causing infections treatable by methods of the invention include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • Some examples of pathogenic fungi causing infections treatable by methods of the invention include Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • Some examples of pathogenic parasites causing infections treatable by methods of the invention include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis.
  • In all of the above methods, PD-L1 blockade can be combined with other forms of immunotherapy such as cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), or bispecific antibody therapy, which provides for enhanced presentation of tumor antigens (see, e.g., Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak (1994) Structure 2:1121-1123).
    • Autoimmune Reactions
  • Anti-PD-L1 antibodies may provoke and amplify autoimmune responses. Indeed, induction of anti-tumor responses using tumor cell and peptide vaccines reveals that many anti-tumor responses involve anti-self reactivities (depigmentation observed in anti-CTLA-4+GM-CSF-modified B16 melanoma in van Elsas et al. supra; depigmentation in Trp-2 vaccinated mice (Overwijk, W. et al. (1999) Proc. Natl. Acad. Sci. U.S.A. 96: 2982-2987); autoimmune prostatitis evoked by TRAMP tumor cell vaccines (Hurwitz, A. (2000) supra), melanoma peptide antigen vaccination and vitilago observed in human clinical trials (Rosenberg, S A and White, D E (1996) J. Immunother Emphasis Tumor Immunol 19 (1): 81-4).
  • Therefore, it is possible to consider using anti-PD-L1 blockade in conjunction with various self proteins in order to devise vaccination protocols to efficiently generate immune responses against these self proteins for disease treatment. For example, Alzheimer's disease involves inappropriate accumulation of Aβ peptide in amyloid deposits in the brain; antibody responses against amyloid are able to clear these amyloid deposits (Schenk et al., (1999) Nature 400: 173-177).
  • Other self proteins may also be used as targets such as IgE for the treatment of allergy and asthma, and TNFα for rheumatoid arthritis. Finally, antibody responses to various hormones may be induced by the use of anti-PD-L1 antibody. Neutralizing antibody responses to reproductive hormones may be used for contraception. Neutralizing antibody response to hormones and other soluble factors that are required for the growth of particular tumors may also be considered as possible vaccination targets.
  • Analogous methods as described above for the use of anti-PD-L1 antibody can be used for induction of therapeutic autoimmune responses to treat patients having an inappropriate accumulation of other self-antigens, such as amyloid deposits, including Aβ in Alzheimer's disease, cytokines such as TNFα, and IgE.
    • Vaccines
  • Anti-PD-L1 antibodies may be used to stimulate antigen-specific immune responses by coadministration of an anti-PD-L1 antibody with an antigen of interest (e.g., a vaccine). Accordingly, in another aspect the invention provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) an anti-PD-L1 antibody, or antigen-binding portion thereof, such that an immune response to the antigen in the subject is enhanced. Preferably, the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody. The antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen. Non-limiting examples of such antigens include those discussed in the sections above, such as the tumor antigens (or tumor vaccines) discussed above, or antigens from the viruses, bacteria or other pathogens described above.
  • Anti-PD-L1 antibodies may also be used to abrogate secondary effects associated with diseases such as T cell suppressed wasting disease with colitis (Kanai et al. (2003) J. Immunol. 171:4156-63). Accordingly, in another aspect the invention provides a method of abrogating leukocyte infiltration, decreasing production of IFN-γ, IL-2, and IFN-α by T cells. Preferably, the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • Anti-PD-L1 antibodies may also be used to treat diseases such as chronic inflammatory diseases, such as lichen planus, a T-cell mediated chronic inflammatory mucocutaneous disease (Youngnak-Piboonratanakit et al. (2004) Immunol Letters 94:215-22). Accordingly, in another aspect the invention provides a method of abrogating chronic inflammatory disease by T cells. Preferably, the antibody is a human anti-human PD-L1 antibody (such as any of the human anti-PD-L1 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • Suitable routes of administering the antibody compositions (e.g., human monoclonal antibodies, multispecific and bispecific molecules and immunoconjugates) of the invention in vivo and in vitro are well known in the art and can be selected by those of ordinary skill. For example, the antibody compositions can be administered by injection (e.g., intravenous or subcutaneous). Suitable dosages of the molecules used will depend on the age and weight of the subject and the concentration and/or formulation of the antibody composition.
  • As previously described, human anti-PD-L1 antibodies of the invention can be co-administered with one or other more therapeutic agents, e.g., a cytotoxic agent, a radiotoxic agent or an immunosuppressive agent. The antibody can be linked to the agent (as an immunocomplex) or can be administered separate from the agent. In the latter case (separate administration), the antibody can be administered before, after or concurrently with the agent or can be co-administered with other known therapies, e.g., an anti-cancer therapy, e.g., radiation. Such therapeutic agents include, among others, anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient. Cisplatin is intravenously administered as a 100 mg/dose once every four weeks and adriamycin is intravenously administered as a 60-75 mg/ml dose once every 21 days. Co-administration of the human anti-PD-L1 antibodies, or antigen binding fragments thereof, of the present invention with chemotherapeutic agents provides two anti-cancer agents which operate via different mechanisms which yield a cytotoxic effect to human tumor cells. Such co-administration can solve problems due to development of resistance to drugs or a change in the antigenicity of the tumor cells which would render them unreactive with the antibody.
  • Also within the scope of the present invention are kits comprising the antibody compositions of the invention (e.g., human antibodies, bispecific or multispecific molecules, or immunoconjugates) and instructions for use. The kit can further contain a least one additional reagent, or one or more additional human antibodies of the invention (e.g., a human antibody having a complementary activity which binds to an epitope in PD-L1 antigen distinct from the first human antibody). Kits typically include a label indicating the intended use of the contents of the kit. The term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
  • The present invention is further illustrated by the following examples which should not be construed as further limiting. The contents of all figures and all references, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.
    • EXAMPLES Example 1: Generation of Human Monoclonal Antibodies Against PD-L1 Antigen
  • Immunization protocols utilized as antigen both (i) a recombinant fusion protein comprising the extracellular portion of PD-L1, and (ii) membrane bound full-length PD-L1. Both antigens were generated by recombinant transfection methods in a CHO cell line.
    • Transgenic Mice (KM-Mouse® Colony)
  • Fully human monoclonal antibodies to PD-L1 were prepared using the KM strain of transgenic transchromosomic mice, which expresses human antibody genes. In this mouse strain, the endogenous mouse kappa light chain gene has been homozygously disrupted as described in Chen et al. (1993) EMBO J. 12:811-820 and the endogenous mouse heavy chain gene has been homozygously disrupted as described in Example 1 of PCT Publication WO 01/09187. Furthermore, this mouse strain carries a human kappa light chain transgene, KCo5, as described in Fishwild et al. (1996) Nature Biotechnology 14:845-851, and a SC20 transchromosome as described in PCT Publication WO 02/43478.
    • KM-Mouse® Immunizations
  • To generate fully human monoclonal antibodies to PD-L1, a cohort of mice of the KM-Mouse® strain were immunized with purified recombinant PD-L1-Ig and PD-L1-transfected CHO cells as antigen. General immunization schemes for HuMab mice are described in Lonberg, N. et al (1994) Nature 368(6474): 856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851 and PCT Publication WO 98/24884. The mice were 6-16 weeks of age upon the first infusion of antigen. A purified recombinant preparation (5-50 μg) of PD-L1-Ig antigen and 5-10×106 cells were used to immunize the HuMab mice intraperitonealy (IP), subcutaneously (Sc) or via footpad injection.
  • Transgenic mice were immunized twice with antigen in complete Freund's adjuvant or Ribi adjuvant IP, followed by 3-21 days IP (up to a total of 11 immunizations) with the antigen in incomplete Freund's or Ribi adjuvant. The immune response was monitored by retroorbital bleeds. The plasma was screened by ELISA (as described below), and mice with sufficient titers of anti-PD-L1 human immunogolobulin were used for fusions. Mice were boosted intravenously with antigen 3 days before sacrifice and removal of the spleen. Typically, 10-35 fusions for each antigen were performed. Several dozen mice were immunized for each antigen.
    • Selection of KM-Mouse® Producing Anti-PD-L1 Antibodies:
  • To select HuMab mice producing antibodies that bound PD-L1, sera from immunized mice were tested by ELISA as described by Fishwild, D. et al. (1996). Briefly, microtiter plates were coated with purified recombinant PD-L1 fusion protein from transfected CHO cells at 1-2 μg/ml in PBS, 100 μl/wells incubated 4° C. overnight then blocked with 200 μl/well of 5% fetal bovine serum in PBS/Tween (0.05%). Dilutions of sera from PD-L1-immunized mice were added to each well and incubated for 1-2 hours at ambient temperature. The plates were washed with PBS/Tween and then incubated with a goat-anti-human IgG polyclonal antibody conjugated with horseradish peroxidase (HRP) for 1 hour at room temperature. After washing, the plates were developed with ABTS substrate (Sigma, A-1888, 0.22 mg/ml) and analyzed by spectrophotometer at OD 415-495. Mice that developed the highest titers of anti-PD-L1 antibodies were used for fusions. Fusions were performed as described below and hybridoma supernatants were tested for anti-PD-L1 activity by ELISA.
    • Generation of Hybridomas Producing Human Monoclonal Antibodies to PD-L1:
  • The mouse splenocytes, isolated from a KM mouse, were fused with PEG to a mouse myeloma cell line based upon standard protocols. The resulting hybridomas were then screened for the production of antigen-specific antibodies. Single cell suspensions of splenocytes from immunized mice were fused to one-fourth the number of SP2/0 nonsecreting mouse myeloma cells (ATCC, CRL 1581) with 50% PEG (Sigma). Cells were plated at approximately 1×105/well in flat bottom microtiter plate, followed by about two week incubation in selective medium containing 10% fetal bovine serum, 10% P388D1 (ATCC, CRL TIB-63) conditioned medium, 3-5% origen (IGEN) in DMEM (Mediatech, CRL 10013, with high glucose, L-glutamine and sodium pyruvate) plus 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 mg/ml gentamycin and 1×HAT (Sigma, CRL P-7185). After 1-2 weeks, cells were cultured in medium in which the HAT was replaced with HT. Individual wells were then screened by ELISA (described above) for human anti-PD-L1 monoclonal IgG antibodies. Once extensive hybridoma growth occurred, medium was monitored usually after 10-14 days. The antibody-secreting hybridomas were re-plated, screened again and, if still positive for human IgG, anti-PD-L1 monoclonal antibodies were subcloned at least twice by limiting dilution. The stable subclones were then cultured in vitro to generate small amounts of antibody in tissue culture medium for further characterization.
  • Hybridoma clones 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 were selected for further analysis.
    • Example 2: Structural Characterization of Human Monoclonal Antibodies 3G10, 12A4, and 10A5
  • The cDNA sequences encoding the heavy and light chain variable regions of the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 monoclonal antibodies were obtained from the 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 hybridomas, respectively, using standard PCR techniques and were sequenced using standard DNA sequencing techniques.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 3G10 are shown in FIG. 1A and in SEQ ID NO:81 and 1, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 3G10 are shown in FIG. 1B and in SEQ ID NO:91 and 11, respectively.
  • Comparison of the 3G10 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 3G10 heavy chain utilizes a VH segment from human germline VH 1-18, an undetermined D segment, and a JH segment from human germline JH 6b. The alignment of the 3G10 VH sequence to the germline VH 1-18 sequence is shown in FIG. 11. Further analysis of the 3G10 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 1A and 11, and in SEQ ID NOs:21, 31 and 41, respectively.
  • Comparison of the 3G10 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 3G10 light chain utilizes a VL segment from human germline VK L6 and a JK segment from human germline JK 1. The alignment of the 3G10 VL sequence to the germline VK L6 sequence is shown in FIG. 21. Further analysis of the 3G10 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 1B and 21, and in SEQ ID NOs:51, 61 and 71, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 12A4 are shown in FIG. 2A and in SEQ ID NO:82 and 2, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 12A4 are shown in FIG. 2B and in SEQ ID NO:92 and 12, respectively.
  • Comparison of the 12A4 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 12A4 heavy chain utilizes a VH segment from human germline VH 1-69, a D segment from human germline 3-10, and a JH segment from human germline JH 6b. The alignment of the 12A4 VH sequence to the germline VH 1-69 sequence is shown in FIG. 12. Further analysis of the 12A4 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 2A and 12, and in SEQ ID NOs:22, 32 and 42, respectively.
  • Comparison of the 12A4 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 12A4 light chain utilizes a VL segment from human germline VK L6 and a JK segment from human germline JK 1. The alignment of the 12A4 VL sequence to the germline VK L6 sequence is shown in FIG. 22. Further analysis of the 12A4 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 2B and 22, and in SEQ ID NOs:52, 62 and 72, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 10A5 are shown in FIG. 3A and in SEQ ID NO:83 and 3, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 10A5 are shown in FIG. 3B and in SEQ ID NO:93 and 13, respectively.
  • Comparison of the 10A5 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 10A5 heavy chain utilizes a VH segment from human germline VH 1-3, a D segment from human germline 5-5, and a JH segment from human germline JH 4b. The alignment of the 10A5 VH sequence to the germline VH 1-3 sequence is shown in FIG. 13. Further analysis of the 10A5 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 3A and 13, and in SEQ ID NOs:23, 33, and 43, respectively.
  • Comparison of the 10A5 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 10A5 light chain utilizes a VL segment from human germline VK L15 and a JK segment from human germline JK 2. The alignment of the 10A5 VL sequence to the germline VK L15 sequence is shown in FIG. 23. Further analysis of the 10A5 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 3B and 23, and in SEQ ID NOs:53, 63, and 73, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 5F8 are shown in FIG. 4A and in SEQ ID NO:84 and 4, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 5F8 are shown in FIG. 4B and in SEQ ID NO:94 and 14, respectively.
  • Comparison of the 5F8 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 5F8 heavy chain utilizes a VH segment from human germline VH 1-69, a D segment from human germline 6-13, and a JH segment from human germline JH 4b. The alignment of the 5F8 VH sequence to the germline VH 1-69 sequence is shown in FIG. 14. Further analysis of the 5F8 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 4A and 14, and in SEQ ID NOs:24, 34, and 44, respectively.
  • Comparison of the 5F8 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 5F8 light chain utilizes a VL segment from human germline VK A27 and a JK segment from human germline JK 1. The alignment of the 5F8 VL sequence to the germline VK A27 sequence is shown in FIG. 24. Further analysis of the 5F8 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 4B and 24, and in SEQ ID NOs:54, 64, and 74, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 10H10 are shown in FIG. 5A and in SEQ ID NO:85 and 5, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 10H10 are shown in FIG. 5B and in SEQ ID NO:95 and 15, respectively.
  • Comparison of the 10H10 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 10H10 heavy chain utilizes a VH segment from human germline VH 3-9, a D segment from human germline 4-17, and a JH segment from human germline JH 4b. The alignment of the 10H10 VH sequence to the germline VH 3-9 sequence is shown in FIG. 15. Further analysis of the 10H10 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 5A and 15, and in SEQ ID NOs:25, 35, and 45, respectively.
  • Comparison of the 10H10 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 10H10 light chain utilizes a VL segment from human germline VK L15 and a JK segment from human germline JK 2. The alignment of the 10H10 VL sequence to the germline VK L15 sequence is shown in FIG. 25. Further analysis of the 10H10 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 5B and 25, and in SEQ ID NOs:55, 65, and 75, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 1B12 are shown in FIG. 6A and in SEQ ID NO:86 and 6, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 1B12 are shown in FIG. 6B and in SEQ ID NO:96 and 16, respectively.
  • Comparison of the 1B12 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 1B12 heavy chain utilizes a VH segment from human germline VH 1-69, a D segment from human germline 3-10, and a JH segment from human germline JH 6b. The alignment of the 1B12 VH sequence to the germline VII 1-69 sequence is shown in FIG. 16. Further analysis of the 1B12 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 6A and 16, and in SEQ ID NOs:26, 36, and 46, respectively.
  • Comparison of the 1B12 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 1B12 light chain utilizes a VL segment from human germline VK L6 and a JK segment from human germline JK 1. The alignment of the 1B12 VL sequence to the germline VK L6 sequence is shown in FIG. 26. Further analysis of the 1B12 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 6B and 26, and in SEQ ID NOs:56, 66, and 76, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 7H1 are shown in FIG. 7A and in SEQ ID NO:87 and 7, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 7H1 are shown in FIG. 7B and in SEQ ID NO:97 and 17, respectively.
  • Comparison of the 7H1 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 7H1 heavy chain utilizes a VH segment from human germline VII 1-69, a D segment from human germline 3-10, and a JH segment from human germline JH 6b. The alignment of the 7H1 VH sequence to the germline VH 1-69 sequence is shown in FIG. 17. Further analysis of the 7H1 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 7A and 17, and in SEQ ID NOs:27, 37, and 47, respectively.
  • Comparison of the 7H1 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 7H1 light, chain utilizes a VL segment from human germline VK L6 and a JK segment from human germline JK 1. The alignment of the 7H1 VL sequence to the germline VK L6 sequence is shown in FIG. 27. Further analysis of the 7H1 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 7B and 27, and in SEQ ID NOs:57, 67, and 77, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 11E6 are shown in FIG. 4A and in SEQ ID NO:84 and 4, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 11E6 are shown in FIG. 4B and in SEQ ID NO:94 and 14, respectively.
  • Comparison of the 11E6 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 11E6 heavy chain utilizes a VH segment from human germline VH 1-69, a D segment from human germline 6-19, and a JH segment from human germline JH 6c. The alignment of the 11E6 VH sequence to the germline VH 1-69 sequence is shown in FIG. 18. Further analysis of the 11E6 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 8A and 18, and in SEQ ID NOs:28, 38, and 48, respectively.
  • Comparison of the 11E6 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 11E6 light chain utilizes a VL segment from human germline VK A27 and a JK segment from human germline JK 4. The alignment of the 11E6 VL sequence to the germline VK A27 sequence is shown in FIG. 27. Further analysis of the 11E6 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 8B and 28, and in SEQ ID NOs:58, 68, and 78, respectively. In addition, a second related clone included the VK sequence as shown in SEQ ID NO:109. This antibody is denoted herein as 11E6a.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 12B7 are shown in FIG. 9A and in SEQ ID NO:89 and 9, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 12B7 are shown in FIG. 9B and in SEQ ID NO:99 and 19, respectively.
  • Comparison of the 12B7 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 12B7 heavy chain utilizes a VII segment from human germline VH 1-69, a D segment from human germline 3-10, and a JH segment from human germline JH 6b. The alignment of the 12B7 VH sequence to the germline VH 1-69 sequence is shown in FIG. 19. Further analysis of the 12B7 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 9A and 19, and in SEQ ID NOs:29, 39, and 49, respectively.
  • Comparison of the 12B7 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 12B7 light chain utilizes a VL segment from human germline VK L6 and a JK segment from human germline JK 5. The alignment of the 12B7 VL sequence to the germline VK L6 sequence is shown in FIG. 29. Further analysis of the 12B7 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 9B and 29, and in SEQ ID NOs:59, 69, and 79, respectively.
  • The nucleotide and amino acid sequences of the heavy chain variable region of 13G4 are shown in FIG. 10A and in SEQ ID NO:90 and 10, respectively.
  • The nucleotide and amino acid sequences of the light chain variable region of 13G4 are shown in FIG. 10B and in SEQ ID NO:100 and 20, respectively.
  • Comparison of the 13G4 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences demonstrated that the 13G4 heavy chain utilizes a VH segment from human germline VH 3-9, a D segment from human germline 3-9, and a JH segment from human germline JH 4b. The alignment of the 13G4 VH sequence to the germline VH 3-9 sequence is shown in FIG. 20. Further analysis of the 13G4 VH sequence using the Kabat system of CDR region determination led to the delineation of the heavy chain CDR1, CDR2 and CD3 regions as shown in FIGS. 10A and 20, and in SEQ ID NOs:30, 40, and 50, respectively.
  • Comparison of the 13G4 light chain immunoglobulin sequence to the known human germline immunoglobulin light chain sequences demonstrated that the 13G4 light chain utilizes a VL segment from human germline VK L18 and a JK segment from human germline JK 3. The alignment of the 13G4 VL sequence to the germline VK L18 sequence is shown in FIG. 30. Further analysis of the 13G4 VL sequence using the Kabat system of CDR region determination led to the delineation of the light chain CDR1, CDR2 and CD3 regions as shown in FIGS. 10B and 30, and in SEQ ID NOs:60, 70, and 80, respectively.
    • Example 3: Characterization of Binding Specificity and Binding Kinetics of Anti-PD-L1 Human Monoclonal Antibodies
  • In this example, binding affinity and binding kinetics of anti-PD-L1 antibodies were examined by Biacore analysis. Binding specificity, and cross-competition were examined by flow cytometry.
    • Binding Affinity and Kinetics
  • Anti-PD-L1 antibodies were characterized for affinities and binding kinetics by Biacore analysis (Biacore AB, Uppsala, Sweden). Purified recombinant human PD-L1 fusion protein was covalently linked to a CMS chip (carboxy methyl dextran coated chip) via primary amines, using standard amine coupling chemistry and kit provided by Biacore, to a density of 562 RUs. Binding was measured by flowing the antibodies in HBS EP buffer (provided by Biacore AB) at a concentration of 133 nM at a flow rate of 50 μl/min. The antigen-antibody association kinetics was followed for 1 minute and the dissociation kinetics was followed for 1 minute. The association and dissociation curves were fit to a 1:1 Langmuir binding model using BIAevaluation software (Biacore AB). To minimize the effects of avidity in the estimation of the binding constants, only the initial segment of data corresponding to association and dissociation phases were used for fitting. The KD, kon and koff values that were determined are shown in Table 2.
  • TABLE 2
    Biacore binding data for PD-L1 human monoclonal antibodies.
    Affinity KD × On rate kon × Off rate koff ×
    Sample # Sample ID 10−9 (M) 105 (1/Ms) 10−4 1/s
    1 3G10 3.39 5.25 17.8
    3 10A5 1.45 2.58 3.72
  • Additional binding data obtained by equilibrium binding method and analyzed on GraphPad Prizm is shown in Table 3.
  • TABLE 3
    Biacore equilibrium binding data for
    PD-L1 human monoclonal antibodies.
    KD (nM) KD (nM)
    Clone ID 37 C. 25 C.
    12A4 1.94 0.76
    7H1 2.15 nd
    1B12 1.38 0.61
    12B7 0.83 0.53
    10A5 2.41 0.57
    10H10 5.93 5.48
    13G4 1.87 3.3
    11E6 0.53 2.9
    5F8 2.17 0.75
    • Binding Specificity by Flow Cytometry
  • Chinese hamster ovary (CHO) cell lines that express recombinant human PD-L1 at the cell surface were developed and used to determine the specificity of PD-L1 human monoclonal antibodies by flow cytometry. CHO cells were transfected with expression plasmids containing full length cDNA encoding transmembrane forms of PD-L1. Binding of the 3G10, 10A5, and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the transfected cells with the anti-PD-L1 human monoclonal antibody. The cells were washed and binding was detected with a FITC-labeled anti-human IgG Ab. Flow cytometric analyses were performed using a FACScan flow cytometry (Becton Dickinson, San Jose, Calif.). The binding was compared to the parent CHO cell line. The results are shown in FIG. 32A (HuMAb 3G10), 32B (HuMAb 10A5) and 32C (HuMAb 12A4). Binding was also tested using varying concentrations of an anti-PD-L1 antibody. The results are shown in FIG. 33. The anti-PD-L1 human monoclonal antibodies 3G10, 10A5, and 12A4 bound to the CHO cells transfected with PD-L1 in a concentration dependent manner. These data demonstrate that the anti-PD-L1 human monoclonal antibodies specifically bind to cell surface PD-L1.
    • Binding Specificity by ELISA
  • The specificity of the anti-PD-L1 monoclonal antibodies was determined using a standard ELISA assay for binding to a human PD-L1 fusion to an immunoglobulin Fc region.
  • An Fc-fusion protein of human PD-L1 was tested for binding against the anti-PD-L1 human monoclonal antibodies 3G10, 12A4, and 10A5. Standard ELISA procedures were performed. The anti-PD-L1 human monoclonal antibodies were added at different concentrations. Goat-anti-human IgG (kappa chain-specific) polyclonal antibody conjugated with horseradish peroxidase (HRP) was used as secondary antibody. The results are shown in FIG. 34. Each of the anti-PD-L1 human monoclonal antibodies 3G10, 12A4, and 10A5 bound with high specificity to PD-L1.
    • Example 4: Characterization of Anti-PD-L1 Antibody Binding to PD-L1 Expressed on the Cell Surface of Human and Monkey T Cells
  • Anti-PD-L1 antibodies were tested by flow cytometry for binding to activated human or cynomolgus monkey T cells expressing PD-L1 on their surface.
  • Human or monkey T cells were activated by anti-CD3 antibody to induce PD-L1 expression prior to binding with a human anti-PD-L1 monoclonal antibody. Binding of the 3G10, 1B12, 13G4, and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the activated cells with serial dilutions of the anti-PD-L1 human monoclonal antibodies. An isotype control antibody was used as a negative control. The cells were washed and binding was detected with a FITC-labeled anti-human Ig-kappa light chain Ab. Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The results are shown in FIGS. 35 and 36. The anti-PD-L1 monoclonal antibodies 3G10, 1B12, 13G4, and 12A4 bound to activated human and monkey T cells. These data demonstrate that the anti-PD-L1 human monoclonal antibodies bind to human and cynomolgus monkey cell surface PD-L1.
    • Example 5: Characterization of Anti-PD-L1 Antibody Binding to PD-L1 Expressed on the Cell Surface of Human T Cells
  • Anti-PD-L1 antibodies were tested for binding to activated human T cells expressing PD-L1 on their cell surface by flow cytometry.
  • Human T cells were activated by anti-CD3 antibody to induce PD-L1 expression on T cells prior to binding with a human anti-PD-L1 monoclonal antibody. Binding of the 3G10, 10A5 and 12A4 anti-PD-L1 human monoclonal antibodies was assessed by incubating the activated T cells with the anti-PD-L1 human monoclonal antibodies at a concentration of 20 μg/ml. An isotype control antibody was used as a negative control. The cells were washed and binding was detected with a FITC-labeled anti-human IgG Ab. Flow cytometric analyses were performed using a FACScalibur flow cytometry (Becton Dickinson, San Jose, Calif.). The results are shown in FIG. 37A (HuMAb 3G10), 37B (HuMAb 10A5) and 37C (HuMAb 12A4). The anti-PD-L1 monoclonal antibodies 3G10, 10A5, and 12A4 bound to activated human T cells (bold line), as shown in histogram plots compared to control (light line). These data demonstrate that the anti-PD-L1 human monoclonal antibodies bind to human cell surface PD-L1.
    • Example 6: Binding Specificity by Flow Cytometry
  • The ES-2 human ovarian carcinoma cell line that expresses human PD-L1 at the cell surface was used to determine the specificity of PD-L1 human monoclonal antibodies by flow cytometry. ES-2 cells were treated overnight with 500 IU/mL of recombinant hIFN-γ to increase PD-L1 expression over the basal level. Binding of the 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 anti-PD-L1 human monoclonal antibodies was assessed by incubating the induced cells with serial dilutions of the anti-PD-L1 human monoclonal antibody. The cells were washed and binding was detected with a PE-labeled anti-human IgG Ab. Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The binding was compared to isotype control antibody. The results are shown in FIG. 38. The anti-PD-L1 human monoclonal antibodies 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 bound to the hIFN-γ-induced ES-2 cells in a concentration dependent manner. These data demonstrate that the anti-PD-L1 human monoclonal antibodies specifically bind to cell surface PD-L1.
    • Example 7: Effect of Human Anti-PD-L1 Antibodies on Cell Proliferation and Cytokine Production in a Mixed Lymphocyte Reaction
  • A mixed lymphocyte reaction was employed to demonstrate the effect of blocking the PD-L1/PD-1 pathway to lymphocyte effector cells. T cells in the assay were tested for proliferation, IFN-γ secretion and IL-2 secretion in the presence or absence of an anti-PD-L1 human monoclonal antibody.
  • Human CD4+ T-cells were purified from PBMC using a CD4+ positive selection kit (Dynal Biotech). Dendritic cells were derived from purified monocytes cultured with 1000 U/ml of IL-4 and 500 U/ml of GM-CSF (R&D Biosystems) for seven days. Monocytes were prepared using a monocyte negative selection kig (Mitenyi Biotech). Each culture contained 105 purified T-cells and 104 allogeneic dendritic cells in a total volume of 200 μl. Anti-PD-L1 monoclonal antibody 10A5, 12A4, or 3G10 was added to each culture at different antibody concentrations. Either no antibody or an isotype control antibody was used as a negative control. The cells were cultured for 5 days at 37° C. After day 5, 100 μI of medium was taken from each culture for cytokine measurement. The levels of IFN-γ and IL-2 were measured using OptEIA ELISA kits (BD Biosciences). The cells were labeled with 3H-thymidine, cultured for another 18 hours, and analyzed for cell proliferation. The results are shown in FIG. 39A (T cell proliferation), 39B (IFN-γ secretion using HuMAb 10A5), 39C (IFN-γ secretion using HuMAb 12A4 or 3G10) and 39D (IL-2 secretion). The anti-PD-L1 human monoclonal antibody 10A5 promotes T-cell proliferation, IFN-γ secretion and IL-2 secretion in a concentration dependent manner. The anti-PD-L1 human monoclonal antibodies 12A4 and 3G10 also showed an increase in IFN-γ secretion. In contrast, cultures containing the control antibody did not show an increase in T cell proliferation, IFN-γ or IL-2 secretion.
  • In a separate experiment, an allogeneic mixed lymphocyte reaction (MLR) was employed to demonstrate the effect of blocking the PD-L1/PD-1 pathway in lymphocyte effector cells. T cells in the assay were tested for proliferation and IFN-γ secretion in the presence or absence of an anti-PD-L1 human monoclonal antibody or isotype control antibody.
  • Human CD4+ T-cells were purified from PBMC using a CD4+ negative selection kit (Miltenyi). Monocytes were prepared using a monocyte negative selection kit (Mitenyi Biotech). Dendritic cells were derived from purified monocytes cultured with 1000 U/ml of IL-4 and 500 U/ml of GM-CSF (R&D Biosystems) for seven days. Each MLR culture contained 105 purified T-cells and 104 allogeneic dendritic cells in a total volume of 200 μl. Anti-PD-L1 monoclonal antibody 12A4, 11E6, 3G10, 13G4, 1B12, 10A5, and 12B7 were added to each culture at different antibody concentrations. Either no antibody or an isotype control antibody was used as a negative control. The cells were cultured for 5 days at 37° C. On day 5, 50 μI of medium was taken from each culture for cytokine measurement and replaced with an equal volume of culture medium containing 1 μCi of 3H-thymidine. The cells were cultured for another 18 hours, harvested, and analyzed for cell proliferation. The levels of IFN-γ in the culture fluid were measured using an OptEIA hIFN-γ ELISA kit (BD Biosciences). The results are shown in FIG. 40. The anti-PD-L1 human monoclonal antibodies promote T-cell proliferation and IFN-γ secretion in a concentration-dependent manner. In contrast, cultures containing the control antibody did not show an increase in T cell proliferation or IFN-γ secretion.
    • Example 8: Effect of Human Anti-PD-L1 Antibody on Function of T Regulatory Cells
  • T regulatory cells (CD4+, CD25+) are lymphocytes that suppress the immune response. The effect of the addition of T regulatory cells on proliferation and IFN-γ secretion in the allogeneic dendritic cell and T cell MLR in the presence or absence of an anti-PD-L1 human monoclonal antibody was tested.
  • T regulatory cells were purified from PBMC using a CD4+CD25+ regulatory T cell isolation kit (Miltenyi Biotec). T regulatory cells were added into a mixed lymphocyte reaction (see above) containing purified CD4+CD25− T cells and allogeneic dendritic cells in a 2:1 ratio of CD4+CD25− to T regulatory cells. Anti-PD-L1 monoclonal antibody 10A5 was added to each culture at a concentration of 10 μg/ml. Either no antibody or an isotype control antibody was used as a negative control. The cells were cultured for 5 days at 37° C. at which time the supernatants were analyzed for IFN-γ secretion using a Beadlyte cytokine detection system (Upstate). The cells were labeled with 3H-thymidine, cultured for another 18 hours, and analyzed for cell proliferation. The results are shown in FIG. 41A (T cell proliferation) and 41B (IFN-γ secretion). The addition of anti-PD-L1 human monoclonal antibody 10A5 promotes both T cell proliferation and IFN-γ secretion in cell cultures of allogeneic dendritic cells, T cells and T regulatory cells, indicating that anti-PD-L1 antibodies can reverse the effect of T regulatory cells in the allogeneic DC-T cell-MLR
  • In a separate experiment, human anti-PD-L1 antibodies 12A4 and 13G4, and a control antibody 1D12, were tested in the MLR assay with T regulatory cells. The results are shown in FIG. 42 (T cell proliferation) and 43 (IFN-γ secretion). The addition of anti-PD-L1 human monoclonal antibodies 12A4 or 13G4 partially reverses the suppression of both T cell proliferation and IFN-γ secretion in cell cultures of allogeneic dendritic cells and T cells containing T-regulatory cells, indicating that anti-PD-L1 antibodies may have an effect on T-regulatory cells.
    • Example 9: Effect of Anti-PD-1 Antibodies on Cytokine Secretion by Viral Antigen-Stimulated PBMC Cells from a PositiveCMV Responsive Donor
  • CMV antigen-responsive human PBMC (Astarte Biologics, Redmond, Wash.) were cultured at 2e5 cells/well in flat bottom TC-treated 96 well plates, in the presence of 0.5 ug/ml CMV lysate (Astarte Biologics)+/−titrated anti-PD-L1 antibodies. AIM-V medium (Invitrogen) supplemented with heat-inactivated FBS (10% final) was used at a total volume of 200 ul/well. The cells were cultured for 4 days at 37° C., 5% CO2 at which time culture supernatant was harvested for determination of secreted interferon-γ by ELISA (OptEIA hIFN-γ ELISA kit-BD Biosciences). The results are shown in FIG. 44. The anti-PD-L1 human monoclonal antibodies promote IFN-γ secretion by CMV-specific T-cells in a dose-dependent manner. The most robust response was generated by antibodies 13G4, 1B12, and 12A4 compared to isotype control. These results shows that anti-PD-L1 HuMAbs can stimulate IFN-γ release in a memory T cell response from PBMC cells previously stimulated against an antigen.
    • Example 10: Blocking of PD-L1 Ligand Binding to PD-1 by Human Anti-PD-L1 Antibodies
  • Anti-PD-L1 human monoclonal antibodies were tested for the ability to block binding of the ligand PD-L1 to PD-1 expressed on transfected CHO cells by using a cell cytometry assay.
  • PD-1 expressing CHO cells were suspended in FACS buffer (PBS with 4% fetal calf serum). Various concentrations of the anti-PD-L1 HuMAbs 3G10, 10A5 or 12A4 was added to the cell suspension tubes at 4° C. for 30 minutes, followed by addition FITC-labeled PD-L1 fused to an immunoglobulin Fc-region. Flow cytometric analyses were performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The results are depicted in FIG. 45. The anti-PD-L1 monoclonal antibodies 3G10, 10A5, and 12A4 blocked binding of PD-L1 to CHO cells transfected with human PD-1, as measured by the mean fluorescent intensity (MFI) of staining. These data demonstrate that the anti-PD-L1 HuMAbs block binding of PD-L1 ligand to cell surface PD-1.
    • Example 11: Inhibition of the Binding of Soluble PD-1 to Cell-Surface PD-L1 by Human Anti-PD-L1 Antibodies
  • Anti-PD-L1 human monoclonal antibodies were tested for the ability to block binding of a soluble dimeric version of the PD-1 receptor (PD-1-hFc) to PD-L1 expressed on hIFN-γ-induced ES-2 human ovarian carcinoma cells using a flow cytometry assay. The blocking was compared to isotype control antibody.
  • ES-2 cells were induced overnight with 500 IU/mL of hIFN-γ to upregulate hPD-L1 cell surface expression. Induced cells were suspended in FACS buffer. Serial dilutions of the anti-PD-L1 HuMAbs 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 were added to the cell suspension tubes at 4° C. for 30 minutes, followed by two washes to remove unbound antibody. Next PD-1-hFc protein was added at a constant 2 ug/mL to all wells at 4° C. for 30 minutes, followed by two washes to remove unbound PD-1-hFc. Next bound PD-1-Fc was detected on the ES-2 cells by addition of biotinylated-non-blocking anti-PD-1 HuMab 26D5, which binds to PD-1 when bound to PD-L1, at 4° C. for 30 minutes, followed by two washes to remove unbound antibody. Finally, bound 26D5 antibody was detected by addition of streptavidin-PE conjugate at 4° C. for 30 minutes, followed by two washes to remove unbound conjugate. Flow cytometric analysis was performed using a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The results are depicted in FIG. 46. The anti-PD-L1 monoclonal antibodies 12A4, 1B12, 3G10, 10A5, 12B7, 13G4, 11E6, and 5F8 blocked binding of PD-1 to ES-2 cells that express human PD-L1, as measured by the geometric mean fluorescent intensity (GMFI) of staining. These data demonstrate that the anti-PD-L1 HuMAbs block binding of soluble PD-1 receptor to cell surface PD-L1.
    • Example 12: Treatment of In Vivo Tumor Model Using Anti-PD-L1 Antibodies
  • Mice implanted with a cancerous tumor are treated in vivo with anti-PD-L1 antibodies to examine the in vivo effect of the antibodies on tumor growth. For the tumor studies, female AJ mice between 6-8 weeks of age (Harlan Laboratories) are randomized by weight into 6 groups. The mice are implanted subcutaneously in the right flank with 2×106 SA1/N fibrosarcoma cells dissolved in 200 μl of DMEM media on day 0. The mice are treated with PBS vehicle, or anti-PD-L1 antibodies at 10 mg/kg. The animals are dosed by intraperitoneal injection with approximately 200 μl of PBS containing antibody or vehicle on days 1, 4, 8 and 11. Each group contains 10 animals and the groups consist of: (i) a vehicle group, (ii) control mouse IgG, and (iii) an anti-PD-L1 antibody. The mice are monitored twice weekly for tumor growth for approximately 6 weeks. Using an electronic caliper, the tumors are measured three dimensionally (height×width×length) and tumor volume is calculated. Mice are euthanized when the tumors reached tumor end point (1500 mm3) or show greater than 15% weight loss.
    • Example 13: In Vivo Efficacy of Combination Therapy (Anti-CTLA-4 and Anti-PD-L1 Antibodies) on Tumor Establishment and Growth
  • MC38 colorectal cancer cells (available from Dr. N. Restifo, National Cancer Institute, Bethesda, Md.; or Jeffrey Schlom, National Institutes of Health, Bethesda, Md.) were implanted in C57BL/6 mice (2×106 cells/mouse) and selected for treatment when tumors reached a size of 100-200 mm3). On day 0 (i.e., the first day of treatment), each of four groups of 10 mice each was injected intraperitoneally (IP) with one of the following: (1) 10 mg/kg mouse IgG and 10 mg/kg of rat IgG (control), (2) 10 mg/kg anti-CTLA-4 monoclonal antibody 9D9 (mouse anti-mouse CTLA-4, obtained from J. Allison, Memorial Sloan-Kettering Cancer Center, New York, N.Y.) and 10 mg/kg rat IgG, (3) anti-PD-L1 monoclonal antibody MIHS (rat anti-mouse PD-L1, eBioscience) and 10 mg/kg mouse IgG, or (4) 10 mg/kg anti-CTLA-4 antibody 9D9 and 10 mg/kg anti-PD-L1 antibody MIHS. Antibody injections were then further administered on days 3 and, 6. Using an electronic caliper, the tumors were measured three dimensionally (height×width×length) and tumor volume was calculated. Mice were euthanized when the tumors reached a designated tumor end-point. The results are shown in FIG. 47.
  • This study indicates that, in the MC38 murine tumor model, anti-PD-L1 antibody treatment alone has a modest effect on tumor growth resulting in a delay of tumor growth while anti-CTLA-4 has little effect in this model. However, the combination treatment of CTLA-4 antibody and PD-L1 antibody has a significantly greater effect on tumor growth and results in tumor free mice.
    • Example 14: Immunohistochemistry Using Anti-PD-L1 Antibodies
  • To assess the tissue binding profiles of HuMab anti-PD-L1, unmodified 12A4, 13G4, 3G10 and 12B7 were examined in a panel of normal (non-neoplastic) human tissues, including spleen, tonsil, cerebrum, cerebellum, heart, liver, lung, kidney, pancreas, pituitary, skin, and small intestine, as well as lung carcinoma tissues (1 sample/each). ES-2 cells were used as positive control. Hu-IgG1 and Hu-IgG4 were used as isotype control antibodies.
  • Snap frozen and OCT embedded normal and tumor tissues were purchased from Cooperative Human Tissue Network (Philadelphia, Pa.) or National Disease Research Institute (Philadelphia, Pa.). Cryostat sections at 5 μm were fixed with acetone for 10 min at room temperature, and stored at −80° C. until use. A Medarex developed immunohistochemistry protocol was performed using unmodified HuMab anti-PD-L1 by pre-complex of the primary antibodies (12A4, 13G4, 3G10 and 12B7) and secondary antibody (FITC conjugated Fab fragment of goat anti-Hu-IgG. Jackson ImmunoResearch Laboratories. West Grove, Pa.) before applying onto the sections. Briefly, 1 μg/ml or 5 μg/ml of the un-conjugated primary antibodies were mixed with 3 fold excess of secondary antibody respectively and incubated for 30 min at room temperature, and then excess human gamma globulin was added for another 30 min to block the unbound secondary antibody. In parallel, isotype control antibodies Hu-IgG1 or Hu-IgG4 were pre-complexed in the same manner. Slides were washed with PBS (Sigma, St. Louis, Mo.) twice, and then incubated with peroxidase block supplied in Dako EnVision+System (Dako. Carpinteria, Calif.) for 10 minutes. After two washes with PBS, slides were incubated with Dako protein block to block the non-specific binding sites. Subsequently, the pre-complex of primary antibodies or isotype controls were applied onto sections and incubated for 1 hr. Following three washes with PBS, slides were incubated with mouse anti-FITC antibody (20 μg/ml. Sigma) for 30 min. After another three washes with PBS, the slides were incubated with the peroxidase-conjugated anti-mouse IgG polymer supplied in the Dako EnVision+System for 30 min. Finally, slides were washed as above and reacted with DAB substrate-chromogen solution supplied in the Dako EnVision+System for 6 min. Slides were then washed with deionized water, counterstained with Mayer's hematoxylin (Dako), dehydrated, cleared and coverslipped with Permount (Fischer Scientific, Fair Lawn, N.J.) following routine histological procedure.
  • Weak to moderate staining was observed in ES-2 cells, as well as in tumor cells of lung carcinoma tissues. In tonsil sections, strong staining was seen in crypt epithelium that is heavily infiltrated by lymphoid cells, but not in the mucous stratified squamous epithelial cells. Moderate staining was seen in some cells in the inter-follicular region, and very weak staining was seen in scattered large cells (dendritic reticulum-like cells) in the germinal center. In lung, weak staining was found in alveoli macrophages. The staining patterns in tonsil and lung tissues were similarly seen in immunohistochemistry sections using commercial anti-PD-L1 mAb (eBiosciences. San Diego, Calif.). There was overall less intense staining by HuMabs, especially for the staining in the germinal centers. In spleen, diffuse weak immunoreactivity in red pulp was slightly above the background staining. In addition, weak to moderate staining was displayed in Kupffer-like cells in liver and scattered cells in Peyer's patch, as well as in scattered macrophage-like cells and fibroblasts mainly in focal region of the muscularis externa of small intestine.
  • In cerebellum, cerebrum, heart, kidney, pancreas, pituitary and skin tissues, no meaningful staining was observed when stained with all four anti-PD-L1 HuMabs. No evident difference in staining was noted among these four antibodies except 12B7 and/or 3G10 displayed slightly stronger staining in liver and ES-2 cells.
    • PD-L1 Antibody Summary
  • SEQ ID NO: SEQUENCE
    1 VH a.a. 3G10
    2 VH a.a. 12A4
    3 VH a.a. 10A5
    4 VH a.a. 5F8
    5 VH a.a. 10H10
    6 VH a.a. 1B12
    7 VH a.a. 7H1
    8 VH a.a. 11E6
    9 VH a.a. 12B7
    10 VH a.a. 13G4
    11 VK a.a. 3G10
    12 VK a.a. 12A4
    13 VK a.a. 10A5
    14 VK a.a. 5F8
    15 VK a.a. 10H10
    16 VK a.a. 1B12
    17 VK a.a. 7H1
    18 VK a.a. 11E6
    19 VK a.a. 12B7
    20 VK a.a. 13G4
    21 VH CDR1 a.a. 3G10
    22 VH CDR1 a.a. 12A4
    23 VH CDR1 a.a. 10A5
    24 VH CDR1 a.a. 5F8
    25 VH CDR1 a.a. 10H10
    26 VH CDR1 a.a. 1B12
    27 VH CDR1 a.a. 7H1
    28 VH CDR1 a.a. 11E6
    29 VH CDR1 a.a. 12B7
    30 VH CDR1 a.a. 13G4
    31 VH CDR2 a.a. 3G10
    32 VH CDR2 a.a. 12A4
    33 VH CDR2 a.a. 10A5
    34 VH CDR2 a.a. 5F8
    35 VH CDR2 a.a. 10H10
    36 VH CDR2 a.a. 1B12
    37 VH CDR2 a.a. 7H1
    38 VH CDR2 a.a. 11E6
    39 VH CDR2 a.a. 12B7
    40 VH CDR2 a.a. 13G4
    41 VH CDR3 a.a. 3G10
    42 VH CDR3 a.a. 12A4
    43 VH CDR3 a.a. 10A5
    44 VH CDR3 a.a. 5F8
    45 VH CDR3 a.a. 10H10
    46 VH CDR3 a.a. 1B12
    47 VH CDR3 a.a. 7H1
    48 VH CDR3 a.a. 11E6
    49 VH CDR3 a.a. 12B7
    50 VH CDR3 a.a. 13G4
    51 VK CDR1 a.a. 3G10
    52 VK CDR1 a.a. 12A4
    53 VK CDR1 a.a. 10A5
    54 VK CDR1 a.a. 5F8
    55 VK CDR1 a.a. 10H10
    56 VK CDR1 a.a. 1B12
    57 VK CDR1 a.a. 7H1
    58 VK CDR1 a.a. 11E6
    59 VK CDR1 a.a. 12B7
    60 VK CDR1 a.a. 13G4
    61 VK CDR2 a.a. 3G10
    62 VK CDR2 a.a. 12A4
    63 VK CDR2 a.a. 10A5
    64 VK CDR2 a.a. 5F8
    65 VK CDR2 a.a. 10H10
    66 VK CDR2 a.a. 1B12
    67 VK CDR2 a.a. 7H1
    68 VK CDR2 a.a. 11E6
    69 VK CDR2 a.a. 12B7
    70 VK CDR2 a.a. 13G4
    71 VK CDR3 a.a. 3G10
    72 VK CDR3 a.a. 12A4
    73 VK CDR3 a.a. 10A5
    74 VK CDR3 a.a. 5F8
    75 VK CDR3 a.a. 10H10
    76 VK CDR3 a.a. 1B12
    77 VK CDR3 a.a. 7H1
    78 VK CDR3 a.a. 11E6
    79 VK CDR3 a.a. 12B7
    80 VK CDR3 a.a. 13G4
    81 VH n.t. 3G10
    82 VH n.t. 12A4
    83 VH n.t. 10A5
    84 VH n.t. 5F8
    85 VH n.t. 10H10
    86 VH n.t. 1B12
    87 VH n.t. 7H1
    88 VH n.t. 11E6
    89 VH n.t. 12B7
    90 VH n.t. 13G4
    91 VK n.t. 3G10
    92 VK n.t. 12A4
    93 VK n.t. 10A5
    94 VK n.t. 5F8
    95 VK n.t. 10H10
    96 VK n.t. 1B12
    97 VK n.t. 7H1
    98 VK n.t. 11E6
    99 VK n.t. 12B7
    100 VK n.t. 13G4
    101 VH 1-18 germline a.a.
    102 VH 1-69 germline a.a.
    103 VH 1-3 germline a.a.
    104 VH 3-9 germline a.a.
    105 VK L6 germline a.a.
    106 VK L15 germline a.a.
    107 VK A27 germline a.a.
    108 VK L18 germline a.a.
    109 VK a.a. 11E6a

Claims (58)

1-67. (canceled)
68. A method for treating a cancer in a human subject comprising administering to the subject a monoclonal anti-PD-L1 antibody, or an antigen-binding portion thereof, which cross-competes for binding to human PD-L1 with a reference antibody, wherein the reference antibody comprises:
(a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:1 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:11;
(b) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:2 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:12;
(c) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:3 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:13;
(d) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:4 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:14;
(e) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:5 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:15;
(f) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:6 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:16;
(g) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:7 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:17;
(h) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:8 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:18;
(i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:9 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:19; or
(j) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:10 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:20; and
wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL),
wherein the VH comprises: (a) a framework region exhibiting at least 90% sequence identity to a framework region of the heavy chain variable region of the reference antibody; (b) a framework region derived from a human VH 1-18 germline sequence; (c) a framework region derived from a human VH 1-69 germline sequence; (d) a framework region derived from a human VH 1-3 germline sequence; or (e) a framework region derived from a human VH 3-9 germline sequence, and/or
wherein the VL comprises: (a) a framework region exhibiting at least 90% sequence identity to a framework region of the light chain variable region of the reference antibody; (b) a framework region derived from a human VK L6 germline sequence; (c) a framework region derived from a human VK L15 germline sequence; (d) a framework region derived from a human VK A27 germline sequence; or (e) a framework region derived from a human VK L18 germline sequence.
69. The method of claim 68, wherein the framework region of the VH of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 95% sequence identity to the framework region of the heavy chain variable region of the reference antibody and/or the framework region of the VL of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 95% sequence identity to the framework region of the light chain variable region of the reference antibody.
70. The method of claim 68, wherein the VL of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 90% sequence identity to:
(a) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:11;
(b) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:12;
(c) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:13;
(d) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:14;
(e) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:15;
(f) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:16;
(g) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:17;
(h) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:18;
(i) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:19; or
(j) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:20.
71. The method of claim 68, wherein the VL of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises a FR1 selected from:
(a) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 with one amino acid substitution;
(b) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 with one amino acid substitution;
(c) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 with one amino acid substitution;
(d) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 with one amino acid substitution;
(e) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 with one amino acid substitution;
(f) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 with one amino acid substitution;
(g) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 with one amino acid substitution;
(h) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 with one amino acid substitution;
(i) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 with one amino acid substitution; and
(j) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 with one amino acid substitution.
72. The method of claim 68, wherein the VL of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises a FR2 selected from:
(a) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 with one amino acid substitution;
(b) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 with one amino acid substitution;
(c) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 with one amino acid substitution;
(d) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 with one amino acid substitution;
(e) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 with one amino acid substitution;
(f) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 with one amino acid substitution;
(g) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 with one amino acid substitution;
(h) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 with one amino acid substitution;
(i) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 with one amino acid substitution; and
(j) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 with one amino acid substitution.
73. The method of claim 68, wherein the VL of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises a FR3 selected from:
(a) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 with one amino acid substitution;
(b) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 with one amino acid substitution;
(c) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 with one amino acid substitution;
(d) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 with one amino acid substitution;
(e) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 with one amino acid substitution;
(f) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 with one amino acid substitution;
(g) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 with one amino acid substitution;
(h) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 with one amino acid substitution;
(i) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 with one amino acid substitution; and
(j) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 with one amino acid substitution.
74. The method of claim 68, wherein the VL of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises a FR4 selected from:
(a) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 with one amino acid substitution;
(b) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 with one amino acid substitution;
(c) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 with one amino acid substitution;
(d) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 with one amino acid substitution;
(e) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 with one amino acid substitution;
(f) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 with one amino acid substitution;
(g) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 with one amino acid substitution;
(h) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 with one amino acid substitution;
(i) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 with one amino acid substitution; and
(j) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 with one amino acid substitution.
75. The method of claim 68, wherein the VH of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises a FR1 selected from:
(a) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 with one amino acid substitution;
(b) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 with one amino acid substitution;
(c) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 with one amino acid substitution;
(d) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 with one amino acid substitution;
(e) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 with one amino acid substitution;
(f) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 with one amino acid substitution;
(g) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 with one amino acid substitution;
(h) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 with one amino acid substitution;
(i) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 with one amino acid substitution; and
(j) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 with one amino acid substitution.
76. The method of claim 68, wherein the VH of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises a FR2 selected from:
(a) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 with one amino acid substitution;
(b) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 with one amino acid substitution;
(c) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 with one amino acid substitution;
(d) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 with one amino acid substitution;
(e) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 with one amino acid substitution;
(f) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 with one amino acid substitution;
(g) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 with one amino acid substitution;
(h) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 with one amino acid substitution;
(i) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 with one amino acid substitution; and
(j) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 with one amino acid substitution.
77. The method of claim 68, wherein the VH of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises a FR3 selected from:
(a) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 with one amino acid substitution;
(b) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 with one amino acid substitution;
(c) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 with one amino acid substitution;
(d) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 with one amino acid substitution;
(e) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 with one amino acid substitution;
(f) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 with one amino acid substitution;
(g) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 with one amino acid substitution;
(h) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 with one amino acid substitution;
(i) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 with one amino acid substitution; and
(j) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 with one amino acid substitution.
78. The method of claim 68, wherein the VH of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises a FR4 selected from:
(a) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 with one amino acid substitution;
(b) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 with one amino acid substitution;
(c) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 with one amino acid substitution;
(d) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 with one amino acid substitution;
(e) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 with one amino acid substitution;
(f) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 with one amino acid substitution;
(g) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 with one amino acid substitution;
(h) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 with one amino acid substitution;
(i) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 with one amino acid substitution; and
(j) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 with one amino acid substitution.
79. The method of claim 68, wherein the framework region of the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 90% sequence identity to the corresponding framework region of a heavy chain variable germline sequence selected from (a) a human VH 1-18 germline sequence; (b) a human VH 1-69 germline sequence; (c) a human VH 1-3 germline sequence; and (d) a human VH 3-9 germline sequence.
80. The method of claim 68, wherein the framework region of the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 95% sequence identity to the corresponding framework region of a heavy chain variable germline sequence selected from (a) a human VH 1-18 germline sequence; (b) a human VH 1-69 germline sequence; (c) a human VH 1-3 germline sequence; and (d) a human VH 3-9 germline sequence.
81. The method of claim 68, wherein the framework region of the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises no more than 10 amino acid differences from the corresponding framework region of a heavy chain variable germline sequence selected from (a) a human VH 1-18 germline sequence; (b) a human VH 1-69 germline sequence; (c) a human VH 1-3 germline sequence; and (d) a human VH 3-9 germline sequence.
82. The method of claim 68, wherein the framework region of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 90% sequence identity to the corresponding framework region of a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence.
83. The method of claim 68, wherein the framework region of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 95% sequence identity to the corresponding framework region of a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence.
84. The method of claim 68, wherein the framework region of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises no more than 10 amino acid differences from the corresponding framework region of a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence.
85. The method of claim 68, wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises amino acids having a sequence at least 90% identical to a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence.
86. The method of claim 68, wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises amino acids having a sequence at least 95% identical to a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence.
87. The method of claim 68, wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises amino acids having a sequence that differs by no more than 10 amino acids from a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence.
88. The method of claim 68, wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises:
(a) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:105;
(b) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:106;
(c) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:107; or
(d) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:108.
89. The method of claim 68, wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises:
(a) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:105;
(b) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:106;
(c) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:107; or
(d) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:108.
90. The method of claim 68, wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises:
(a) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:101;
(b) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:102;
(c) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:103; or
(d) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:104.
91. The method of claim 68, wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises:
(a) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:101;
(b) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:102;
(c) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:103; or
(d) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:104.
92. The method of claim 68, wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR1 selected from:
(a) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 with one amino acid substitution;
(b) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 106 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 106 with one amino acid substitution;
(c) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 107 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 107 with one amino acid substitution; and
(d) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 with one amino acid substitution.
93. The method of claim 68, wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR2 selected from:
(a) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 with one amino acid substitution;
(b) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 106 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 106 with one amino acid substitution;
(c) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 107 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 107 with one amino acid substitution; and
(d) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 with one amino acid substitution.
94. The method of claim 68, wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR3 selected from:
(a) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 with one amino acid substitution;
(b) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 106 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 106 with one amino acid substitution;
(c) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 107 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 107 with one amino acid substitution; and
(d) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 with one amino acid substitution.
95. The method of claim 68, wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR1 selected from:
(a) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 with one amino acid substitution;
(b) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 102 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 102 with one amino acid substitution;
(c) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 103 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 103 with one amino acid substitution; and
(d) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 with one amino acid substitution.
96. The method of claim 68, wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR2 selected from:
(a) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 with one amino acid substitution;
(b) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 102 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 102 with one amino acid substitution;
(c) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 103 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 103 with one amino acid substitution; and
(d) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 with one amino acid substitution.
97. The method of claim 68, wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR3 selected from:
(a) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 with one amino acid substitution;
(b) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 102 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 102 with one amino acid substitution;
(c) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 103 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 103 with one amino acid substitution; and
(d) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 with one amino acid substitution.
98. The method of claim 68, wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 5×10−9 M or less.
99. The method of claim 68, wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 2×10−9M or less.
100. The method of claim 68, wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 1×10−9M or less.
101. The method of claim 68, wherein the reference antibody binds to human PD-L1 with a KD of about 5×10−9M.
102. The method of claim 68, wherein the reference antibody binds to human PD-L1 with a KD of 2×10−9M or less.
103. The method of claim 68, wherein the reference antibody binds to human PD-L1 with a KD of 1×10−9M or less.
104. The method of claim 68, wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits the following properties:
(a) binds with high affinity to human PD-L1 with a KD of about 2×10−9M or lower as determined by surface plasmon resonance analysis;
(b) augments T cell proliferation, IFN-γ and IL-2 secretion in mixed lymphocyte reactions;
(c) inhibits binding of PD-L1 to the PD-1 receptor;
(d) stimulates antibody responses; and
(e) reverses the suppressive effect of T regulatory cells on T cell effector cells and/or dendritic cells.
105. The method of claim 68, wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is a human or a humanized antibody or a portion thereof.
106. The method of claim 68, wherein the cancer is selected from melanoma, lung cancer, renal cancer, colon cancer, colorectal cancer, prostate cancer, breast cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphocytic lymphoma, T-cell lymphoma, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, environmentally induced cancers including those induced by asbestos, a metastatic cancer, and combinations of said cancers.
107. The method of claim 68, wherein the cancer is selected from melanoma, lung cancer, renal cancer, colon cancer, colorectal cancer, head or neck cancer, prostate cancer, breast cancer, or bladder cancer.
108. The method of claim 68, further comprising administering to the subject a monoclonal anti-CTLA-4 antibody.
109. A method for treating a cancer in a human subject comprising administering to the subject a monoclonal anti-PD-L1 antibody, or an antigen-binding portion thereof, which cross-competes for binding to human PD-L1 with a reference antibody, wherein the reference antibody comprises:
(a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:1 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:11;
(b) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:2 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:12;
(c) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:3 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:13;
(d) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:4 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:14;
(e) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:5 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:15;
(f) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:6 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:16;
(g) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:7 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:17;
(h) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:8 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:18;
(i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:9 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:19; or
(j) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:10 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:20; and
wherein the monoclonal antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 and a light chain variable region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4, wherein the FR1 of the light chain variable region is selected from:
(a) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 11 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 11 with one amino acid substitution;
(b) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 with one amino acid substitution;
(c) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 with one amino acid substitution;
(d) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 14 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 14 with one amino acid substitution;
(e) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 15 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 15 with one amino acid substitution;
(f) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 16 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 16 with one amino acid substitution;
(g) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 17 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 17 with one amino acid substitution;
(h) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 18 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 18 with one amino acid substitution;
(i) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 19 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 19 with one amino acid substitution; and
(j) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 20 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 20 with one amino acid substitution.
110. The method of claim 109, wherein the FR2 of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is selected from:
(a) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 11 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 11 with one amino acid substitution;
(b) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 with one amino acid substitution;
(c) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 with one amino acid substitution;
(d) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 14 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 14 with one amino acid substitution;
(e) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 15 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 15 with one amino acid substitution;
(f) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 16 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 16 with one amino acid substitution;
(g) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 17 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 17 with one amino acid substitution;
(h) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 18 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 18 with one amino acid substitution;
(i) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 19 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 19 with one amino acid substitution; and
(j) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 20 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 20 with one amino acid substitution.
111. The method of claim 109, wherein the FR3 of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is selected from:
(a) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 11 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 11 with one amino acid substitution;
(b) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 with one amino acid substitution;
(c) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 with one amino acid substitution;
(d) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 14 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 14 with one amino acid substitution;
(e) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 15 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 15 with one amino acid substitution;
(f) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 16 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 16 with one amino acid substitution;
(g) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 17 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 17 with one amino acid substitution;
(h) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 18 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 18 with one amino acid substitution;
(i) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 19 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 19 with one amino acid substitution; and
(j) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 20 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 20 with one amino acid substitution.
112. The method of claim 109, wherein the FR4 of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is selected from:
(a) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 11 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 11 with one amino acid substitution;
(b) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 with one amino acid substitution;
(c) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 with one amino acid substitution;
(d) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 14 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 14 with one amino acid substitution;
(e) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 15 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 15 with one amino acid substitution;
(f) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 16 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 16 with one amino acid substitution;
(g) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 17 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 17 with one amino acid substitution;
(h) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 18 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 18 with one amino acid substitution;
(i) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 19 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 19 with one amino acid substitution; and
(j) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 20 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 20 with one amino acid substitution.
113. The method of claim 109, wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR1 selected from:
(a) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 1 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 1 with one amino acid substitution;
(b) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 2 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 2 with one amino acid substitution;
(c) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 3 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 3 with one amino acid substitution;
(d) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 4 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 4 with one amino acid substitution;
(e) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 5 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 5 with one amino acid substitution;
(f) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 6 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 6 with one amino acid substitution;
(g) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 with one amino acid substitution;
(h) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 8 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 8 with one amino acid substitution;
(i) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 9 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 9 with one amino acid substitution; and
(j) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 10 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 10 with one amino acid substitution.
114. The method of claim 109, wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR2 selected from:
(a) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 1 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 1 with one amino acid substitution;
(b) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 2 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 2 with one amino acid substitution;
(c) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 3 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 3 with one amino acid substitution;
(d) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 4 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 4 with one amino acid substitution;
(e) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 5 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 5 with one amino acid substitution;
(f) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 6 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 6 with one amino acid substitution;
(g) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 with one amino acid substitution;
(h) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 8 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 8 with one amino acid substitution;
(i) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 9 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 9 with one amino acid substitution; and
(j) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 10 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 10 with one amino acid substitution.
115. The method of claim 109, wherein the FR3 of the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is selected from:
(a) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 1 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 1 with one amino acid substitution;
(b) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 2 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 2 with one amino acid substitution;
(c) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 3 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 3 with one amino acid substitution;
(d) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 4 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 4 with one amino acid substitution;
(e) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 5 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 5 with one amino acid substitution;
(f) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 6 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 6 with one amino acid substitution;
(g) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 with one amino acid substitution;
(h) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 8 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 8 with one amino acid substitution;
(i) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 9 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 9 with one amino acid substitution; and
(j) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 10 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 10 with one amino acid substitution.
116. The method of claim 109, wherein the FR4 of the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is selected from:
(a) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 1 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 1 with one amino acid substitution;
(b) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 2 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 2 with one amino acid substitution;
(c) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 3 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 3 with one amino acid substitution;
(d) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 4 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 4 with one amino acid substitution;
(e) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 5 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 5 with one amino acid substitution;
(f) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 6 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 6 with one amino acid substitution;
(g) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 with one amino acid substitution;
(h) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 8 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 8 with one amino acid substitution;
(i) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 9 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 9 with one amino acid substitution; and
(j) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 10 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 10 with one amino acid substitution.
117. The method of claim 109, wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 5×10−9 M or less.
118. The method of claim 109, wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 2×10−9 M or less.
119. The method of claim 109, wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 1×10−9 M or less.
120. The method of claim 109, wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits the following properties:
(a) binds with high affinity to human PD-L1 with a KD of about 2×10−9 M or lower as determined by surface plasmon resonance analysis;
(b) augments T cell proliferation, IFN-γ and IL-2 secretion in mixed lymphocyte reactions;
(c) inhibits binding of PD-L1 to the PD-1 receptor;
(d) stimulates antibody responses; and
(e) reverses the suppressive effect of T regulatory cells on T cell effector cells and/or dendritic cells.
121. The method of claim 109, wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is a human or a humanized antibody or a portion thereof.
122. The method of claim 109, wherein the cancer is selected from melanoma, lung cancer, renal cancer, colon cancer, colorectal cancer, prostate cancer, breast cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphocytic lymphoma, T-cell lymphoma, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, environmentally induced cancers including those induced by asbestos, a metastatic cancer, and combinations of said cancers.
123. The method of claim 109, wherein the cancer is selected from melanoma, lung cancer, renal cancer, colon cancer, colorectal cancer, head or neck cancer, prostate cancer, breast cancer, or bladder cancer.
124. The method of claim 109, further comprising administering to the subject a monoclonal anti-CTLA-4 antibody.
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US13/091,936 US8383796B2 (en) 2005-07-01 2011-04-21 Nucleic acids encoding monoclonal antibodies to programmed death ligand 1 (PD-L1)
US13/746,773 US9102725B2 (en) 2005-07-01 2013-01-22 Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
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US15/188,860 US9580507B2 (en) 2005-07-01 2016-06-21 Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017220602A1 (en) 2016-06-21 2017-12-28 Herlev Hospital Pdl1 peptides for use in cancer vaccines
US10081681B2 (en) 2013-09-20 2018-09-25 Bristol-Myers Squibb Company Combination of anti-LAG-3 antibodies and anti-PD-1 antibodies to treat tumors
WO2019075097A1 (en) * 2017-10-11 2019-04-18 Board Of Regents, The University Of Texas System Human pd-l1 antibodies and methods of use therefor
US10266591B2 (en) 2012-07-02 2019-04-23 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US10336824B2 (en) 2015-03-13 2019-07-02 Cytomx Therapeutics, Inc. Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of thereof
US10344089B2 (en) 2008-08-11 2019-07-09 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US10512689B2 (en) 2015-04-17 2019-12-24 Bristol-Myers Squibb Company Compositions comprising a combination of nivolumab and ipilimumab
WO2020215049A1 (en) * 2019-04-19 2020-10-22 ImmunoBrain Checkpoint, Inc. Modified anti-pd-l1 antibodies and methods and uses for treating a neurodegenerative disease
WO2021062184A1 (en) * 2019-09-26 2021-04-01 Orionis Biosciences, Inc. Pd-l1 targeted chimeric proteins and uses thereof
US11078278B2 (en) 2015-05-29 2021-08-03 Bristol-Myers Squibb Company Treatment of renal cell carcinoma
US11168144B2 (en) 2017-06-01 2021-11-09 Cytomx Therapeutics, Inc. Activatable anti-PDL1 antibodies, and methods of use thereof
US11542332B2 (en) 2016-03-26 2023-01-03 Bioatla, Inc. Anti-CTLA4 antibodies, antibody fragments, their immunoconjugates and uses thereof
US11723975B2 (en) 2017-05-30 2023-08-15 Bristol-Myers Squibb Company Compositions comprising an anti-LAG-3 antibody or an anti-LAG-3 antibody and an anti-PD-1 or anti-PD-L1 antibody
US11807686B2 (en) 2017-05-30 2023-11-07 Bristol-Myers Squibb Company Treatment of LAG-3 positive tumors
US11976128B2 (en) 2018-03-23 2024-05-07 Board Of Regents, The University Of Texas System Human PD-L2 antibodies and methods of use therefor
US12134648B2 (en) 2018-03-23 2024-11-05 Board Of Regents, The University Of Texas System Dual specificity antibodies to human PD-L1 and PD-L2 and methods of use therefor
US12187799B2 (en) 2018-03-23 2025-01-07 Board Of Regents, The University Of Texas System Dual specificity antibodies to PD-L1 and PD-L2 and methods of use therefor

Families Citing this family (1794)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7030219B2 (en) 2000-04-28 2006-04-18 Johns Hopkins University B7-DC, Dendritic cell co-stimulatory molecules
DK2206517T3 (en) 2002-07-03 2023-11-06 Ono Pharmaceutical Co Immunopotentiating compositions comprising anti-PD-L1 antibodies
AR045563A1 (en) 2003-09-10 2005-11-02 Warner Lambert Co ANTIBODIES DIRECTED TO M-CSF
DE10347710B4 (en) 2003-10-14 2006-03-30 Johannes-Gutenberg-Universität Mainz Recombinant vaccines and their use
CA3151350A1 (en) 2005-05-09 2006-11-16 E. R. Squibb & Sons, L.L.C. Human monoclonal antibodies to programmed death 1 (pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
CA2611861C (en) 2005-06-08 2017-11-28 The Brigham And Women's Hospital, Inc. Methods and compositions for the treatment of persistent infections
CA3201163A1 (en) * 2005-07-01 2007-01-11 E. R. Squibb & Sons, L.L.C. Human monoclonal antibodies to programmed death ligand 1 (pd-l1)
DE102005046490A1 (en) 2005-09-28 2007-03-29 Johannes-Gutenberg-Universität Mainz New nucleic acid molecule comprising promoter, a transcriptable nucleic acid sequence, a first and second nucleic acid sequence for producing modified RNA with transcriptional stability and translational efficiency
US7700567B2 (en) 2005-09-29 2010-04-20 Supergen, Inc. Oligonucleotide analogues incorporating 5-aza-cytosine therein
EP2061504A4 (en) * 2006-09-20 2010-01-27 Univ Johns Hopkins COMBINATORY THERAPY AGAINST CANCER AND INFECTIOUS DISEASES USING VACCINE AND ANTI-B7-H1
EP2102241A2 (en) 2006-12-15 2009-09-23 Ablynx N.V. Amino acid sequences that modulate the interaction between cells of the immune system
AU2013200388B2 (en) * 2006-12-27 2014-10-23 Dana-Farber Cancer Institute, Inc. Compositions and methods for the treatment of infections and tumors
BRPI0808551B1 (en) * 2007-03-01 2022-04-05 Symphogen A/S Antibody compositions for recombinant antiepidermal growth factor receptor, bispecific binding molecule and pharmaceutical composition comprising them
CN102131828B (en) 2007-06-18 2015-06-17 默沙东有限责任公司 Antibody against human programmed death receptor PD-1
US20110014117A1 (en) * 2007-06-28 2011-01-20 Schering Corporation Anti-igf1r
HRP20160270T1 (en) * 2007-07-17 2016-05-06 E. R. Squibb & Sons, L.L.C. MONOCLONIC ANTIBODIES AGAINST GLIPICAN-3
US8062852B2 (en) 2007-10-01 2011-11-22 The Children's Hospital And Regional Medical Center Detection and treatment of autoimmune disorders
TWI468174B (en) * 2007-12-14 2015-01-11 Novo Nordisk As Antibodies against human kng2d and uses thereof
HUE032025T2 (en) 2008-01-31 2017-08-28 Inserm - Inst Nat De La Sante Et De La Rech Medicale Antibodies against human cd39 and use thereof for inhibiting t regulatory cells activity
US8168757B2 (en) 2008-03-12 2012-05-01 Merck Sharp & Dohme Corp. PD-1 binding proteins
CN110082533B (en) 2008-04-09 2023-01-10 健泰科生物技术公司 Novel compositions and methods for the treatment of immune-related diseases
US9650639B2 (en) 2008-05-19 2017-05-16 Advaxis, Inc. Dual delivery system for heterologous antigens
US9017660B2 (en) 2009-11-11 2015-04-28 Advaxis, Inc. Compositions and methods for prevention of escape mutation in the treatment of Her2/neu over-expressing tumors
DK2853269T3 (en) 2008-05-19 2019-08-05 Advaxis Inc Double delivery system for heterologous antigens comprising a recombinant Listeria strain attenuated by dal / dat mutation and deletion of ActA comprising a nucleic acid molecule encoding a listeriolysine O prostate-specific antigen fusion protein
US20110223188A1 (en) * 2008-08-25 2011-09-15 Solomon Langermann Targeted costimulatory polypeptides and methods of use to treat cancer
EP2927240A1 (en) 2008-08-25 2015-10-07 Amplimmune, Inc. Compositions of pd-1 antagonists and methods of use
AU2013204861B2 (en) * 2008-09-26 2016-05-12 Dana-Farber Cancer Institute, Inc. Human anti-PD-1, PD-L1, and PD-L2 antibodies and uses therefor
AU2009296392B2 (en) 2008-09-26 2016-06-02 Dana-Farber Cancer Institute, Inc. Human anti-PD-1, PD-L1, and PD-L2 antibodies and uses therefor
JP5520961B2 (en) 2008-11-28 2014-06-11 エモリー ユニバーシティ Methods for treating infections and tumors
PT4209510T (en) * 2008-12-09 2024-04-02 Hoffmann La Roche Anti-pd-l1 antibodies and their use to enhance t-cell function
EP3192811A1 (en) * 2009-02-09 2017-07-19 Université d'Aix-Marseille Pd-1 antibodies and pd-l1 antibodies and uses thereof
HUE029577T2 (en) 2009-03-30 2017-03-28 Eisai R&D Man Co Ltd Liposome composition
PL2426148T3 (en) 2009-04-27 2016-01-29 Kyowa Hakko Kirin Co Ltd Anti-il-3ra antibody for use in treatment of blood tumor
JP5960597B2 (en) 2009-09-30 2016-08-02 メモリアル スローン−ケタリング キャンサー センター Combined immunotherapy for cancer treatment
US10016617B2 (en) 2009-11-11 2018-07-10 The Trustees Of The University Of Pennsylvania Combination immuno therapy and radiotherapy for the treatment of Her-2-positive cancers
ES2646863T3 (en) * 2009-11-24 2017-12-18 Medimmune Limited B7-H1 specific binding agents
US20110280877A1 (en) * 2010-05-11 2011-11-17 Koji Tamada Inhibition of B7-H1/CD80 interaction and uses thereof
EP2575818A4 (en) 2010-06-03 2013-11-06 Pharmacyclics Inc USE OF INHIBITORS OF BRUTON TYROSINE KINASE (BTK)
US9783578B2 (en) 2010-06-25 2017-10-10 Aurigene Discovery Technologies Limited Immunosuppression modulating compounds
US8907053B2 (en) 2010-06-25 2014-12-09 Aurigene Discovery Technologies Limited Immunosuppression modulating compounds
WO2012138377A2 (en) 2010-10-01 2012-10-11 Trustees Of The University Of Pennsylvania The use of listeria vaccine vectors to reverse vaccine unresponsiveness in parasitically infected individuals
US9428567B2 (en) 2010-12-22 2016-08-30 The Board Of Trustees Of The Leland Stanford Junior University Antagonists of interleukin-2 receptor
WO2012125551A1 (en) 2011-03-11 2012-09-20 Advaxis Listeria-based adjuvants
US8722044B2 (en) 2011-03-15 2014-05-13 Janssen Biotech, Inc. Human tissue factor antibody and uses thereof
KR101970025B1 (en) 2011-04-20 2019-04-17 메디뮨 엘엘씨 Antibodies and other molecules that bind b7-h1 and pd-1
CA2834548C (en) 2011-04-28 2021-06-01 The Broad Institute, Inc. Inhibitors of histone deacetylase
HUE046152T2 (en) 2011-05-24 2020-02-28 Biontech Rna Pharmaceuticals Gmbh Individualized vaccines for cancer
CN103732238A (en) 2011-06-08 2014-04-16 奥瑞基尼探索技术有限公司 Therapeutic compounds for immunomodulation
EP3626739A1 (en) 2011-06-24 2020-03-25 Stephen D. Gillies Light chain immunoglobulin fusion proteins and methods of use thereof
US9416132B2 (en) 2011-07-21 2016-08-16 Tolero Pharmaceuticals, Inc. Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitors
TWI835048B (en) 2011-08-01 2024-03-11 美商建南德克公司 Methods of treating cancer using pd-1 axis binding antagonists and mek inhibitors
AU2012302051B2 (en) 2011-08-30 2017-04-27 Astex Pharmaceuticals, Inc. Decitabine derivative formulations
AU2012344260B2 (en) 2011-11-28 2017-09-07 Merck Patent Gmbh Anti-PD-L1 antibodies and uses thereof
SG10201604654RA (en) * 2012-01-25 2016-07-28 Dnatrix Inc Biomarkers and combination therapies using oncolytic virus and immunomodulation
US10058599B2 (en) 2012-03-12 2018-08-28 Advaxis, Inc. Suppressor cell function inhibition following Listeria vaccine treatment
WO2013143555A1 (en) 2012-03-26 2013-10-03 Biontech Ag Rna formulation for immunotherapy
WO2013155493A1 (en) 2012-04-12 2013-10-17 Yale University Methods of treating inflammatory and autoimmune diseases and disorders
JP6448533B2 (en) * 2012-05-15 2019-01-09 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Cancer immunotherapy by disrupting PD-1 / PD-L1 signaling
HK1204557A1 (en) * 2012-05-31 2015-11-27 Sorrento Therapeutics, Inc. Antigen binding proteins that bind pd-l1
CN104271601B (en) 2012-05-31 2020-02-04 霍夫曼-拉罗奇有限公司 Methods of treating cancer using PD-1 axis binding antagonists and VEGF antagonists
ES2984771T3 (en) 2012-06-13 2024-10-31 Incyte Holdings Corp Substituted tricyclic compounds as FGFR inhibitors
CN112587671A (en) 2012-07-18 2021-04-02 博笛生物科技有限公司 Targeted immunotherapy for cancer
EP3550031A1 (en) 2012-07-24 2019-10-09 Pharmacyclics, LLC Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (btk)
US9790184B2 (en) 2012-07-27 2017-10-17 The Broad Institute, Inc. Inhibitors of histone deacetylase
CN111499755A (en) 2012-08-03 2020-08-07 丹娜法伯癌症研究院 Anti-PD-L1 and PD-L2 double binding antibody single reagent and method of use
KR101594032B1 (en) * 2012-08-23 2016-02-15 강원대학교산학협력단 Pharmaceutical composition for preventing or treating inflammation or skin aging and cosmetic composition for improving inflammation or skin aging
JP6457940B2 (en) 2012-08-30 2019-01-23 アムジエン・インコーポレーテツド Method for treating melanoma using herpes simplex virus and immune checkpoint inhibitors
DK2904011T3 (en) 2012-10-02 2017-12-04 Bristol Myers Squibb Co COMBINATION OF ANTI-KIR ANTIBODIES AND ANTI-PD-1 ANTIBODIES FOR TREATMENT OF CANCER
CA3139031A1 (en) * 2012-10-04 2014-04-10 Dana-Farber Cancer Institute, Inc. Human monoclonal anti-pd-l1 antibodies and methods of use
EP2914622B1 (en) 2012-11-05 2023-06-07 Foundation Medicine, Inc. Novel fusion molecules and uses thereof
EP2914621B1 (en) 2012-11-05 2023-06-07 Foundation Medicine, Inc. Novel ntrk1 fusion molecules and uses thereof
WO2014082729A1 (en) 2012-11-28 2014-06-05 Biontech Ag Individualized vaccines for cancer
AU2014207342C1 (en) 2013-01-18 2019-04-04 Foundation Medicine, Inc. Methods of treating cholangiocarcinoma
EP2950814A4 (en) 2013-01-31 2016-06-08 Univ Jefferson Pd-l1 and pd-l2-based fusion proteins and uses thereof
US20150377891A1 (en) 2013-02-07 2015-12-31 (Institute National De La Santé Et De La Rechere Médicale) Methods for Predicting the Survival Time of Patients Suffering from Diffuse Large B-Cell Lymphomas
US9573988B2 (en) 2013-02-20 2017-02-21 Novartis Ag Effective targeting of primary human leukemia using anti-CD123 chimeric antigen receptor engineered T cells
KR102685501B1 (en) 2013-02-20 2024-07-17 노파르티스 아게 Treatment of cancer using humanized anti-egfrviii chimeric antigen receptor
CA2897858A1 (en) 2013-02-22 2014-08-28 Curevac Gmbh Combination of vaccination and inhibition of the pd-1 pathway
EP2958588B1 (en) 2013-02-22 2017-08-23 CureVac AG Combination of vaccination and inhibition of the pd-1 pathway
EP3563836A1 (en) 2013-03-01 2019-11-06 Astex Pharmaceuticals, Inc. Drug combinations
MY186126A (en) 2013-03-06 2021-06-24 Astrazeneca Ab Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor
HUE035865T2 (en) 2013-03-14 2018-05-28 Bristol Myers Squibb Co Combination of DR5 agonist and anti-PD-1 antagonist and methods of use
KR20230070054A (en) * 2013-03-15 2023-05-19 제넨테크, 인크. Biomarkers and methods of treating pd-1 and pd-l1 related conditions
US9308236B2 (en) 2013-03-15 2016-04-12 Bristol-Myers Squibb Company Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-L1 protein/protein interactions
UY35468A (en) 2013-03-16 2014-10-31 Novartis Ag CANCER TREATMENT USING AN ANTI-CD19 CHEMERIC ANTIGEN RECEIVER
US20160084839A1 (en) 2013-04-02 2016-03-24 Marisa Dolled-Filhart Immunohistochemical assay for detecting expression of programmed death ligand 1 (pd-l1) in tumor tissue
EP2983790A2 (en) 2013-04-09 2016-02-17 Boston Biomedical, Inc. Methods for treating cancer
CN105209036B (en) 2013-04-09 2018-10-26 莱克斯特生物技术公司 The preparation of oxa-bicyclo heptane and oxabicyclo heptene
ES2657451T3 (en) 2013-04-19 2018-03-05 Incyte Holdings Corporation Bicyclic heterocyclics as FGFR inhibitors
WO2014180490A1 (en) 2013-05-10 2014-11-13 Biontech Ag Predicting immunogenicity of t cell epitopes
WO2014194293A1 (en) 2013-05-30 2014-12-04 Amplimmune, Inc. Improved methods for the selection of patients for pd-1 or b7-h4 targeted therapies, and combination therapies thereof
CA3175360C (en) * 2013-05-31 2024-05-28 Sorrento Therapeutics, Inc. Antigen binding proteins that bind pd-1
BR112015028326A8 (en) 2013-06-03 2018-01-23 Novartis Ag combinations of anti-pd-l1 antibody, mek inhibitor and / or braf inhibitor, their kits and their uses, and pharmaceutical composition
HRP20201404T1 (en) 2013-07-16 2020-11-27 F. Hoffmann - La Roche Ag PROCEDURES FOR THE TREATMENT OF CANCER USING PD-1 BASIC BINDING ANTAGONIST AND TIGIT INHIBITOR
SI3030262T1 (en) 2013-08-08 2020-03-31 Cytune Pharma Combined pharmaceutical composition
BR112016002614B8 (en) 2013-08-08 2023-11-07 Hopitaux Paris Assist Publique Immunocytokine and pharmaceutical composition
ES2827679T3 (en) 2013-08-20 2021-05-24 Merck Sharp & Dohme Cancer treatment with a combination of a PD-1 antagonist and dinaciclib
AR097306A1 (en) 2013-08-20 2016-03-02 Merck Sharp & Dohme MODULATION OF TUMOR IMMUNITY
BR112016005408B1 (en) 2013-09-13 2023-03-21 Beigene Switzerland Gmbh ANTI-PD1, F(AB) OR F(AB)2 ANTIBODIES AND REFERRED USE ANTIBODY FOR TREATMENT OF CANCER OR VIRAL INFECTION
CN105722860A (en) 2013-09-24 2016-06-29 梅迪塞纳医疗股份有限公司 Interleukin-2 fusion proteins and uses thereof
EP3757130A1 (en) 2013-09-26 2020-12-30 Costim Pharmaceuticals Inc. Methods for treating hematologic cancers
CA2926856A1 (en) * 2013-10-25 2015-04-30 Dana-Farber Cancer Institute, Inc. Anti-pd-l1 monoclonal antibodies and fragments thereof
BR112016009200A8 (en) * 2013-10-25 2020-03-24 Pharmacyclics Llc use of a btk inhibitor and a checkpoint immune inhibitor
CN110302162A (en) 2013-11-01 2019-10-08 耶鲁大学 Modularization particle for immunotherapy
WO2015066413A1 (en) 2013-11-01 2015-05-07 Novartis Ag Oxazolidinone hydroxamic acid compounds for the treatment of bacterial infections
US20150140036A1 (en) 2013-11-13 2015-05-21 Novartis Institutes For Biomedical Research, Inc. Low, immune enhancing, dose mtor inhibitors and uses thereof
US10801070B2 (en) 2013-11-25 2020-10-13 The Broad Institute, Inc. Compositions and methods for diagnosing, evaluating and treating cancer
WO2015081158A1 (en) * 2013-11-26 2015-06-04 Bristol-Myers Squibb Company Method of treating hiv by disrupting pd-1/pd-l1 signaling
WO2015085147A1 (en) 2013-12-05 2015-06-11 The Broad Institute Inc. Polymorphic gene typing and somatic change detection using sequencing data
WO2015088930A1 (en) 2013-12-10 2015-06-18 Merck Sharp & Dohme Corp. Immunohistochemical proximity assay for pd-1 positive cells and pd-ligand positive cells in tumor tissue
US9045545B1 (en) * 2014-07-15 2015-06-02 Kymab Limited Precision medicine by targeting PD-L1 variants for treatment of cancer
RU2016128726A (en) 2013-12-17 2018-01-23 Дженентек, Инк. METHODS FOR TREATING MALIGNANT TUMORS USING PD-1 BINDING ANTAGONISTS AND ANTIBODIES AGAINST CD20
KR20160099092A (en) 2013-12-17 2016-08-19 제넨테크, 인크. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
US9067998B1 (en) * 2014-07-15 2015-06-30 Kymab Limited Targeting PD-1 variants for treatment of cancer
DE202014010499U1 (en) 2013-12-17 2015-10-20 Kymab Limited Targeting of human PCSK9 for cholesterol treatment
RS60443B1 (en) * 2013-12-17 2020-07-31 Genentech Inc Anti-cd3 antibodies and methods of use
AU2014364601A1 (en) 2013-12-17 2016-07-07 Genentech, Inc. Methods of treating HER2-positive cancers using PD-1 axis binding antagonists and anti-HER2 antibodies
US20160304969A1 (en) 2013-12-17 2016-10-20 Merck Sharp & Dohme Corp. Ifn-gamma gene signature biomarkers of tumor response to pd-1 antagonists
CA3225453A1 (en) 2013-12-19 2015-06-25 Novartis Ag Human mesothelin chimeric antigen receptors and uses thereof
EP3082853A2 (en) 2013-12-20 2016-10-26 The Broad Institute, Inc. Combination therapy with neoantigen vaccine
CN108558871B (en) 2013-12-24 2022-02-18 百时美施贵宝公司 Tricyclic compounds as anticancer agents
CA2935375C (en) * 2014-01-06 2023-08-08 The Trustees Of The University Of Pennsylvania Pd1 and pdl1 antibodies and vaccine combinations and use of same for immunotherapy
AU2015205753A1 (en) 2014-01-10 2016-07-21 Birdie Biopharmaceuticals Inc. Compounds and compositions for treating HER2 positive tumors
DK3094351T3 (en) * 2014-01-15 2022-02-21 Kadmon Corp Llc IMMUNE MODULATORY AGENTS
JO3517B1 (en) 2014-01-17 2020-07-05 Novartis Ag N-azaspirocycloalkane substituted n-heteroaryl compounds and compositions for inhibiting the activity of shp2
TWI680138B (en) * 2014-01-23 2019-12-21 美商再生元醫藥公司 Human antibodies to pd-l1
TWI681969B (en) 2014-01-23 2020-01-11 美商再生元醫藥公司 Human antibodies to pd-1
JOP20200094A1 (en) 2014-01-24 2017-06-16 Dana Farber Cancer Inst Inc Antibody Molecules of PD-1 and Their Uses
CA2937407A1 (en) 2014-01-27 2015-07-30 Molecular Templates, Inc. De-immunized shiga toxin a subunit effector polypeptides for applications in mammals
JOP20200096A1 (en) 2014-01-31 2017-06-16 Children’S Medical Center Corp Antibody molecules to tim-3 and uses thereof
HUE057205T2 (en) 2014-02-04 2022-04-28 Pfizer Combination of a pd-1 antagonist and a vegfr inhibitor for treating cancer
EP3102604B1 (en) 2014-02-04 2020-01-15 Pfizer Inc Combination of a pd-1 antagonist and a 4-1bb agonist for treating cancer
KR20160108568A (en) 2014-02-04 2016-09-19 인사이트 코포레이션 Combination of a pd-1 antagonist and an ido1 inhibitor for treating cancer
US9676863B2 (en) 2014-02-10 2017-06-13 Merck Patent Gmbh Targeted TGFβ inhibitors
GB201403775D0 (en) 2014-03-04 2014-04-16 Kymab Ltd Antibodies, uses & methods
KR20240144452A (en) 2014-03-05 2024-10-02 브리스톨-마이어스 스큅 컴퍼니 Treatment of renal cancer using a combination of an anti-pd-1 antibody and another anti-cancer agent
US11142584B2 (en) 2014-03-11 2021-10-12 Molecular Templates, Inc. CD20-binding proteins comprising Shiga toxin A subunit effector regions for inducing cellular internalization and methods using same
KR20230097209A (en) * 2014-03-12 2023-06-30 예다 리서치 앤드 디벨럽먼트 캄파니 리미티드 Reducing systemic regulatory t cell levels or activity for treatment of disease and injury of the cns
EP3116535B1 (en) 2014-03-12 2019-08-07 CureVac AG Combination of vaccination and ox40 agonists
US10618963B2 (en) 2014-03-12 2020-04-14 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US10519237B2 (en) 2014-03-12 2019-12-31 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
EA201691765A1 (en) 2014-03-14 2016-12-30 Новартис Аг ANTIBODY MOLECULES AGAINST LAG-3 AND THEIR APPLICATIONS
JP2017513818A (en) 2014-03-15 2017-06-01 ノバルティス アーゲー Treatment of cancer using chimeric antigen receptors
JP2017509336A (en) 2014-03-20 2017-04-06 ファーマサイクリックス エルエルシー Mutations associated with phospholipase C gamma 2 and resistance
TWI714525B (en) 2014-03-24 2021-01-01 瑞士商諾華公司 Monobactam organic compounds for the treatment of bacterial infections
WO2015148683A1 (en) * 2014-03-26 2015-10-01 Tocagen Inc. A retroviral vector having immune-stimulating activity
LT3126394T (en) 2014-03-31 2020-01-27 F. Hoffmann-La Roche Ag Anti-ox40 antibodies and methods of use
CA2943834A1 (en) 2014-03-31 2015-10-08 Genentech, Inc. Combination therapy comprising anti-angiogenesis agents and ox40 binding agonists
WO2015157162A1 (en) * 2014-04-06 2015-10-15 H. Lee Moffitt Cancer Center And Research Institute, Inc. Histone deacetylase as a modulator of pdl1 expression and activity
WO2015157252A1 (en) 2014-04-07 2015-10-15 BROGDON, Jennifer Treatment of cancer using anti-cd19 chimeric antigen receptor
WO2015157636A1 (en) 2014-04-10 2015-10-15 H. Lee Moffitt Cancer Center And Research Institute, Inc. Enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy
WO2015164815A1 (en) 2014-04-24 2015-10-29 The Board Of Trustees Of The Leland Stanford Junior University Superagonists, partial agonists and antagonists of interleukin-2
CA2947471A1 (en) * 2014-05-13 2015-11-19 Medimmune Limited Anti-b7-h1 and anti-ctla-4 antibodies for treating non-small cell lung cancer
KR20170003692A (en) 2014-05-15 2017-01-09 브리스톨-마이어스 스큅 컴퍼니 Treatment of lung cancer using a combination of an anti-pd-1 antibody and another anti-cancer agent
MX393818B (en) 2014-05-23 2025-03-24 Eisai R&D Man Co Ltd COMBINATION THERAPIES FOR CANCER TREATMENT.
EP3149207A4 (en) * 2014-05-28 2018-05-23 Dana-Farber Cancer Institute, Inc. Activating jak kinase biomarkers predictive of anti-immune checkpoint inhibitor response
WO2015181624A2 (en) 2014-05-28 2015-12-03 Idenix Pharmaceuticals, Inc Nucleoside derivatives for the treatment of cancer
EP3151921B1 (en) 2014-06-06 2019-08-28 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
EP3151820A4 (en) 2014-06-06 2017-11-22 Flexus Biosciences, Inc. Immunoregulatory agents
EP3514168B1 (en) 2014-06-11 2021-09-01 Molecular Templates, Inc. Protease-cleavage resistant cytotoxic cell-targeting molecules
TWI693232B (en) 2014-06-26 2020-05-11 美商宏觀基因股份有限公司 Covalently bonded diabodies having immunoreactivity with pd-1 and lag-3, and methods of use thereof
KR102130600B1 (en) 2014-07-03 2020-07-08 베이진 엘티디 Anti-PD-L1 Antibodies and Their Use as Therapeutics and Diagnostics
AU2015286043B2 (en) 2014-07-09 2020-08-20 Birdie Biopharmaceuticals Inc. Anti-PD-L1 combinations for treating tumors
KR102360693B1 (en) 2014-07-11 2022-02-08 벤타나 메디컬 시스템즈, 인코포레이티드 Anti-pd-l1 antibodies and diagnostic uses thereof
US9139648B1 (en) 2014-07-15 2015-09-22 Kymab Limited Precision medicine by targeting human NAV1.9 variants for treatment of pain
SG10202007111TA (en) 2014-07-15 2020-09-29 Genentech Inc Compositions for treating cancer using pd-1 axis binding antagonists and mek inhibitors
US9907849B2 (en) 2014-07-18 2018-03-06 Advaxis, Inc. Combination of a PD-1 antagonist and a listeria-based vaccine for treating prostate cancer
WO2016014576A1 (en) 2014-07-21 2016-01-28 Novartis Ag Treatment of cancer using a cd33 chimeric antigen receptor
AU2015292744C1 (en) 2014-07-21 2021-01-21 Novartis Ag Treatment of cancer using humanized anti-BCMA chimeric antigen receptor
JP2017528433A (en) 2014-07-21 2017-09-28 ノバルティス アーゲー Low immunoenhancing dose of mTOR inhibitor and CAR combination
US11542488B2 (en) 2014-07-21 2023-01-03 Novartis Ag Sortase synthesized chimeric antigen receptors
NZ728688A (en) 2014-07-22 2023-06-30 Cb Therapeutics Inc Anti-pd-1 antibodies
EP3174546B1 (en) 2014-07-31 2019-10-30 Novartis AG Subset-optimized chimeric antigen receptor-containing t-cells
EP3177649B1 (en) * 2014-08-05 2024-02-28 Apollomics Inc. Anti-pd-l1 antibodies
CN107001316A (en) 2014-08-06 2017-08-01 诺华股份有限公司 It is used as the Carbostyril derivative of antiseptic
EP3699189A1 (en) * 2014-08-08 2020-08-26 The Board of Trustees of the Leland Stanford Junior University High affinity pd-1 agents and methods of use
WO2016019472A1 (en) * 2014-08-08 2016-02-11 Quest Pharmatech Inc. Tumor antigen specific antibodies and tlr3 stimulation to enhance the performance of checkpoint interference therapy of cancer
US20170224777A1 (en) 2014-08-12 2017-08-10 Massachusetts Institute Of Technology Synergistic tumor treatment with il-2, a therapeutic antibody, and a cancer vaccine
US10166273B2 (en) 2014-08-12 2019-01-01 The Board Of Trustees Of The Leland Stanford Junior University Synergistic tumor treatment with antibodies targeting PD-1, PD-L1 or CTLA4 and integrin-binding-Fc-fusion protein
JP6919118B2 (en) 2014-08-14 2021-08-18 ノバルティス アーゲー Treatment of cancer with GFRα-4 chimeric antigen receptor
RU2020117196A (en) 2014-08-19 2020-10-15 Новартис Аг CHIMERIC ANTIGENIC RECEPTOR (CAR) AGAINST CD123 FOR USE IN THE TREATMENT OF MALIGNANT TUMORS
US10695426B2 (en) 2014-08-25 2020-06-30 Pfizer Inc. Combination of a PD-1 antagonist and an ALK inhibitor for treating cancer
WO2016030455A1 (en) * 2014-08-28 2016-03-03 Medimmune Limited Anti-b7-h1 and anti-ctla-4 antibodies for treating non-small lung cancer
EP3186281B1 (en) 2014-08-28 2019-04-10 Halozyme, Inc. Combination therapy with a hyaluronan-degrading enzyme and an immune checkpoint inhibitor
CN112546238A (en) 2014-09-01 2021-03-26 博笛生物科技有限公司 anti-PD-L1 conjugates for the treatment of tumors
US9535074B2 (en) 2014-09-08 2017-01-03 Merck Sharp & Dohme Corp. Immunoassay for soluble PD-L1
RU2718914C2 (en) 2014-09-13 2020-04-15 Новартис Аг Combined treatment methods using alk inhibitors
CN107001466B (en) 2014-09-16 2021-10-26 依奈特制药公司 Neutralization of inhibitory pathways in lymphocytes
ES2891332T3 (en) 2014-09-17 2022-01-27 Novartis Ag Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
RS60349B8 (en) 2014-09-23 2022-10-31 Hoffmann La Roche Method of using anti-cd79b immunoconjugates
WO2016045732A1 (en) 2014-09-25 2016-03-31 Biontech Rna Pharmaceuticals Gmbh Stable formulations of lipids and liposomes
EP3201230B1 (en) * 2014-09-30 2020-12-23 Intervet International B.V. Pd-l1 antibodies binding canine pd-l1
JP2017535528A (en) 2014-10-03 2017-11-30 ノバルティス アーゲー Combination therapy
CN114107424A (en) 2014-10-08 2022-03-01 诺华股份有限公司 Biomarkers for predicting therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof
MA41044A (en) 2014-10-08 2017-08-15 Novartis Ag COMPOSITIONS AND METHODS OF USE FOR INCREASED IMMUNE RESPONSE AND CANCER TREATMENT
US9732119B2 (en) 2014-10-10 2017-08-15 Bristol-Myers Squibb Company Immunomodulators
CA2964155A1 (en) 2014-10-10 2016-04-14 Idera Pharmaceuticals, Inc. Treatment of cancer using tlr9 agonist with checkpoint inhibitors
CN106852149B (en) 2014-10-10 2021-08-27 依奈特制药公司 CD73 blockade
CA3203273A1 (en) 2014-10-14 2016-04-21 Halozyme, Inc. Compositions of adenosine deaminase-2 (ada2), variants thereof and methods of using same
KR102513870B1 (en) * 2014-10-14 2023-03-23 노파르티스 아게 Antibody molecules to pd-l1 and uses thereof
JP6687612B2 (en) 2014-10-24 2020-04-22 アストラゼネカ アクチボラグ combination
SMT202100301T1 (en) 2014-10-29 2021-07-12 Bicyclerd Ltd Bicyclic peptide ligands specific for mt1-mmp
EA036261B1 (en) 2014-10-29 2020-10-20 Файв Прайм Терапьютикс, Инк. Combination therapy for cancer
DK3212233T3 (en) * 2014-10-31 2020-07-27 Oncomed Pharm Inc COMBINATION THERAPY FOR TREATMENT OF DISEASE
CA2964958A1 (en) 2014-10-31 2016-05-06 The Trustees Of The University Of Pennsylvania Methods and compositions for modified t cells
KR20170074246A (en) 2014-11-03 2017-06-29 제넨테크, 인크. Methods and biomarkers for predicting efficacy and evaluation of an 0x40 agonist treatment
EP3215850B1 (en) 2014-11-03 2019-07-03 F. Hoffmann-La Roche AG Assays for detecting t cell immune subsets and methods of use thereof
UY36390A (en) 2014-11-05 2016-06-01 Flexus Biosciences Inc MODULATING COMPOUNDS OF INDOLAMINE ENZYME 2,3-DIOXYGENASE (IDO), ITS SYNTHESIS METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
JP7305300B2 (en) 2014-11-05 2023-07-10 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Combination immunotherapy
UY36391A (en) 2014-11-05 2016-06-01 Flexus Biosciences Inc MODULATING COMPOUNDS OF INDOLAMINE ENZYME 2,3-DIOXYGENASE (IDO1), ITS SYNTHESIS METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
JP2017538678A (en) 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． Immunomodulator
ES2987508T3 (en) 2014-11-14 2024-11-15 Novartis Ag Antibody-drug conjugates
US9856292B2 (en) 2014-11-14 2018-01-02 Bristol-Myers Squibb Company Immunomodulators
CA2967368A1 (en) 2014-11-17 2016-05-26 Genentech, Inc. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
CN107106608B (en) 2014-11-20 2022-01-21 普洛麦格公司 Systems and methods for evaluating immune checkpoint modulators
MY192999A (en) 2014-11-20 2022-09-20 Hoffmann La Roche Combination therapy of t cell activating bispecific antigen binding molecules and pd-1 axis binding antagonists
CN107250157B (en) 2014-11-21 2021-06-29 百时美施贵宝公司 Antibodies comprising modified heavy chain constant regions
CA2968357A1 (en) 2014-11-21 2016-05-26 Bristol-Myers Squibb Company Antibodies against cd73 and uses thereof
CN107406494B (en) 2014-11-25 2022-03-25 百时美施贵宝公司 Novel PD-L1-binding peptides for imaging
MX385081B (en) 2014-11-25 2025-03-14 Bristol Myers Squibb Co METHODS AND COMPOSITIONS FOR 18F RADIO-LABELING OF BIOLOGICAL PRODUCTS.
EP3224258B1 (en) 2014-11-27 2019-08-14 Genentech, Inc. 4,5,6,7-tetrahydro-1h-pyrazolo[4,3-c]pyridin-3-amine compounds as cbp and/or ep300 inhibitors
WO2016090034A2 (en) 2014-12-03 2016-06-09 Novartis Ag Methods for b cell preconditioning in car therapy
KR20170088984A (en) 2014-12-04 2017-08-02 브리스톨-마이어스 스큅 컴퍼니 Combination of anti-cs1 and anti-pd1 antibodies to treat cancer (myeloma)
EP3227337A1 (en) 2014-12-05 2017-10-11 F. Hoffmann-La Roche AG Methods and compositions for treating cancer using pd-1 axis antagonists and hpk1 antagonists
EP3226690B1 (en) 2014-12-05 2020-05-20 Merck Sharp & Dohme Corp. Novel tricyclic compounds as inhibitors of mutant idh enzymes
US10508108B2 (en) 2014-12-05 2019-12-17 Merck Sharp & Dohme Corp. Tricyclic compounds as inhibitors of mutant IDH enzymes
WO2016089797A1 (en) 2014-12-05 2016-06-09 Merck Sharp & Dohme Corp. Novel tricyclic compounds as inhibitors of mutant idh enzymes
EP4399969A3 (en) 2014-12-09 2024-10-30 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized cluster of differentiation 274 gene
JP2018505658A (en) 2014-12-09 2018-03-01 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Systems and methods for obtaining genetic signature biomarkers of response to PD-1 antagonists
PL3233843T3 (en) 2014-12-16 2020-04-30 Novartis Ag Isoxazole hydroxamic acid compounds as lpxc inhibitors
CN107580626A (en) 2014-12-18 2018-01-12 美国安进公司 Stabilized frozen virus preparations
US9861680B2 (en) 2014-12-18 2018-01-09 Bristol-Myers Squibb Company Immunomodulators
US9944678B2 (en) 2014-12-19 2018-04-17 Bristol-Myers Squibb Company Immunomodulators
EP3234193B1 (en) 2014-12-19 2020-07-15 Massachusetts Institute of Technology Molecular biomarkers for cancer immunotherapy
US20170340733A1 (en) 2014-12-19 2017-11-30 Novartis Ag Combination therapies
EP3234130B1 (en) 2014-12-19 2020-11-25 The Broad Institute, Inc. Methods for profiling the t-cell- receptor repertoire
AR103232A1 (en) 2014-12-22 2017-04-26 Bristol Myers Squibb Co TGFbR ANTAGONISTS
KR102644115B1 (en) 2014-12-23 2024-03-05 브리스톨-마이어스 스큅 컴퍼니 Antibodies to tigit
EP3240801B1 (en) 2014-12-31 2021-01-20 Checkmate Pharmaceuticals, Inc. Combination tumor immunotherapy
GB201500319D0 (en) 2015-01-09 2015-02-25 Agency Science Tech & Res Anti-PD-L1 antibodies
WO2016115201A1 (en) 2015-01-14 2016-07-21 Bristol-Myers Squibb Company Heteroarylene-bridged benzodiazepine dimers, conjugates thereof, and methods of making and using
MA41414A (en) 2015-01-28 2017-12-05 Centre Nat Rech Scient ICOS AGONIST BINDING PROTEINS
CA3012602A1 (en) 2015-01-30 2016-08-04 President And Fellows Of Harvard College Peritumoral and intratumoral materials for cancer therapy
JP7170394B2 (en) 2015-01-31 2022-11-14 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア Compositions and methods for T cell delivery of therapeutic molecules
US11161907B2 (en) 2015-02-02 2021-11-02 Novartis Ag Car-expressing cells against multiple tumor antigens and uses thereof
MA41460A (en) 2015-02-03 2017-12-12 Oncomed Pharm Inc TNFRSF LIAISON AGENTS AND THEIR USES
US20160222060A1 (en) 2015-02-04 2016-08-04 Bristol-Myers Squibb Company Immunomodulators
ES2856457T3 (en) 2015-02-05 2021-09-27 Molecular Templates Inc Multivalent CD20-binding molecules comprising effector regions of a shiga toxin subunit and enriched compositions thereof
US10983128B2 (en) 2015-02-05 2021-04-20 Bristol-Myers Squibb Company CXCL11 and SMICA as predictive biomarkers for efficacy of anti-CTLA4 immunotherapy
WO2016128060A1 (en) 2015-02-12 2016-08-18 Biontech Ag Predicting t cell epitopes useful for vaccination
MA41551A (en) 2015-02-20 2017-12-26 Incyte Corp BICYCLIC HETEROCYCLES USED AS FGFR4 INHIBITORS
CN107438607B (en) 2015-02-20 2021-02-05 因赛特公司 Bicyclic heterocycles as FGFR inhibitors
RU2742312C1 (en) * 2015-02-26 2021-02-04 Мерк Патент Гмбх Pd-1/pd-l1 inhibitors for treating cancer
EP3262073A1 (en) * 2015-02-26 2018-01-03 Merck Patent GmbH Pd-1 / pd-l1 inhibitors for the treatment of cancer
JP6836998B2 (en) 2015-03-02 2021-03-03 ライジェル ファーマシューティカルズ， インコーポレイテッド TGF-β inhibitor
WO2016140717A1 (en) 2015-03-04 2016-09-09 Merck Sharp & Dohme Corp. Combination of a pd-1 antagonist and a vegfr/fgfr/ret tyrosine kinase inhibitor for treating cancer
US10945990B2 (en) 2015-03-04 2021-03-16 Eisai R&D Management Co., Ltd. Combination of a PD-1 antagonist and eribulin for treating cancer
SG11201707127VA (en) 2015-03-06 2017-09-28 Beyondspring Pharmaceuticals Inc Method of treating cancer associated with a ras mutation
CA2978679A1 (en) 2015-03-06 2016-09-15 Beyondspring Pharmaceuticals, Inc. Method of treating a brain tumor
EP3268037B1 (en) 2015-03-09 2022-08-31 Celldex Therapeutics, Inc. Cd27 agonists
JP6692826B2 (en) 2015-03-10 2020-05-13 アドゥロ バイオテック，インク． Compositions and methods for activation of "interferon gene stimulator" dependent signaling
EP3067062A1 (en) 2015-03-13 2016-09-14 Ipsen Pharma S.A.S. Combination of tasquinimod or a pharmaceutically acceptable salt thereof and a pd1 and/or pdl1 inhibitor, for use as a medicament
US9809625B2 (en) 2015-03-18 2017-11-07 Bristol-Myers Squibb Company Immunomodulators
EP3274370B1 (en) 2015-03-23 2019-11-20 Bayer Pharma Aktiengesellschaft Anti-ceacam6 antibodies and uses thereof
US10478494B2 (en) 2015-04-03 2019-11-19 Astex Therapeutics Ltd FGFR/PD-1 combination therapy for the treatment of cancer
CN108093636A (en) 2015-04-03 2018-05-29 百时美施贵宝公司 Indoleamine 2, 3-dioxygenase inhibitors for the treatment of cancer
CN108136001B (en) 2015-04-03 2022-07-29 佐马技术有限公司 Cancer treatment with TGF-β inhibitors and PD-1 inhibitors
US20180140602A1 (en) 2015-04-07 2018-05-24 Novartis Ag Combination of chimeric antigen receptor therapy and amino pyrimidine derivatives
CA2981183A1 (en) 2015-04-07 2016-10-13 Greg Lazar Antigen binding complex having agonistic activity and methods of use
CN107708733B (en) 2015-04-07 2022-11-15 艾利妥 Anti-sortilin antibodies and methods of use thereof
TW201642897A (en) 2015-04-08 2016-12-16 Ｆ 星生物科技有限公司 HER2 binding agent therapies
GB201506411D0 (en) 2015-04-15 2015-05-27 Bergenbio As Humanized anti-axl antibodies
JP7114457B2 (en) 2015-04-17 2022-08-08 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア Methods for Improving Efficacy and Growth of Chimeric Antigen Receptor-Expressing Cells
WO2016168133A1 (en) 2015-04-17 2016-10-20 Merck Sharp & Dohme Corp. Blood-based biomarkers of tumor sensitivity to pd-1 antagonists
EP3286211A1 (en) 2015-04-23 2018-02-28 Novartis AG Treatment of cancer using chimeric antigen receptor and protein kinase a blocker
KR20170138555A (en) 2015-04-28 2017-12-15 브리스톨-마이어스 스큅 컴퍼니 Treatment of PD-L1-negative melanoma with anti-PD-1 antibody and anti-CTLA-4 antibody
KR20170140316A (en) 2015-04-28 2017-12-20 브리스톨-마이어스 스큅 컴퍼니 Treatment of PD-L1-positive melanoma with anti-PD-1 antibody
US10683290B2 (en) 2015-05-11 2020-06-16 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
WO2016183115A1 (en) 2015-05-12 2016-11-17 Bristol-Myers Squibb Company 5h-pyrido[3,2-b]indole compounds as anticancer agents
US9725449B2 (en) 2015-05-12 2017-08-08 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
CA2983282A1 (en) 2015-05-12 2016-11-17 Genentech, Inc. Therapeutic and diagnostic methods for cancer
CN107849073B (en) 2015-05-18 2020-04-03 特雷罗药物股份有限公司 Avocidide prodrugs with increased bioavailability
WO2016187594A1 (en) 2015-05-21 2016-11-24 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
WO2016189055A1 (en) 2015-05-27 2016-12-01 Idenix Pharmaceuticals Llc Nucleotides for the treatment of cancer
US20180155429A1 (en) 2015-05-28 2018-06-07 Bristol-Myers Squibb Company Treatment of pd-l1 positive lung cancer using an anti-pd-1 antibody
EP4335931A3 (en) 2015-05-29 2024-06-19 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for cancer
SG10201913500TA (en) 2015-05-29 2020-03-30 Agenus Inc Anti-ctla-4 antibodies and methods of use thereof
WO2016196381A1 (en) * 2015-05-29 2016-12-08 Genentech, Inc. Pd-l1 promoter methylation in cancer
TN2019000101A1 (en) 2015-05-29 2020-07-15 Bristol Myers Squibb Co Antibodies against ox40 and uses thereof.
ES2985394T3 (en) 2015-05-29 2024-11-05 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a CpG-C-type oligonucleotide for the treatment of cancer
DK3303373T3 (en) 2015-05-30 2020-06-02 Molecular Templates Inc De-immunized Shiga toxin A subunit scaffolds and cell-targeted molecules comprising the same
CN115554399A (en) 2015-05-31 2023-01-03 源生公司 Combination composition for immunotherapy
MX2017015618A (en) 2015-06-03 2018-08-15 Boston Biomedical Inc Compositions comprising a cancer stemness inhibitor and an immunotherapeutic agent for use in treating cancer.
AU2016274585A1 (en) 2015-06-08 2017-12-14 Genentech, Inc. Methods of treating cancer using anti-OX40 antibodies
AU2016274584A1 (en) 2015-06-08 2018-01-04 Genentech, Inc. Methods of treating cancer using anti-OX40 antibodies and PD-1 axis binding antagonists
EP3307777A4 (en) 2015-06-11 2019-02-13 Wuxi Biologics (Shanghai) Co. Ltd. NEW ANTI-PD-L1 ANTIBODIES
EA201792522A1 (en) 2015-06-12 2018-05-31 Бристол-Майерс Сквибб Компани TREATMENT OF MALIGNANT TUMOR WITH THE HELP OF THE COMBINED BLOCK OF SIGNAL PATH OF PD-1 AND CXCR4
TWI870335B (en) 2015-06-12 2025-01-21 美商宏觀基因股份有限公司 Variant chimeric 4d5 antibodies and uses thereof in combination with anti-pd-1 antibodies for the treatment of cancer
AU2016280003B2 (en) 2015-06-16 2021-09-16 Merck Patent Gmbh PD-L1 antagonist combination treatments
CN116327953A (en) 2015-06-17 2023-06-27 豪夫迈·罗氏有限公司 Methods of treating locally advanced or metastatic breast cancer using PD-1 axis binding antagonists and taxanes
WO2016203432A1 (en) 2015-06-17 2016-12-22 Novartis Ag Antibody drug conjugates
EP3313886A1 (en) 2015-06-29 2018-05-02 The Rockefeller University Antibodies to cd40 with enhanced agonist activity
EA201890199A1 (en) 2015-07-02 2018-06-29 Селджин Корпорейшн COMBINED THERAPY FOR THE TREATMENT OF HEMOBLASTOSIS AND SOLID TUMORS
KR20180024010A (en) 2015-07-02 2018-03-07 오쓰까 세이야꾸 가부시키가이샤 The lyophilized pharmaceutical composition
GB201511790D0 (en) 2015-07-06 2015-08-19 Iomet Pharma Ltd Pharmaceutical compound
SG10202108194XA (en) 2015-07-13 2021-09-29 Beyondspring Pharmaceuticals Inc Plinabulin compositions
JP2018522887A (en) 2015-07-14 2018-08-16 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Cancer treatment using immune checkpoint inhibitors
MA42459A (en) 2015-07-16 2018-05-23 Bioxcel Therapeutics Inc NEW APPROACH TO CANCER TREATMENT BY IMMUNOMODULATION
US10682390B2 (en) 2015-07-16 2020-06-16 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
CN109476722A (en) 2015-07-21 2019-03-15 诺华股份有限公司 Methods for improving the efficacy and expansion of immune cells
CN108137597A (en) 2015-07-28 2018-06-08 百时美施贵宝公司 Tgf beta receptor antagonists
EP3878465A1 (en) 2015-07-29 2021-09-15 Novartis AG Combination therapies comprising antibody molecules to tim-3
WO2017019896A1 (en) 2015-07-29 2017-02-02 Novartis Ag Combination therapies comprising antibody molecules to pd-1
EP3328407A1 (en) 2015-07-29 2018-06-06 Novartis AG Combination of pd-1 antagonist with an egfr inhibitor
LT3317301T (en) 2015-07-29 2021-07-26 Novartis Ag Combination therapies comprising antibody molecules to lag-3
TWI762879B (en) 2015-07-30 2022-05-01 美商宏觀基因股份有限公司 Pd-1-binding molecules and methods of use thereof
CN106397592A (en) * 2015-07-31 2017-02-15 苏州康宁杰瑞生物科技有限公司 Single-domain antibody directed at programmed death ligand (PD-L1) and derived protein thereof
WO2017020291A1 (en) 2015-08-06 2017-02-09 Wuxi Biologics (Shanghai) Co. Ltd. Novel anti-pd-l1 antibodies
WO2017025871A1 (en) 2015-08-07 2017-02-16 Glaxosmithkline Intellectual Property Development Limited Combination therapy comprising anti ctla-4 antibodies
WO2017025498A1 (en) 2015-08-07 2017-02-16 Pieris Pharmaceuticals Gmbh Novel fusion polypeptide specific for lag-3 and pd-1
EA201890468A1 (en) 2015-08-11 2018-07-31 Уси Байолоджикс (Кайман) Инк. NEW ANTIBODIES AGAINST PD-1 PROTEIN
HK1249109A1 (en) 2015-08-13 2018-10-26 Merck Sharp & Dohme Corp. Cyclic di-nucleotide compounds as sting agonists
US11453697B1 (en) 2015-08-13 2022-09-27 Merck Sharp & Dohme Llc Cyclic di-nucleotide compounds as sting agonists
AR105654A1 (en) 2015-08-24 2017-10-25 Lilly Co Eli ANTIBODIES PD-L1 (LINKING 1 OF PROGRAMMED CELL DEATH)
CN108349976A (en) 2015-08-25 2018-07-31 百时美施贵宝公司 TGF β receptor antagonists
US11385231B2 (en) 2015-08-27 2022-07-12 Inserm (Institut National De La Sante Et De La Recherche Scientifique) Methods for predicting the survival time of patients suffering from a lung cancer
MY197664A (en) * 2015-09-03 2023-06-30 Ono Pharmaceutical Co Immunity enhancing agent for cancer by allergin-1 antagonist
US11747346B2 (en) 2015-09-03 2023-09-05 Novartis Ag Biomarkers predictive of cytokine release syndrome
US20170114098A1 (en) 2015-09-03 2017-04-27 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
JP6980649B2 (en) 2015-09-14 2021-12-15 インフィニティー ファーマシューティカルズ， インコーポレイテッド The solid form of the isoquinolinone derivative, the method for producing it, the composition containing it, and the method for using it.
MA44909A (en) 2015-09-15 2018-07-25 Acerta Pharma Bv THERAPEUTIC ASSOCIATION OF A CD19 INHIBITOR AND A BTK INHIBITOR
WO2017055320A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of cytotoxic lymphocytes in a tissue sample
WO2017055324A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of cells of monocytic origin in a tissue sample
WO2017055321A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of fibroblasts in a tissue sample
WO2017055319A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of b cells in a tissue sample
WO2017055322A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of neutrophils in a tissue sample
WO2017055327A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of endothelial cells in a tissue sample
WO2017055326A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of myeloid dendritic cells in a tissue sample
WO2017055325A1 (en) 2015-09-29 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of nk cells in a tissue sample
US10947598B2 (en) 2015-09-29 2021-03-16 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods for determining the metabolic status of lymphomas
US20180282415A1 (en) 2015-09-30 2018-10-04 Merck Patent Gmbh Combination of a PD-1 Axis Binding Antagonist and an ALK Inhibitor for Treating ALK-Negative Cancer
WO2017059224A2 (en) 2015-10-01 2017-04-06 Gilead Sciences, Inc. Combination of a btk inhibitor and a checkpoint inhibitor for treating cancers
CR20180161A (en) 2015-10-02 2018-05-25 Hoffmann La Roche Bispecific Antibodies for PD1 and TIM3
MY190297A (en) 2015-10-02 2022-04-12 Hoffmann La Roche Anti-pd1 antibodies and methods of use
WO2017059902A1 (en) 2015-10-07 2017-04-13 Biontech Rna Pharmaceuticals Gmbh 3' utr sequences for stabilization of rna
RU2731202C2 (en) 2015-10-08 2020-08-31 Макродженикс, Инк. Combined therapy for cancer treatment
WO2017060397A1 (en) 2015-10-09 2017-04-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the survival time of subjects suffering from melanoma metastases
US11130817B2 (en) 2015-10-12 2021-09-28 Innate Pharma CD73 blocking agents
JP6954648B2 (en) 2015-10-19 2021-10-27 シージー オンコロジー， インコーポレイテッド Treatment of solid tumors or lymphoid tumors with combination therapy
US10149887B2 (en) 2015-10-23 2018-12-11 Canbas Co., Ltd. Peptides and peptidomimetics in combination with t cell activating and/or checkpoint inhibiting agents for cancer treatment
MA44334A (en) 2015-10-29 2018-09-05 Novartis Ag ANTIBODY CONJUGATES INCLUDING A TOLL-TYPE RECEPTOR AGONIST
HRP20220436T1 (en) 2015-11-03 2022-05-27 Janssen Biotech, Inc. ANTIBODIES SPECIFICALLY BINDING TO PD-1 AND THEIR USES
US11702477B2 (en) 2015-11-06 2023-07-18 Orionis Biosciences BV Bi-functional chimeric proteins and uses thereof
WO2017087280A1 (en) 2015-11-16 2017-05-26 Genentech, Inc. Methods of treating her2-positive cancer
US10815304B2 (en) * 2015-11-17 2020-10-27 Suzhou Suncadia Biopharmaceuticals Co., Ltd. PD-L1 antibody, antigen-binding fragment thereof and medical application thereof
TWI795347B (en) 2015-11-18 2023-03-11 美商必治妥施貴寶公司 Treatment of lung cancer using a combination of an anti-pd-1 antibody and an anti-ctla-4 antibody
UA121914C2 (en) 2015-11-18 2020-08-10 Мерк Шарп І Доум Корп. Pd1 and/or lag3 binders
JP6952691B2 (en) 2015-11-19 2021-10-20 ジェネンテック， インコーポレイテッド How to Treat Cancer with B-RAF Inhibitors and Immune Checkpoint Inhibitors
AU2016356780A1 (en) 2015-11-19 2018-06-28 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof
JP2019505476A (en) 2015-12-01 2019-02-28 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Combination treatment and method
AU2016362697B2 (en) 2015-12-03 2018-07-12 Glaxosmithkline Intellectual Property Development Limited Cyclic purine dinucleotides as modulators of STING
WO2017098421A1 (en) 2015-12-08 2017-06-15 Glaxosmithkline Intellectual Property Development Limited Benzothiadiazine compounds
EP3178848A1 (en) 2015-12-09 2017-06-14 F. Hoffmann-La Roche AG Type ii anti-cd20 antibody for reducing formation of anti-drug antibodies
MX2018005229A (en) 2015-12-09 2019-04-29 F Hoffmann­La Roche Ag ANTIBODY ANTI-CD20 TYPE II AND USES OF THE SAME.
EP3389714A4 (en) 2015-12-14 2019-11-13 MacroGenics, Inc. BISPECIFIC MOLECULES HAVING IMMUNOREACTIVITY TO PD-1 AND CTLA-4 AND METHODS OF USE
CN108602829A (en) 2015-12-15 2018-09-28 百时美施贵宝公司 Cxcr4 receptor antagonists
EP3389783B1 (en) 2015-12-15 2024-07-03 Merck Sharp & Dohme LLC Novel compounds as indoleamine 2,3-dioxygenase inhibitors
IL259988B2 (en) 2015-12-15 2023-02-01 Oncoimmune Inc Chimeric and humanized monoclonal antibodies against ctla-4 and uses thereof
US10392442B2 (en) 2015-12-17 2019-08-27 Bristol-Myers Squibb Company Use of anti-PD-1 antibody in combination with anti-CD27 antibody in cancer treatment
WO2017106453A1 (en) 2015-12-17 2017-06-22 University Of Maryland, Baltimore County A recombinant bi-specific polypeptide for coordinately activating tumor-reactive t-cells and neutralizing immune suppression
AU2016369537B2 (en) 2015-12-17 2024-03-14 Novartis Ag Antibody molecules to PD-1 and uses thereof
GB201522309D0 (en) 2015-12-17 2016-02-03 Photocure Asa Use
KR20180089510A (en) 2015-12-18 2018-08-08 노파르티스 아게 Antibodies targeting CD32b and methods of using the same
US11433136B2 (en) 2015-12-18 2022-09-06 The General Hospital Corporation Polyacetal polymers, conjugates, particles and uses thereof
JP2019505575A (en) 2015-12-21 2019-02-28 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Mutant antibodies for site-specific binding
BR112018012756A2 (en) 2015-12-22 2018-12-04 Incyte Corp heterocyclic compounds as immunomodulators
SMT202300304T1 (en) 2015-12-22 2023-11-13 Regeneron Pharma Combination of anti-pd-1 antibodies and bispecific anti-cd20/anti-cd3 antibodies to treat cancer
EP3393504B1 (en) 2015-12-22 2025-09-24 Novartis AG Mesothelin chimeric antigen receptor (car) and antibody against pd-l1 inhibitor for combined use in anticancer therapy
PT3394093T (en) 2015-12-23 2022-05-30 Modernatx Inc Methods of using ox40 ligand encoding polynucleotides
CN105461808B (en) * 2015-12-24 2019-03-19 长春金赛药业股份有限公司 Monoclonal antibody and its application
CN106939047B (en) * 2016-01-04 2021-08-31 江苏怀瑜药业有限公司 PD-L1 antibody and preparation method thereof
EP3400443B1 (en) 2016-01-04 2020-09-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma
CN106943596A (en) 2016-01-07 2017-07-14 博笛生物科技（北京）有限公司 Anti-CD20 Combinations for Treating Tumors
CN115252792A (en) 2016-01-07 2022-11-01 博笛生物科技有限公司 anti-EGFR combinations for the treatment of tumors
CN115350279A (en) 2016-01-07 2022-11-18 博笛生物科技有限公司 anti-HER 2 combinations for the treatment of tumors
CN108601777B (en) 2016-01-08 2021-08-03 细胞基因公司 2-(4-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2 ,2-Difluoroacetamide preparation
WO2017120415A1 (en) 2016-01-08 2017-07-13 Celgene Corporation Solid forms of 2-(4-chlorophenyl)-n-((2-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide, and their pharmaceutical compositions and uses
BR112018011029A2 (en) 2016-01-08 2018-11-21 Hoffmann La Roche methods for treating or delaying cancer progression and improving immune function in a cancer individual, uses of a binding antagonist and a bispecific antibody, compositions and kits
TWI782395B (en) 2016-01-08 2022-11-01 美商西建公司 Antiproliferative compounds, and their pharmaceutical compositions and uses
DK3402503T3 (en) 2016-01-13 2020-12-21 Acerta Pharma Bv THERAPEUTIC COMBINATIONS OF AN ANTIFOLATE AND A BTK INHIBITOR
SI3405495T1 (en) 2016-01-21 2021-08-31 Innate Pharma Neutralization of inhibitory pathways in lymphocytes
JP7252760B2 (en) 2016-01-22 2023-04-05 メルク・シャープ・アンド・ドーム・エルエルシー anticoagulant factor XI antibody
ES3034233T3 (en) * 2016-01-22 2025-08-14 MabQuest SA Non-blocking pd1 specific antibodies
WO2017129763A1 (en) 2016-01-28 2017-08-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer
US10822415B2 (en) 2016-01-28 2020-11-03 Inserm (Institut National De La Santéet De La Recherche Médicale) Methods for enhancing the potency of the immune checkpoint inhibitors
US10918737B2 (en) 2016-01-28 2021-02-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of cancer
CA3013551A1 (en) 2016-02-05 2017-08-10 Orionis Biosciences Nv Clec9a binding agents and use thereof
IL260937B2 (en) 2016-02-06 2024-07-01 Epimab Biotherapeutics Inc Fabs-in-tandem immunoglobulin and uses thereof
RU2753543C1 (en) 2016-02-08 2021-08-17 Бейондспринг Фармасьютикалс, Инк. Compositions containing tucaresol or analogues thereof
BR112018016842A2 (en) 2016-02-19 2018-12-26 Novartis Ag tetracyclic pyridone compounds as antivirals
CN108699154A (en) 2016-02-26 2018-10-23 国家医疗保健研究所 There is the antibody and application thereof of specificity to BTLA
WO2017151517A1 (en) 2016-02-29 2017-09-08 Foundation Medicine, Inc. Methods of treating cancer
AU2017225854B2 (en) 2016-02-29 2020-11-19 Foundation Medicine, Inc. Therapeutic and diagnostic methods for cancer
IL295230A (en) 2016-03-04 2022-10-01 Bristol Myers Squibb Co Combination therapy with anti-cd73 antibodies
WO2017148424A1 (en) * 2016-03-04 2017-09-08 四川科伦博泰生物医药股份有限公司 Pdl-1 antibody, pharmaceutical composition thereof, and uses thereof
US10143746B2 (en) 2016-03-04 2018-12-04 Bristol-Myers Squibb Company Immunomodulators
BR112018067679A2 (en) 2016-03-04 2019-01-15 Novartis Ag cells expressing multiple chimeric antigen receptor (car) molecules and their use
WO2017155981A1 (en) 2016-03-07 2017-09-14 Massachusetts Institute Of Technology Protein-chaperoned t-cell vaccines
EP3426688A1 (en) 2016-03-08 2019-01-16 Innate Pharma Siglec neutralizing antibodies
JP7208492B2 (en) 2016-03-10 2023-01-19 シージー オンコロジー， インコーポレイテッド Methods of treating solid tumors or lymphoid tumors with combination therapy
WO2017153952A1 (en) 2016-03-10 2017-09-14 Glaxosmithkline Intellectual Property Development Limited 5-sulfamoyl-2-hydroxybenzamide derivatives
WO2017160599A1 (en) 2016-03-14 2017-09-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Use of cd300b antagonists to treat sepsis and septic shock
MX2018011204A (en) 2016-03-15 2019-03-07 Mersana Therapeutics Inc Napi2b-targeted antibody-drug conjugates and methods of use thereof.
US11767362B1 (en) 2016-03-15 2023-09-26 Chugai Seiyaku Kabushiki Kaisha Methods of treating cancers using PD-1 axis binding antagonists and anti-GPC3 antibodies
KR20180127971A (en) * 2016-03-23 2018-11-30 맵스페이스 바이오사이언시즈 (쑤저우) 컴퍼니 리미티드 New anti-PD-L1 antibodies
WO2017165683A1 (en) 2016-03-23 2017-09-28 Novartis Ag Cell secreted minibodies and uses thereof
WO2017165778A1 (en) 2016-03-24 2017-09-28 Millennium Pharmaceuticals, Inc. Methods of treating gastrointestinal immune-related adverse events in immune oncology treatments
CN109311885A (en) 2016-03-24 2019-02-05 诺华股份有限公司 Inhibitor of the alkynyl nucleoside analog as human rhinovirus
WO2017165742A1 (en) 2016-03-24 2017-09-28 Millennium Pharmaceuticals, Inc. Methods of treating gastrointestinal immune-related adverse events in anti-ctla4 anti-pd-1 combination treatments
CA3018382A1 (en) 2016-03-29 2017-10-05 University Of Southern California Chimeric antigen receptors targeting cancer
US20200232974A1 (en) 2016-03-30 2020-07-23 Centre Léon-Bérard Lymphocytes expressing cd73 in cancerous patient dictates therapy
EP3436066A1 (en) 2016-04-01 2019-02-06 Checkmate Pharmaceuticals, Inc. Fc receptor-mediated drug delivery
WO2017176925A1 (en) 2016-04-05 2017-10-12 Bristol-Myers Squibb Company Cytokine profiling analysis for predicting prognosis of a patient in need of an anti-cancer treatment
US10358463B2 (en) 2016-04-05 2019-07-23 Bristol-Myers Squibb Company Immunomodulators
CN113549110B (en) 2016-04-07 2024-08-16 葛兰素史密斯克莱知识产权发展有限公司 Heterocyclic amides as protein modulators
AU2017247806B2 (en) 2016-04-07 2019-11-14 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
WO2017177179A1 (en) 2016-04-08 2017-10-12 Gilead Sciences, Inc. Compositions and methods for treating cancer, inflammatory diseases and autoimmune diseases
MX380780B (en) 2016-04-12 2025-03-12 Lilly Co Eli COMBINATION THERAPY WITH NOTCH AND PI3K/mTOR INHIBITORS.
KR102418765B1 (en) 2016-04-12 2022-07-08 일라이 릴리 앤드 캄파니 Combination Therapy of Notch and CDK4/6 Inhibitors for the Treatment of Cancer
EP3442567A4 (en) 2016-04-13 2019-12-18 Orimabs Ltd. ANTI-PSMA ANTIBODIES AND THEIR USE
JP7038353B2 (en) 2016-04-13 2022-03-18 ヴィヴィア バイオテック，エス．エル Exvivo BITE-activated T cells
HUE068840T2 (en) 2016-04-14 2025-01-28 Ose Immunotherapeutics New anti-sirpa antibodies and their therapeutic applications
MX2018012493A (en) 2016-04-15 2019-06-06 Genentech Inc Methods for monitoring and treating cancer.
ES2850428T3 (en) 2016-04-15 2021-08-30 Hoffmann La Roche Cancer monitoring and treatment procedures
KR102414558B1 (en) 2016-04-18 2022-06-29 셀덱스 쎄라퓨틱스, 인크. Agonistic antibodies that bind to human CD40 and uses thereof
JP7015237B2 (en) 2016-04-28 2022-02-02 エーザイ・アール・アンド・ディー・マネジメント株式会社 How to control tumor growth
CN109640959B (en) 2016-04-29 2023-03-17 西奈山伊坎医学院 Targeting the innate immune system to induce long-term tolerance and address macrophage accumulation in atherosclerosis
KR20190004742A (en) 2016-05-04 2019-01-14 브리스톨-마이어스 스큅 컴퍼니 Inhibitors of indoleamine 2,3-dioxygenase and methods of use thereof
US10544099B2 (en) 2016-05-04 2020-01-28 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
EP3452030A4 (en) 2016-05-04 2019-11-13 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN109348714A (en) 2016-05-04 2019-02-15 百时美施贵宝公司 The inhibitor and its application method of indole amine 2,3-dioxygenase
WO2017192874A1 (en) 2016-05-04 2017-11-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Albumin-binding immunomodulatory compositions and methods of use thereof
US10323004B2 (en) 2016-05-04 2019-06-18 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
AU2017260854B2 (en) 2016-05-05 2020-01-30 Glaxosmithkline Intellectual Property (No.2) Limited Enhancer of Zeste Homolog 2 inhibitors
KR20190005924A (en) 2016-05-10 2019-01-16 브리스톨-마이어스 스큅 컴퍼니 Antibody-drug conjugates of tuburicin analogs with improved stability
TWI822521B (en) 2016-05-13 2023-11-11 美商再生元醫藥公司 Methods of treating skin cancer by administering a pd-1 inhibitor
EP3243832A1 (en) 2016-05-13 2017-11-15 F. Hoffmann-La Roche AG Antigen binding molecules comprising a tnf family ligand trimer and pd1 binding moiety
US11236141B2 (en) 2016-05-13 2022-02-01 Orionis Biosciences BV Targeted mutant interferon-beta and uses thereof
EP3455245A2 (en) 2016-05-13 2019-03-20 Orionis Biosciences NV Therapeutic targeting of non-cellular structures
SI3458474T1 (en) 2016-05-18 2022-10-28 Modernatx, Inc. Combinations of mRNA encoding immunomodulatory polypeptides and their use
US11414491B2 (en) 2016-05-18 2022-08-16 Mayo Foundation For Medical Education And Research Targeting PD-L1 on tumor cells
SG11201809381XA (en) 2016-05-18 2018-12-28 Modernatx Inc Polynucleotides encoding interleukin-12 (il12) and uses thereof
JP7194022B2 (en) * 2016-05-20 2022-12-21 イーライ リリー アンド カンパニー Combination therapy with Notch inhibitors and PD-1 or PD-L1 inhibitors
RS65474B1 (en) 2016-05-20 2024-05-31 Biohaven Therapeutics Ltd Use of riluzole, riluzole prodrugs or riluzole analogs with immunotherapies to treat cancers
CN105968200B (en) * 2016-05-20 2019-03-15 瑞阳(苏州)生物科技有限公司 Anti-human PD-L1 humanized monoclonal antibody and its application
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
US20190292259A1 (en) 2016-05-24 2019-09-26 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and pharmaceutical compositions for the treatment of non small cell lung cancer (nsclc) that coexists with chronic obstructive pulmonary disease (copd)
CN115028617A (en) 2016-05-24 2022-09-09 基因泰克公司 Heterocyclic inhibitors of CBP/EP300 and their use in the treatment of cancer
WO2017205538A1 (en) 2016-05-24 2017-11-30 Genentech, Inc. Pyrazolopyridine derivatives for the treatment of cancer
WO2017202949A1 (en) 2016-05-25 2017-11-30 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers
BR112018074463A2 (en) 2016-05-27 2019-03-06 Agenus Inc. anti-tim-3 antibodies and methods of use.
CN109562195A (en) 2016-06-01 2019-04-02 百时美施贵宝公司 PET imaging is carried out with PD-L1 combination polypeptide
WO2017210335A1 (en) 2016-06-01 2017-12-07 Bristol-Myers Squibb Company Imaging methods using 18f-radiolabeled biologics
EP3252078A1 (en) 2016-06-02 2017-12-06 F. Hoffmann-La Roche AG Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer
MX390955B (en) 2016-06-02 2025-03-19 Seagen Inc USE OF AN ANTI-PD-1 ANTIBODY IN COMBINATION WITH AN ANTI-CD30 ANTIBODY FOR THE TREATMENT OF LYMPHOMA.
JP7175198B2 (en) 2016-06-02 2022-11-18 ブリストル－マイヤーズ スクイブ カンパニー PD-1 Blockade with Nivolumab in Refractory Hodgkin Lymphoma
WO2018220099A1 (en) 2017-06-02 2018-12-06 F. Hoffmann-La Roche Ag Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer
PT3463436T (en) 2016-06-02 2023-12-28 Ultimovacs As A vaccine in combination with an immune checkpoint inhibitor for use in treating cancer
CN109476754A (en) 2016-06-03 2019-03-15 百时美施贵宝公司 Use of anti-PD-1 antibodies in the treatment of colorectal cancer patients
US20190292260A1 (en) 2016-06-03 2019-09-26 Bristol-Myers Squibb Company Anti-pd-1 antibody for use in a method of treatment of recurrent small cell lung cancer
EP3464369A1 (en) 2016-06-03 2019-04-10 Bristol-Myers Squibb Company Anti-pd-1 antibody for use in a method of treating a tumor
CN118304304A (en) 2016-06-06 2024-07-09 大连万春布林医药有限公司 Compositions and methods for reducing neutropenia
AU2017279027A1 (en) 2016-06-08 2018-12-20 Glaxosmithkline Intellectual Property Development Limited Chemical Compounds
WO2017212425A1 (en) 2016-06-08 2017-12-14 Glaxosmithkline Intellectual Property Development Limited Chemical compounds as atf4 pathway inhibitors
EP3468581A1 (en) 2016-06-13 2019-04-17 Torque Therapeutics, Inc. Methods and compositions for promoting immune cell function
JP6730466B2 (en) * 2016-06-13 2020-07-29 アイ−エムエービー バイオファーマ ユーエス リミテッド Anti-PD-L1 antibody and use thereof
CN107488229B (en) * 2016-06-13 2020-11-17 天境生物科技(上海)有限公司 PD-L1 antibodies and uses thereof
MY201852A (en) 2016-06-14 2024-03-20 Merck Sharp & Dohme Llc Anti-coagulation factor xi antibodies
US10071973B2 (en) 2016-06-14 2018-09-11 Novartis Ag Crystalline isoxazole hydroxamic acid compounds
WO2017216686A1 (en) 2016-06-16 2017-12-21 Novartis Ag 8,9-fused 2-oxo-6,7-dihydropyrido-isoquinoline compounds as antivirals
WO2017216685A1 (en) 2016-06-16 2017-12-21 Novartis Ag Pentacyclic pyridone compounds as antivirals
WO2018029474A2 (en) 2016-08-09 2018-02-15 Kymab Limited Anti-icos antibodies
SMT202200392T1 (en) 2016-06-20 2022-11-18 Incyte Corp Heterocyclic compounds as immunomodulators
WO2017220989A1 (en) 2016-06-20 2017-12-28 Kymab Limited Anti-pd-l1 and il-2 cytokines
SI3472207T1 (en) * 2016-06-20 2021-04-30 F-Star Delta Limited Binding molecules that bind PD-L1 and LAG-3
US9567399B1 (en) 2016-06-20 2017-02-14 Kymab Limited Antibodies and immunocytokines
CN109311993B (en) 2016-06-20 2022-12-20 F-星治疗有限公司 LAG-3 binding element
IL263680B1 (en) 2016-06-24 2025-06-01 Infinity Pharmaceuticals Inc PI3K inhibitors for use in combination with a second therapeutic agent for the treatment, management or prevention of cancer
RU2749109C2 (en) * 2016-06-29 2021-06-04 Чекпойнт Терапьютикс, Инк. Specific antibodies to pd-l1 and methods for their application
SG11201811600PA (en) 2016-06-30 2019-01-30 Oncorus Inc Pseudotyped oncolytic viral delivery of therapeutic polypeptides
US10864203B2 (en) 2016-07-05 2020-12-15 Beigene, Ltd. Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer
US11098077B2 (en) 2016-07-05 2021-08-24 Chinook Therapeutics, Inc. Locked nucleic acid cyclic dinucleotide compounds and uses thereof
KR102602137B1 (en) * 2016-07-06 2023-11-13 브리스톨-마이어스 스큅 컴퍼니 Combinations and methods of use of TIM-4 antagonists and PD-1 antagonists
WO2018009894A1 (en) 2016-07-07 2018-01-11 Iovance Biotherapeutics, Inc. Programmed death 1 ligand 1 (pd-l1) binding proteins and methods of use thereof
WO2018011166A2 (en) 2016-07-12 2018-01-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for quantifying the population of myeloid dendritic cells in a tissue sample
MY200602A (en) 2016-07-14 2024-01-04 Bristol Myers Squibb Co Antibodies against tim3 and uses thereof
GB201612520D0 (en) 2016-07-19 2016-08-31 F-Star Beta Ltd Binding molecules
US11365252B2 (en) 2016-07-20 2022-06-21 University Of Utah Research Foundation CD229 CAR T cells and methods of use thereof
EP3487503A1 (en) 2016-07-20 2019-05-29 GlaxoSmithKline Intellectual Property Development Limited Isoquinoline derivatives as perk inhibitors
US20190292179A1 (en) 2016-07-21 2019-09-26 Bristol-Myers Squibb Company TGF Beta RECEPTOR ANTAGONISTS
JP2019525934A (en) 2016-07-29 2019-09-12 イーライ リリー アンド カンパニー Combination therapy with melestinib and anti-PD-L1 or anti-PD-1 inhibitor for use in the treatment of cancer
EP3490548A4 (en) 2016-08-01 2020-04-15 Molecular Templates, Inc. ADMINISTRATION OF HYPOXY-ACTIVATED PRODRUGS IN COMBINATION WITH IMMUNO MODULATORS FOR TREATING CANCER
BR112019002127A2 (en) 2016-08-03 2019-09-17 Nextcure Inc fusion protein, vector, cell, pharmaceutical composition, and fusion protein use
JP6925421B2 (en) * 2016-08-05 2021-08-25 ワイ−バイオロジクス・インコーポレイテッド Antibodies to programmed cell death protein ligand-1 (PD-L1) and their uses
US11046776B2 (en) 2016-08-05 2021-06-29 Genentech, Inc. Multivalent and multiepitopic antibodies having agonistic activity and methods of use
WO2018026249A1 (en) * 2016-08-05 2018-02-08 주식회사 와이바이오로직스 Antibody against programmed death-ligand 1 (pd-l1), and use thereof
CN109476748B (en) 2016-08-08 2023-05-23 豪夫迈·罗氏有限公司 Methods for the treatment and diagnosis of cancer
CA3032897A1 (en) 2016-08-09 2018-02-15 Kymab Limited Anti-icos antibodies
BR112019002394B1 (en) 2016-08-10 2021-12-21 Ajou University Industry-Academic Cooperation Foundation HETERODIMERIC PROTEIN FLUTED WITH CF AND ITS USE
TW201811369A (en) 2016-08-12 2018-04-01 美商建南德克公司 Combination therapy with a MEK inhibitor, a PD-1 axis inhibitor, and a VEGF inhibitor
WO2018029336A1 (en) 2016-08-12 2018-02-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for determining whether a subject was administered with an activator of the ppar beta/delta pathway.
US20180118832A1 (en) 2016-08-12 2018-05-03 Merck Patent Gmbh Combination therapy for cancer
EP3498838A4 (en) 2016-08-15 2020-01-08 National University Corporation Hokkaido University Anti-pd-l1 antibody
ES2902179T3 (en) 2016-08-19 2022-03-25 Bristol Myers Squibb Co Seco-cyclopropapyrroloindole compounds, antibody-drug conjugates thereof, and methods of making and use
HUE065528T2 (en) 2016-08-19 2024-06-28 Beigene Switzerland Gmbh Combination of zanubrutinib with an anti-cd20 or an anti-pd-1 antibody for use in treating cancer
US11351164B2 (en) 2016-08-26 2022-06-07 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US10323248B2 (en) 2016-09-01 2019-06-18 Chimera Bioengineering, Inc. Gold optimized CAR T-cells
CN106248955A (en) * 2016-09-03 2016-12-21 长春工业大学 A kind of test kit detecting humanization PD L1 antibody
KR102557900B1 (en) 2016-09-07 2023-07-19 트러스티즈 오브 터프츠 칼리지 Combination therapy using an immuno-DASH inhibitor and a PGE2 antagonist
WO2018049263A1 (en) 2016-09-09 2018-03-15 Tg Therapeutics, Inc. Combination of an anti-cd20 antibody, pi3 kinase-delta inhibitor, and anti-pd-1 or anti-pd-l1 antibody for treating hematological cancers
WO2018048975A1 (en) 2016-09-09 2018-03-15 Bristol-Myers Squibb Company Use of an anti-pd-1 antibody in combination with an anti-mesothelin antibody in cancer treatment
WO2018047109A1 (en) 2016-09-09 2018-03-15 Novartis Ag Polycyclic pyridone compounds as antivirals
WO2018046736A1 (en) 2016-09-12 2018-03-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the survival time of patients suffering from cancer
WO2018046738A1 (en) 2016-09-12 2018-03-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the survival time of patients suffering from cancer
WO2018053434A1 (en) 2016-09-16 2018-03-22 The Johns Hopkins University Protein nanocages with enhanced mucus penetration for targeted tissue and intracellular delivery
JP7072576B2 (en) 2016-09-16 2022-05-20 シャンハイ・ヘンリウス・バイオテック・インコーポレイテッド Anti-PD-1 antibody
CA3037230A1 (en) * 2016-09-20 2018-03-29 Merck Patent Gmbh Diagnostic anti-pd-l1 antibody and use thereof
EP4360714A3 (en) 2016-09-21 2024-07-24 Nextcure, Inc. Antibodies for siglec-15 and methods of use thereof
KR102644544B1 (en) 2016-09-21 2024-03-11 넥스트큐어 인코포레이티드 Antibodies for SIGLEC-15 and methods of using the same
US11077178B2 (en) 2016-09-21 2021-08-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Chimeric antigen receptor (CAR) that targets chemokine receptor CCR4 and its use
EP3515453A1 (en) 2016-09-22 2019-07-31 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for reprograming immune environment in a subject in need thereof
US11673971B2 (en) 2016-09-23 2023-06-13 Marengo Therapeutics, Inc. Multispecific antibody molecules comprising lambda and kappa light chains
JP7089507B2 (en) 2016-09-26 2022-06-22 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Predicting response to PD-1 axis inhibitors
CA3037008A1 (en) 2016-09-27 2018-04-05 Oncologie, Inc. Methods for treating cancer with bavituximab based on levels of .beta.2-glycoprotein 1, and assays therefor
JOP20190061A1 (en) 2016-09-28 2019-03-26 Novartis Ag Beta-lactamase inhibitors
EP3518970A1 (en) 2016-09-29 2019-08-07 Genentech, Inc. Combination therapy with a mek inhibitor, a pd-1 axis inhibitor, and a taxane
CR20190168A (en) 2016-10-04 2019-05-17 Merck Sharp & Dohme BENZO[b]THIOPHENE COMPOUNDS AS STING AGONISTS
BR112019006504A2 (en) 2016-10-06 2019-06-25 Merck Patent Gmbh Avelumab Dosage Regimen For Cancer Treatment
AU2017339517B2 (en) 2016-10-06 2024-03-14 Foundation Medicine, Inc. Therapeutic and diagnostic methods for cancer
EP3523331A1 (en) 2016-10-07 2019-08-14 Novartis AG Chimeric antigen receptors for the treatment of cancer
CA3039774A1 (en) 2016-10-10 2018-04-19 The National Institute for Biotechnology in the Negev Ltd. Non-cytotoxic modified cells and use thereof
JP7066696B2 (en) 2016-10-11 2022-05-13 アジェナス インコーポレイテッド Anti-LAG-3 antibody and its usage
WO2018071307A1 (en) 2016-10-12 2018-04-19 Eli Lilly And Company Targeted treatment of mature t-cell lymphoma
WO2018071576A1 (en) 2016-10-14 2018-04-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Treatment of tumors by inhibition of cd300f
CN110072552A (en) 2016-10-14 2019-07-30 默沙东公司 Combination of PD-1 antagonist and eribulin for the treatment of urothelial carcinoma
TW201819380A (en) 2016-10-18 2018-06-01 瑞士商諾華公司 Fused tetracyclic pyridone compounds as antivirals
WO2018075447A1 (en) 2016-10-19 2018-04-26 The Trustees Of Columbia University In The City Of New York Combination of braf inhibitor, talimogene laherparepvec, and immune checkpoint inhibitor for use in the treatment cancer (melanoma)
US10398783B2 (en) 2016-10-20 2019-09-03 Bristol-Myers Squibb Company Antiproliferative compounds and conjugates made therefrom
CA3040802A1 (en) 2016-10-24 2018-05-03 Orionis Biosciences Nv Targeted mutant interferon-gamma and uses thereof
LT3532607T (en) 2016-10-26 2024-05-10 Iovance Biotherapeutics, Inc. Restimulation of cryopreserved tumor infiltrating lymphocytes
CN107987153A (en) * 2016-10-27 2018-05-04 广东香雪精准医疗技术有限公司 The soluble PD-1 molecules of high-affinity
CN106478819B (en) * 2016-10-27 2018-12-07 常州费洛斯药业科技有限公司 A kind of monoclonal antibody or antibody fragment for PD-L1
JP7258747B2 (en) 2016-10-28 2023-04-17 ブリストル－マイヤーズ スクイブ カンパニー Method for treating urothelial cancer using anti-PD-1 antibody
WO2018081531A2 (en) 2016-10-28 2018-05-03 Ariad Pharmaceuticals, Inc. Methods for human t-cell activation
CN110267678A (en) 2016-10-29 2019-09-20 霍夫曼-拉罗奇有限公司 Anti-MIC antibodies and methods of use
CA3041078A1 (en) * 2016-10-30 2018-05-03 Shanghai Henlius Biotech, Inc. Anti-pd-l1 antibodies and variants
TWI788307B (en) 2016-10-31 2023-01-01 美商艾歐凡斯生物治療公司 Engineered artificial antigen presenting cells for tumor infiltrating lymphocyte expansion
EA201990787A1 (en) 2016-11-02 2019-12-30 Энгмаб Сарл SPECIFIC ANTIBODY TO BCMA AND CD3 AND IMMUNOLOGICAL MEDICINE FOR COMBINED USE IN TREATMENT OF MULTIPLE MYELOMA
WO2018085555A1 (en) 2016-11-03 2018-05-11 Bristol-Myers Squibb Company Activatable anti-ctla-4 antibodies and uses thereof
EP3534947A1 (en) 2016-11-03 2019-09-11 Kymab Limited Antibodies, combinations comprising antibodies, biomarkers, uses & methods
US10342785B2 (en) 2016-11-04 2019-07-09 Askat Inc. Use of EP4 receptor antagonists for the treatment of NASH-associated liver cancer
JP7085545B2 (en) 2016-11-07 2022-06-16 ブリストル－マイヤーズ スクイブ カンパニー Immune modifier
US20190345500A1 (en) 2016-11-14 2019-11-14 |Nserm (Institut National De La Santé Et De La Recherche Médicale) Methods and pharmaceutical compositions for modulating stem cells proliferation or differentiation
TWI791471B (en) 2016-11-15 2023-02-11 美商建南德克公司 Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies
US10660909B2 (en) 2016-11-17 2020-05-26 Syntrix Biosystems Inc. Method for treating cancer using chemokine antagonists
WO2018094167A1 (en) 2016-11-17 2018-05-24 Iovance Biotherapeutics, Inc. Remnant tumor infiltrating lymphocytes and methods of preparing and using the same
WO2018094275A1 (en) 2016-11-18 2018-05-24 Tolero Pharmaceuticals, Inc. Alvocidib prodrugs and their use as protein kinase inhibitors
CN106496327B (en) * 2016-11-18 2019-01-15 昆山百尔泰生物科技有限公司 Human antibody or antibody fragment and purposes, nucleotide sequence and carrier for PD-L1 extracellular fragment
WO2018091542A1 (en) 2016-11-21 2018-05-24 Idenix Pharmaceuticals Llc Cyclic phosphate substituted nucleoside derivatives for the treatment of liver diseases
WO2018098352A2 (en) 2016-11-22 2018-05-31 Jun Oishi Targeting kras induced immune checkpoint expression
US11135307B2 (en) 2016-11-23 2021-10-05 Mersana Therapeutics, Inc. Peptide-containing linkers for antibody-drug conjugates
WO2018102427A1 (en) 2016-11-29 2018-06-07 Boston Biomedical, Inc. Naphthofuran derivatives, preparation, and methods of use thereof
EP3548071A4 (en) 2016-11-30 2020-07-15 OncoMed Pharmaceuticals, Inc. Methods for treatment of cancer comprising tigit-binding agents
JP2020511407A (en) 2016-12-01 2020-04-16 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Combination therapy
US20190343803A1 (en) 2016-12-01 2019-11-14 Glaxosmithkline Intellectual Property Development Limited Combination therapy
US10736976B2 (en) * 2016-12-01 2020-08-11 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-PD-L1 antibodies for immuno-PET imaging
MA46961A (en) 2016-12-03 2019-10-09 Juno Therapeutics Inc CAR MODIFIED T LYMPHOCYTES MODULATION PROCESSES
WO2018106738A1 (en) 2016-12-05 2018-06-14 Massachusetts Institute Of Technology Brush-arm star polymers, conjugates and particles, and uses thereof
MD3551660T2 (en) 2016-12-07 2024-03-31 Agenus Inc Anti-CTLA-4 antibodies and methods of use thereof
WO2018106895A1 (en) 2016-12-07 2018-06-14 Molecular Templates, Inc. Shiga toxin a subunit effector polypeptides, shiga toxin effector scaffolds, and cell-targeting molecules for site-specific conjugation
AU2017373945B2 (en) 2016-12-07 2025-01-23 Agenus Inc. Antibodies and methods of use thereof
BR112019011627A2 (en) 2016-12-08 2019-11-12 Lixte Biotechnology Inc oxabicycloheptanes for immune response modulation
MX2019006331A (en) 2016-12-12 2019-07-12 Genentech Inc Methods of treating cancer using anti-pd-l1 antibodies and antiandrogens.
WO2018112266A1 (en) 2016-12-14 2018-06-21 The Board Of Trustees Of The Leland Stanford Junior University Il-13 superkine: immune cell targeting constructs and methods of use thereof
RU2759952C2 (en) 2016-12-14 2021-11-19 Янссен Байотек, Инк. Cd8a-binding domains of iii fibronectin type
WO2018111978A1 (en) 2016-12-14 2018-06-21 Janssen Biotech, Inc. Cd137 binding fibronectin type iii domains
WO2018111976A1 (en) 2016-12-14 2018-06-21 Janssen Biotech, Inc. Pd-l1 binding fibronectin type iii domains
WO2018112364A1 (en) 2016-12-16 2018-06-21 Evelo Biosciences, Inc. Combination therapies for treating melanoma
WO2018112360A1 (en) 2016-12-16 2018-06-21 Evelo Biosciences, Inc. Combination therapies for treating cancer
CN108218987B (en) * 2016-12-21 2019-08-20 南京金斯瑞生物科技有限公司 A highly functional anti-human CTLA4 antibody with high affinity, high specificity, and multiple antigen recognition epitopes
CN110582493B (en) 2016-12-22 2024-03-08 因赛特公司 Benzoxazole derivatives as immunomodulators
JP7128529B2 (en) * 2016-12-23 2022-08-31 アールイーエムディー バイオセラピューティクス，インコーポレイテッド Immunization using an antibody that binds programmed death ligand-1 (PD-L1)
EP3559032A1 (en) 2016-12-23 2019-10-30 Innate Pharma Heterodimeric antigen binding proteins
CA3047508A1 (en) 2016-12-23 2018-06-28 Virttu Biologics Limited Treatment of cancer
WO2018122249A1 (en) 2016-12-28 2018-07-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the survival time of patients suffering from a microsatellite stable colorectal cancer
WO2018122245A1 (en) 2016-12-28 2018-07-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of predicting the survival time of patients suffering from cms3 colorectal cancer
CN110291105B (en) 2017-01-05 2024-03-01 奈特里斯药物公司 Combination therapy of guide-1 interfering drugs and immune checkpoint inhibitor drugs
US10961239B2 (en) 2017-01-05 2021-03-30 Bristol-Myers Squibb Company TGF beta receptor antagonists
EP3565812B1 (en) 2017-01-06 2023-12-27 Beyondspring Pharmaceuticals, Inc. Tubulin binding compounds and therapeutic use thereof
CA3049165A1 (en) 2017-01-06 2018-07-12 Iovance Biotherapeutics, Inc. Expansion of tumor infiltrating lymphocytes with potassium channel agonists and therapeutic uses thereof
US11584733B2 (en) 2017-01-09 2023-02-21 Shuttle Pharmaceuticals, Inc. Selective histone deacetylase inhibitors for the treatment of human disease
EP3565560B1 (en) 2017-01-09 2024-05-29 OnkosXcel Therapeutics, LLC Predictive and diagnostic methods for prostate cancer
CA3049435A1 (en) 2017-01-09 2018-07-12 Scott Grindrod Selective histone deacetylase inhibitors for the treatment of human disease
EP3568466A4 (en) 2017-01-10 2020-07-15 The General Hospital Corporation TARGETED T-CELLS WITH CYTOTOXICITY TO IMMUNE-SUPPRESSIVE CELLS
EA201991696A1 (en) 2017-01-13 2020-02-05 Эйдженус Инк. T-CELL RECEPTORS RELATING TO NY-ESO-1 AND METHODS OF APPLICATION
WO2018134279A1 (en) 2017-01-18 2018-07-26 Pieris Pharmaceuticals Gmbh Novel fusion polypeptides specific for lag-3 and pd-1
EP3570844B1 (en) 2017-01-20 2023-09-06 Arcus Biosciences, Inc. Azolopyrimidine for the treatment of cancer-related disorders
EP3573989A4 (en) 2017-01-25 2020-11-18 Beigene, Ltd. CRYSTALLINE FORMS OF (S) -7- (1- (BUT-2-YNOYL) -PIPERIDINE-4-YL) -2- (4-PHENOXYPHENYL) -4,5,6,7-TETRAHYDROPYRAZOLO [1,5-A ] PYRIMIDINE-3-CARBOXAMIDE, MANUFACTURING AND USES THEREOF
CA3049456A1 (en) 2017-01-25 2018-08-02 Molecular Templates, Inc. Cell-targeting molecules comprising de-immunized, shiga toxin a subunit effectors and cd8+ t-cell epitopes
JP7062010B2 (en) 2017-01-27 2022-05-02 セルジーン コーポレイション 3- (1-oxo-4-((4-((3-oxomorpholino) methyl) benzyl) oxy) isoindoline-2-yl) piperidine-2,6-dione and its isotopolog
EP3573718B1 (en) 2017-01-27 2022-06-01 Janssen Biotech, Inc. Cyclic dinucleotides as sting agonists
CN110234404A (en) 2017-01-27 2019-09-13 詹森生物科技公司 Cyclic annular dinucleotides as STING agonist
CN110381938A (en) 2017-02-01 2019-10-25 大连万春布林医药有限公司 The method for reducing neutrophil leucocyte deficiency disease
JOP20190187A1 (en) 2017-02-03 2019-08-01 Novartis Ag Anti-ccr7 antibody drug conjugates
EP3576765B1 (en) 2017-02-06 2025-07-16 Orionis Biosciences, Inc. Targeted engineered interferon and uses thereof
EP3577138A1 (en) 2017-02-06 2019-12-11 Innate Pharma Immunomodulatory antibody drug conjugates binding to a human mica polypeptide
CN110546160A (en) 2017-02-06 2019-12-06 奥里尼斯生物科学公司 Targeted chimeric proteins and their uses
WO2018146148A1 (en) 2017-02-07 2018-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) A method for predicting the response to checkpoint blockade cancer immunotherapy
WO2018146128A1 (en) 2017-02-07 2018-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Detection of kit polymorphism for predicting the response to checkpoint blockade cancer immunotherapy
EP3580237B1 (en) 2017-02-08 2025-05-14 Novartis AG Fgf21 mimetic antibodies and uses thereof
EP3579874B1 (en) 2017-02-10 2021-07-21 Novartis AG 1-(4-amino-5-bromo-6-(1 h-pyrazol-1-yl)pyrimidin-2-yl)-1 h-pyrazol-4-ol and use thereof in the treatment of cancer
EP3583127B1 (en) 2017-02-16 2024-11-20 Ying Zhang Anti-programmed death-ligand 1 (pd-l1) antibodies and therapeutic uses thereof
US20200291089A1 (en) 2017-02-16 2020-09-17 Elstar Therapeutics, Inc. Multifunctional molecules comprising a trimeric ligand and uses thereof
US11845803B2 (en) 2017-02-17 2023-12-19 Fred Hutchinson Cancer Center Combination therapies for treatment of BCMA-related cancers and autoimmune disorders
TWI674261B (en) 2017-02-17 2019-10-11 美商英能腫瘤免疫股份有限公司 Nlrp3 modulators
CN110536905B (en) 2017-02-21 2023-10-27 瑞泽恩制药公司 Anti-PD-1 antibodies for lung cancer treatment
CN108456251A (en) * 2017-02-21 2018-08-28 上海君实生物医药科技股份有限公司 Anti- PD-L1 antibody and its application
WO2018156740A1 (en) 2017-02-24 2018-08-30 Macrogenics, Inc. Bispecific binding molecules that are capable of binding cd137 and tumor antigens, and uses thereof
KR20190107719A (en) 2017-02-27 2019-09-20 노파르티스 아게 Dosing schedule for the combination of seritinib and anti-PD-1 antibody molecules
EP3585782A1 (en) 2017-02-27 2020-01-01 GlaxoSmithKline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
US20180271996A1 (en) 2017-02-28 2018-09-27 Mersana Therapeutics, Inc. Combination therapies of her2-targeted antibody-drug conjugates
EP3366703B1 (en) 2017-02-28 2019-04-03 Ralf Kleef Immune checkpoint therapy with hyperthermia
WO2018160841A1 (en) 2017-03-01 2018-09-07 Genentech, Inc. Diagnostic and therapeutic methods for cancer
EP3372615A1 (en) * 2017-03-06 2018-09-12 Merck Patent GmbH Composition comprising avelumab
EP4527854A3 (en) 2017-03-09 2025-06-25 Genmab A/S Antibodies against pd-l1
AU2018236272B2 (en) 2017-03-15 2022-03-31 Silverback Therapeutics, Inc. Benzazepine compounds, conjugates, and uses thereof
EP3595690A1 (en) 2017-03-15 2020-01-22 Amgen Inc. Use of oncolytic viruses, alone or in combination with a checkpoint inhibitor, for the treatment of cancer
CN110402248B (en) 2017-03-15 2023-01-06 豪夫迈·罗氏有限公司 Azaindoles as HPK1 inhibitors
EP3596124A1 (en) 2017-03-16 2020-01-22 Innate Pharma Compositions and methods for treating cancer
US20200102618A1 (en) * 2017-03-17 2020-04-02 Nantomics, Llc LIQUID BIOPSY FOR cfRNA
WO2018172508A1 (en) 2017-03-24 2018-09-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
CN108623686A (en) 2017-03-25 2018-10-09 信达生物制药(苏州)有限公司 Anti- OX40 antibody and application thereof
JOP20190224A1 (en) 2017-03-29 2019-09-26 Iovance Biotherapeutics Inc Operations for the production of tumor-infiltrating lymphocytes and their use in immunotherapy
US11254913B1 (en) 2017-03-29 2022-02-22 Iovance Biotherapeutics, Inc. Processes for production of tumor infiltrating lymphocytes and uses of same in immunotherapy
BR112019018093A2 (en) 2017-03-30 2020-06-16 F. Hoffmann-La Roche Ag COMPOUNDS, COMPOSITION, HPK1 INHIBITION METHOD, METHODS TO IMPROVE AN IMMUNE RESPONSE AND TO TREAT A DISORDER AND COMPOUND USES
PE20200008A1 (en) 2017-03-30 2020-01-06 Hoffmann La Roche ISOQUINOLINS AS INHIBITORS OF HPK1
EP3600410A1 (en) 2017-03-30 2020-02-05 Merck Patent GmbH Combination of an anti-pd-l1 antibody and a dna-pk inhibitor for the treatment of cancer
AU2018243754B2 (en) 2017-03-31 2025-04-10 Bristol-Myers Squibb Company Methods of treating tumor
AU2018249493A1 (en) 2017-04-03 2019-09-19 Oncxerna Therapeutics, Inc. Methods for treating cancer using PS-targeting antibodies with immuno-oncology agents
CA3053357A1 (en) 2017-04-03 2018-10-11 F. Hoffmann-La Roche Ag Immunoconjugates of an anti-pd-1 antibody with a mutant il-2 or with il-15
CA3057989C (en) 2017-04-05 2023-03-21 Korea Research Institute Of Bioscience And Biotechnology Nk cell-activating fusion protein, nk cell, and pharmaceutical composition including same
SG11201909154SA (en) 2017-04-05 2019-10-30 Hoffmann La Roche Bispecific antibodies specifically binding to pd1 and lag3
US11603407B2 (en) 2017-04-06 2023-03-14 Regeneron Pharmaceuticals, Inc. Stable antibody formulation
TWI788340B (en) 2017-04-07 2023-01-01 美商必治妥美雅史谷比公司 Anti-icos agonist antibodies and uses thereof
BR112019021411A2 (en) 2017-04-13 2020-05-05 Hoffmann La Roche methods to treat or slow the progression of cancer and to improve function, uses of an immunoconjugate, an agonist, an antagonist, compositions, kit and invention
MA50956A (en) 2017-04-13 2020-10-14 Agenus Inc ANTI-CD137 ANTIBODIES AND RELATED METHODS OF USE
MX2019012192A (en) 2017-04-14 2020-01-21 Genentech Inc Diagnostic and therapeutic methods for cancer.
RU2665790C1 (en) * 2017-04-17 2018-09-04 Закрытое Акционерное Общество "Биокад" Monoclonal pd-l1 antibody
CN108728444A (en) 2017-04-18 2018-11-02 长春华普生物技术股份有限公司 Immunoregulation polynucleotide and its application
CA3060554A1 (en) 2017-04-18 2018-10-25 Tempest Therapeutics, Inc. Bicyclic compounds and their use in the treatment of cancer
AU2018256406A1 (en) 2017-04-19 2019-10-17 Marengo Therapeutics, Inc. Multispecific molecules and uses thereof
US20200129637A1 (en) 2017-04-20 2020-04-30 Adc Therapeutics Sa Combination therapy with an anti-axl antibody-drug conjugate
JOP20180040A1 (en) 2017-04-20 2019-01-30 Gilead Sciences Inc Pd-1/pd-l1 inhibitors
CN106939049B (en) 2017-04-20 2019-10-01 苏州思坦维生物技术股份有限公司 The monoclonal antibody and the preparation method and application thereof of antagonism inhibition people PD-1 antigen and its ligand binding
CA3057744A1 (en) 2017-04-20 2018-10-25 Adc Therapeutics Sa Combination therapy with an anti-cd25 antibody-drug conjugate
SG11201909710XA (en) 2017-04-21 2019-11-28 Kyn Therapeutics Indole ahr inhibitors and uses thereof
CN110621341A (en) 2017-04-26 2019-12-27 百时美施贵宝公司 Antibody production method that minimizes disulfide bond reduction
AR111419A1 (en) 2017-04-27 2019-07-10 Novartis Ag INDAZOL PIRIDONA FUSIONED COMPOUNDS AS ANTIVIRALS
CN108794467A (en) 2017-04-27 2018-11-13 博笛生物科技有限公司 2-amino-quinoline derivatives
SG11201908296VA (en) 2017-04-28 2019-10-30 Merck Sharp & Dohme Biomarkers for cancer therapeutics
EP3615068A1 (en) 2017-04-28 2020-03-04 Novartis AG Bcma-targeting agent, and combination therapy with a gamma secretase inhibitor
WO2018201056A1 (en) 2017-04-28 2018-11-01 Novartis Ag Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor
AR111651A1 (en) 2017-04-28 2019-08-07 Novartis Ag CONJUGATES OF ANTIBODIES THAT INCLUDE TOLL TYPE RECEIVER AGONISTS AND COMBINATION THERAPIES
WO2018201047A1 (en) 2017-04-28 2018-11-01 Elstar Therapeutics, Inc. Multispecific molecules comprising a non-immunoglobulin heterodimerization domain and uses thereof
UY37695A (en) 2017-04-28 2018-11-30 Novartis Ag BIS 2’-5’-RR- (3’F-A) (3’F-A) CYCLE DINUCLEOTIDE COMPOUND AND USES OF THE SAME
DK3618863T3 (en) 2017-05-01 2023-08-21 Agenus Inc ANTI-TIGIT ANTIBODIES AND METHODS OF USING THEREOF
UY37718A (en) 2017-05-05 2018-11-30 Novartis Ag 2-TRYCLINAL QUINOLINONES AS ANTIBACTERIAL AGENTS
JP7296367B2 (en) 2017-05-08 2023-06-22 シャンハイ ジェイエムティー－バイオ テクノロジー カンパニー リミテッド Bispecific recombinant protein and its application
WO2018208667A1 (en) 2017-05-12 2018-11-15 Merck Sharp & Dohme Corp. Cyclic di-nucleotide compounds as sting agonists
US10543271B2 (en) 2017-05-12 2020-01-28 Harpoon Therapeutics, Inc. Mesothelin binding proteins
WO2018209049A1 (en) 2017-05-12 2018-11-15 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN110869392A (en) 2017-05-16 2020-03-06 百时美施贵宝公司 Treatment of cancer with anti-GITR agonistic antibodies
US11359014B2 (en) * 2017-05-16 2022-06-14 Alector Llc Anti-siglec-5 antibodies and methods of use thereof
KR102623679B1 (en) * 2017-05-16 2024-01-11 지앙수 헨그루이 파마슈티컬스 컴퍼니 리미티드 PD-L1 antibody pharmaceutical composition and uses thereof
WO2018213377A1 (en) 2017-05-17 2018-11-22 Arcus Biosciences, Inc. Quinazoline-pyrazole derivatives for the treatment of cancer-related disorders
US10646464B2 (en) 2017-05-17 2020-05-12 Boston Biomedical, Inc. Methods for treating cancer
EP3625246A1 (en) 2017-05-18 2020-03-25 ModernaTX, Inc. Polynucleotides encoding tethered interleukin-12 (il12) polypeptides and uses thereof
MY206158A (en) 2017-05-24 2024-12-02 Novartis Ag Antibody-cytokine engrafted proteins and methods of use in the treatment of cancer
EP4098662A1 (en) 2017-05-25 2022-12-07 Bristol-Myers Squibb Company Antibodies comprising modified heavy constant regions
AR111960A1 (en) 2017-05-26 2019-09-04 Incyte Corp CRYSTALLINE FORMS OF A FGFR INHIBITOR AND PROCESSES FOR ITS PREPARATION
BR112019018759A2 (en) 2017-05-30 2020-05-05 Bristol-Myers Squibb Company compositions comprising a combination of an anti-lag-3 antibody, an inhibitor of the pd-1 pathway, and an immunotherapeutic agent
EP3630834A1 (en) 2017-05-31 2020-04-08 STCube & Co., Inc. Methods of treating cancer using antibodies and molecules that immunospecifically bind to btn1a1
EP3630836A1 (en) 2017-05-31 2020-04-08 Elstar Therapeutics, Inc. Multispecific molecules that bind to myeloproliferative leukemia (mpl) protein and uses thereof
JOP20190279A1 (en) 2017-05-31 2019-11-28 Novartis Ag Crystalline images of 5-bromo-2,6-dye (1H-pyrazole-1-yl) pyrimidine-4-amine and novel salts
AU2018275109A1 (en) 2017-06-01 2020-01-02 Xencor, Inc. Bispecific antibodies that bind CD 123 CD3
WO2018223004A1 (en) 2017-06-01 2018-12-06 Xencor, Inc. Bispecific antibodies that bind cd20 and cd3
WO2018223040A1 (en) 2017-06-01 2018-12-06 Bristol-Myers Squibb Company Methods of treating a tumor using an anti-pd-1 antibody
MX2019014268A (en) 2017-06-02 2020-08-03 Juno Therapeutics Inc Articles of manufacture and methods for treatment using adoptive cell therapy.
AR112072A1 (en) 2017-06-05 2019-09-18 Iovance Biotherapeutics Inc METHODS OF USE OF INFILTRATING TUMOR LYMPHOCYTES IN DOUBLE REFRACTORY MELANOMA
KR20250097991A (en) 2017-06-06 2025-06-30 주식회사 에스티큐브앤컴퍼니 Methods of treating cancer using antibodies and molecules that bind to btn1a1 or btn1a1-ligands
WO2018225093A1 (en) 2017-06-07 2018-12-13 Glaxosmithkline Intellectual Property Development Limited Chemical compounds as atf4 pathway inhibitors
WO2018225033A1 (en) 2017-06-09 2018-12-13 Glaxosmithkline Intellectual Property Development Limited Combination therapy
EP3634584B1 (en) 2017-06-09 2024-09-18 Providence Health & Services - Oregon Tumor-infiltrating t-cells for use in the treatment of cancer
WO2018224166A1 (en) 2017-06-09 2018-12-13 Biontech Rna Pharmaceuticals Gmbh Methods for predicting the usefulness of disease specific amino acid modifications for immunotherapy
WO2018229222A1 (en) 2017-06-14 2018-12-20 Adc Therapeutics Sa Dosage regimes for the administration of an anti-cd19 adc
WO2018229715A1 (en) 2017-06-16 2018-12-20 Novartis Ag Compositions comprising anti-cd32b antibodies and methods of use thereof
WO2018234862A1 (en) 2017-06-19 2018-12-27 Medicenna Therapeutics Inc. USES AND METHODS FOR IL-2 SUPERAGONISTS AND AGONISTS AND FUSIONS THEREOF
GB201709808D0 (en) 2017-06-20 2017-08-02 Kymab Ltd Antibodies
EP3641739A1 (en) 2017-06-20 2020-04-29 Institut Curie Inhibitor of suv39h1 histone methyltransferase for use in cancer combination therapy
CA3061874A1 (en) 2017-06-22 2018-12-27 Novartis Ag Il-1beta binding antibodies for use in treating cancer
CN110996955A (en) 2017-06-22 2020-04-10 细胞基因公司 Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection
US20200172628A1 (en) 2017-06-22 2020-06-04 Novartis Ag Antibody molecules to cd73 and uses thereof
WO2018235056A1 (en) 2017-06-22 2018-12-27 Novartis Ag IL-1BETA BINDING ANTIBODIES FOR USE IN THE TREATMENT OF CANCER
CN110785187B (en) 2017-06-22 2024-04-05 诺华股份有限公司 Antibody molecules targeting CD73 and uses thereof
WO2018237153A1 (en) 2017-06-23 2018-12-27 Bristol-Myers Squibb Company IMMUNOMODULATORS ACTING AS PD-1 ANTAGONISTS
MX2019015744A (en) 2017-06-23 2020-02-20 Birdie Biopharmaceuticals Inc Pharmaceutical compositions.
KR102757960B1 (en) 2017-06-26 2025-01-22 베이진 엘티디 Immunotherapy for hepatocellular carcinoma (HCC)
MX2019015738A (en) 2017-06-27 2020-02-20 Novartis Ag Dosage regimens for anti-tim-3 antibodies and uses thereof.
US11560425B2 (en) 2017-06-27 2023-01-24 Neuracle Science Co., Ltd. Use of anti-FAM19A5 antibodies for treating cancers
MX2019015155A (en) 2017-06-29 2020-08-03 Juno Therapeutics Inc MOUSE MODEL TO ASSESS TOXICITIES ASSOCIATED WITH IMMUNOTHERAPIES.
EA202090119A1 (en) 2017-06-30 2020-04-21 Бристол-Маерс Сквибб Компани AMORPHIC AND CRYSTALLINE FORMS OF IDO INHIBITORS
MX2019015886A (en) 2017-06-30 2020-09-10 Celgene Corp Compositions and methods of use of 2-(4-chlorophenyl)-n-((2-(2,6- doxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl) -2,2-difluoroacetamide.
US20200140383A1 (en) 2017-07-03 2020-05-07 Glaxosmithkline Intellectual Property Development Limited 2-(4-chlorophenoxy)-n-((1 -(2-(4-chlorophenoxy)ethynazetidin-3-yl)methyl)acetamide derivatives and related compounds as atf4 inhibitors for treating cancer and other diseases
BR112020000122A2 (en) 2017-07-03 2020-07-07 Glaxosmithkline Intellectual Property Development Limited derivatives of n- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pentan-1-yl) -2-cyclobutane-1-carboxamide and related compounds as inhibitors of atf4 for treatment against cancer and other diseases
GB201710973D0 (en) 2017-07-07 2017-08-23 Avacta Life Sciences Ltd Scaffold proteins
CN110869021B (en) 2017-07-10 2023-06-30 细胞基因公司 Antiproliferative compounds and methods of use thereof
CA3066514A1 (en) 2017-07-10 2019-01-17 Innate Pharma Siglec-9-neutralizing antibodies
CN107266572A (en) * 2017-07-13 2017-10-20 无锡傲锐东源生物科技有限公司 Anti- PD L1 protein monoclonal antibodies and application thereof
CN111793060B (en) 2017-07-14 2023-06-06 先天肿瘤免疫公司 NLRP3 modulators
EP3655542A1 (en) 2017-07-18 2020-05-27 Institut Gustave Roussy Method for assessing the response to pd-1/pdl-1 targeting drugs
JP2020527572A (en) 2017-07-20 2020-09-10 ノバルティス アーゲー Anti-LAG-3 antibody dosage regimen and its use
MX2020000604A (en) 2017-07-21 2020-09-10 Genentech Inc Therapeutic and diagnostic methods for cancer.
US11926664B2 (en) 2017-07-25 2024-03-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for modulating monocytopoiesis
WO2019021208A1 (en) 2017-07-27 2019-01-31 Glaxosmithkline Intellectual Property Development Limited Indazole derivatives useful as perk inhibitors
EP3658914A1 (en) 2017-07-28 2020-06-03 Bristol-Myers Squibb Company Predictive peripheral blood biomarker for checkpoint inhibitors
MX2020001233A (en) 2017-08-03 2020-07-20 Otsuka Pharma Co Ltd Drug compound and purification methods thereof.
WO2019027857A1 (en) 2017-08-04 2019-02-07 Merck Sharp & Dohme Corp. COMBINATIONS OF PD-1 ANTAGONISTS AND BENZO[b]THIOPHENE STING AGONISTS FOR CANCER TREATMENT
KR102758346B1 (en) 2017-08-04 2025-01-24 젠맵 에이/에스 Binding agent that binds to PD-L1 and CD137 and uses thereof
JP7670481B2 (en) 2017-08-04 2025-04-30 バイスクルテクス・リミテッド Bicyclic peptide ligands specific for CD137 - Patent application
WO2019027858A1 (en) 2017-08-04 2019-02-07 Merck Sharp & Dohme Corp. BENZO[b]THIOPHENE STING AGONISTS FOR CANCER TREATMENT
EP3664844A1 (en) 2017-08-07 2020-06-17 Amgen Inc. Treatment of triple negative breast cancer or colorectal cancer with liver metastases with an anti pd-l1 antibody and an oncolytic virus
US10508115B2 (en) 2017-08-16 2019-12-17 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having heteroatom-linked aromatic moieties, conjugates thereof, and methods and uses therefor
US10487084B2 (en) 2017-08-16 2019-11-26 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a heterobiaryl moiety, conjugates thereof, and methods and uses therefor
US10472361B2 (en) 2017-08-16 2019-11-12 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a benzotriazole moiety, conjugates thereof, and methods and uses therefor
US10457681B2 (en) 2017-08-16 2019-10-29 Bristol_Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a tricyclic moiety, conjugates thereof, and methods and uses therefor
WO2019035938A1 (en) 2017-08-16 2019-02-21 Elstar Therapeutics, Inc. Multispecific molecules that bind to bcma and uses thereof
US10494370B2 (en) 2017-08-16 2019-12-03 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a pyridine or pyrazine moiety, conjugates thereof, and methods and uses therefor
KR20200051646A (en) 2017-08-17 2020-05-13 이케나 온콜로지, 인코포레이티드 AHR inhibitors and uses thereof
KR20240138135A (en) 2017-08-25 2024-09-20 파이브 프라임 테라퓨틱스, 인크. B7-h4 antibodies and methods of use thereof
KR20200044899A (en) 2017-08-28 2020-04-29 브리스톨-마이어스 스큅 컴퍼니 TIM-3 antagonist for the treatment and diagnosis of cancer
CN111278854A (en) 2017-09-04 2020-06-12 艾吉纳斯公司 T cell receptors that bind to mixed lineage leukemia (MLL) specific phosphopeptides and methods of use thereof
TW201922721A (en) 2017-09-07 2019-06-16 英商葛蘭素史克智慧財產發展有限公司 Chemical compounds
WO2019051164A1 (en) 2017-09-07 2019-03-14 Augusta University Research Institute, Inc. Antibodies to programmed cell death protein 1
JP7196160B2 (en) 2017-09-12 2022-12-26 スミトモ ファーマ オンコロジー， インコーポレイテッド Treatment Regimens for Cancers Insensitive to BCL-2 Inhibitors Using the MCL-1 Inhibitor Albocidib
WO2019053617A1 (en) 2017-09-12 2019-03-21 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
US20210060158A1 (en) 2017-09-19 2021-03-04 Institut Curie Agonist of aryl hydrocarbon receptor for use in cancer combination therapy
WO2019059411A1 (en) 2017-09-20 2019-03-28 Chugai Seiyaku Kabushiki Kaisha Dosage regimen for combination therapy using pd-1 axis binding antagonists and gpc3 targeting agent
MX2020003190A (en) 2017-09-22 2020-11-11 Kymera Therapeutics Inc Protein degraders and uses thereof.
US11358948B2 (en) 2017-09-22 2022-06-14 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
KR20200058506A (en) 2017-10-03 2020-05-27 브리스톨-마이어스 스큅 컴퍼니 Immunomodulators
EA039662B1 (en) 2017-10-03 2022-02-24 Закрытое Акционерное Общество "Биокад" Antibodies specific to cd47 and pd-l1
JP2020536106A (en) 2017-10-05 2020-12-10 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Interferon gene stimulator (STING) regulator useful for the treatment of HIV
JP7291130B2 (en) 2017-10-05 2023-06-14 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド A modulator of the stimulator of the interferon gene (STING)
KR102710877B1 (en) 2017-10-06 2024-09-26 이나뜨 파르마 에스.에이. Restoration of T cell activation through the CD39/CD73 axis
WO2019074822A1 (en) 2017-10-09 2019-04-18 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11203592B2 (en) 2017-10-09 2021-12-21 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CA3075337A1 (en) 2017-10-10 2019-04-18 Numab Therapeutics AG Antibodies targeting cd137 and methods of use thereof
MX2020003562A (en) 2017-10-10 2020-10-01 Numab Therapeutics AG Multispecific antibody.
EP3470426A1 (en) 2017-10-10 2019-04-17 Numab Therapeutics AG Multispecific antibody
AU2018347582B2 (en) 2017-10-13 2025-08-28 Harpoon Therapeutics, Inc. Trispecific proteins and methods of use
CN111511766B (en) 2017-10-13 2024-06-07 Ose免疫疗法 Modified anti-SIRPa antibodies and uses thereof
IL315737A (en) 2017-10-13 2024-11-01 Harpoon Therapeutics Inc B cell maturation antigen binding proteins
WO2019075468A1 (en) 2017-10-15 2019-04-18 Bristol-Myers Squibb Company Methods of treating tumor
EP4488366A3 (en) 2017-10-18 2025-03-12 Vivia Biotech, S.L. Bite-activated car-t cells
TW202500579A (en) 2017-10-18 2025-01-01 美商艾爾潘免疫科學有限公司 Variant icos ligand immunomodulatory proteins and related compositions and methods
KR20200072507A (en) 2017-10-19 2020-06-22 데비오팜 인터네셔날 에스 에이 Combination products for cancer treatment
WO2019081983A1 (en) 2017-10-25 2019-05-02 Novartis Ag Antibodies targeting cd32b and methods of use thereof
US11718679B2 (en) 2017-10-31 2023-08-08 Compass Therapeutics Llc CD137 antibodies and PD-1 antagonists and uses thereof
MA49911A (en) 2017-11-01 2020-06-24 Juno Therapeutics Inc ANTIBODIES AND CHEMERICAL ANTIGENIC RECEPTORS SPECIFIC TO THE B-LYMPHOCYTE MATURATION ANTIGEN
US12275729B2 (en) 2017-11-01 2025-04-15 Merck Sharp & Dohme Llc Substituted tetrahydroquinolin compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
TW201932482A (en) 2017-11-01 2019-08-16 美商奇諾治療有限公司 Chimeric antigen receptor and polynucleotide encoding specific for B cell maturation antigen
US12031975B2 (en) 2017-11-01 2024-07-09 Juno Therapeutics, Inc. Methods of assessing or monitoring a response to a cell therapy
JP2021501801A (en) 2017-11-01 2021-01-21 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Immunostimulatory agonist antibody for use in the treatment of cancer
ES2925450T3 (en) 2017-11-06 2022-10-18 Bristol Myers Squibb Co Isofuranone compounds useful as HPK1 inhibitors
WO2019090364A1 (en) 2017-11-06 2019-05-09 Juno Therapeutics, Inc. Combination of a cell therapy and a gamma secretase inhibitor
ES2984919T3 (en) 2017-11-06 2024-10-31 Hoffmann La Roche Diagnostic and therapeutic procedures for cancer
US20210292415A1 (en) 2017-11-06 2021-09-23 Bristol-Myers Squibb Company Methods of treating a tumor
JP7544598B2 (en) 2017-11-10 2024-09-03 アーモ・バイオサイエンシーズ・インコーポレイテッド Compositions and methods of use of interleukin-10 in combination with immune checkpoint pathway inhibitors
AR113878A1 (en) 2017-11-14 2020-06-24 Merck Sharp & Dohme BIARYL COMPOUNDS SUBSTITUTED AS INHIBITORS OF INDOLAMINE 2,3-DIOXYGENASE (IDO)
CA3082287C (en) 2017-11-14 2023-02-28 Pfizer Inc. Ezh2 inhibitor combination therapies
US11498904B2 (en) 2017-11-14 2022-11-15 Merck Sharp & Dohme Llc Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US20200277573A1 (en) 2017-11-17 2020-09-03 Iovance Biotherapeutics, Inc. Til expansion from fine needle aspirates and small biopsies
EP3710455A1 (en) 2017-11-17 2020-09-23 Novartis AG Novel dihydroisoxazole compounds and their use for the treatment of hepatitis b
MA50900A (en) 2017-11-17 2020-09-23 Merck Sharp & Dohme TRANSCRIT 3 SPECIFIC ANTIBODIES OF IMMUNOGLOBULIN TYPE (ILT3) AND THEIR USES
JP7408036B2 (en) 2017-11-24 2024-01-05 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル Methods and compositions for treating cancer
EP3717021A1 (en) 2017-11-27 2020-10-07 Mersana Therapeutics, Inc. Pyrrolobenzodiazepine antibody conjugates
US11786529B2 (en) 2017-11-29 2023-10-17 Beigene Switzerland Gmbh Treatment of indolent or aggressive B-cell lymphomas using a combination comprising BTK inhibitors
CA3083949A1 (en) 2017-11-30 2020-06-06 Novartis Ag Bcma-targeting chimeric antigen receptor, and uses thereof
CN111356702B (en) * 2017-12-06 2022-07-26 正大天晴药业集团南京顺欣制药有限公司 anti-PD-L1 antibodies and antigen binding fragments thereof
US20200377571A1 (en) 2017-12-08 2020-12-03 Elstar Therapeutics, Inc. Multispecific molecules and uses thereof
US11946094B2 (en) 2017-12-10 2024-04-02 Augusta University Research Institute, Inc. Combination therapies and methods of use thereof
CN112204048A (en) 2017-12-15 2021-01-08 朱诺治疗学股份有限公司 Anti-CCT5 binding molecules and methods of use
JP7317014B2 (en) 2017-12-15 2023-07-28 ヤンセン バイオテツク，インコーポレーテツド Cyclic dinucleotides as STING agonists
CN111741976B (en) 2017-12-19 2024-09-17 英沃克斯制药有限公司 FC binding fragment including PD-L1 antigen binding site
GB201721338D0 (en) 2017-12-19 2018-01-31 Kymab Ltd Anti-icos Antibodies
WO2019125846A1 (en) 2017-12-19 2019-06-27 The Rockefeller University HUMAN IgG Fc DOMAIN VARIANTS WITH IMPROVED EFFECTOR FUNCTION
WO2019122882A1 (en) 2017-12-19 2019-06-27 Kymab Limited Bispecific antibody for icos and pd-l1
EP3727401A4 (en) 2017-12-20 2022-04-06 Merck Sharp & Dohme Corp. Cyclic di-nucleotide compounds as sting agonists
US11234977B2 (en) 2017-12-20 2022-02-01 Novartis Ag Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals
CN111757757A (en) 2017-12-21 2020-10-09 梅尔莎纳医疗公司 Pyrrolobenzodiazepine antibody conjugates
IL315310A (en) 2017-12-26 2024-10-01 Kymera Therapeutics Inc IRAK joints and used in them
WO2019129054A1 (en) 2017-12-27 2019-07-04 信达生物制药(苏州)有限公司 Triabody, preparation method and use thereof
CN111788227B (en) 2017-12-27 2025-02-25 百时美施贵宝公司 Anti-CD40 antibodies and uses thereof
WO2019129137A1 (en) 2017-12-27 2019-07-04 信达生物制药(苏州)有限公司 Anti-lag-3 antibody and uses thereof
CN109970856B (en) 2017-12-27 2022-08-23 信达生物制药(苏州)有限公司 anti-LAG-3 antibodies and uses thereof
CN115925943A (en) * 2017-12-27 2023-04-07 信达生物制药(苏州)有限公司 Anti-PD-L1 antibodies and uses thereof
SG11202006200RA (en) 2017-12-28 2020-07-29 Massachusetts Gen Hospital Targeting the cbm signalosome complex induces regulatory t cells to inflame the tumor microenvironment
EP3731850A4 (en) 2017-12-29 2021-12-01 Oncorus, Inc. ONCOLYTIC VIRAL ADMINISTRATION OF THERAPEUTIC POLYPEPTIDES
CA3082036A1 (en) * 2017-12-29 2019-07-04 Ap Biosciences, Inc. Monospecific and bispecific proteins with immune checkpoint regulation for cancer therapy
WO2019134946A1 (en) 2018-01-04 2019-07-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma resistant
US11324774B2 (en) 2018-01-05 2022-05-10 Augusta University Research Institute, Inc. Compositions of oral alkaline salts and metabolic acid inducers and uses thereof
US11447449B2 (en) 2018-01-05 2022-09-20 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11713446B2 (en) 2018-01-08 2023-08-01 Iovance Biotherapeutics, Inc. Processes for generating TIL products enriched for tumor antigen-specific T-cells
WO2019136459A1 (en) 2018-01-08 2019-07-11 Iovance Biotherapeutics, Inc. Processes for generating til products enriched for tumor antigen-specific t-cells
WO2019136456A1 (en) 2018-01-08 2019-07-11 Iovance Biotherapeutics, Inc. Processes for generating til products enriched for tumor antigen-specific t-cells
WO2019136432A1 (en) 2018-01-08 2019-07-11 Novartis Ag Immune-enhancing rnas for combination with chimeric antigen receptor therapy
US11407723B2 (en) 2018-01-09 2022-08-09 Shuttle Pharmaceuticals, Inc. Selective histone deacetylase inhibitors for the treatment of human disease
WO2019139987A1 (en) 2018-01-09 2019-07-18 Elstar Therapeutics, Inc. Calreticulin binding constructs and engineered t cells for the treatment of diseases
BR112020013475A2 (en) * 2018-01-10 2020-12-08 Jiangsu Hengrui Medicine Co., Ltd. PD-L1 ANTIBODY, ANTIGEN BINDING FRAGMENT OF THE SAME, AND PHARMACEUTICAL USE OF THE SAME
US12129297B2 (en) 2018-01-12 2024-10-29 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
CN111770936A (en) 2018-01-12 2020-10-13 百时美施贵宝公司 Anti-IL-8 Antibody and Anti-PD-1 Antibody Combination Therapy for Cancer
EP3737666A4 (en) 2018-01-12 2022-01-05 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US12128018B2 (en) 2018-01-12 2024-10-29 KDAc Therapeutics, Inc. Combination of a selective histone deacetylase 3 (HDAC3) inhibitor and an immunotherapy agent for the treatment of cancer
WO2019140387A1 (en) 2018-01-12 2019-07-18 Kymera Therapeutics, Inc. Crbn ligands and uses thereof
US20210363242A1 (en) 2018-01-16 2021-11-25 Bristol-Myers Squibb Company Methods of treating cancer with antibodies against tim3
WO2019143884A1 (en) * 2018-01-19 2019-07-25 Vanderbilt University Conserved hiv antibody clonotypes and methods of use
WO2019144098A1 (en) 2018-01-22 2019-07-25 Bristol-Myers Squibb Company Compositions and methods of treating cancer
WO2019144126A1 (en) 2018-01-22 2019-07-25 Pascal Biosciences Inc. Cannabinoids and derivatives for promoting immunogenicity of tumor and infected cells
US12398209B2 (en) 2018-01-22 2025-08-26 Janssen Biotech, Inc. Methods of treating cancers with antagonistic anti-PD-1 antibodies
AU2019211326A1 (en) 2018-01-23 2020-09-10 Nextcure, Inc. B7-H4 antibodies and methods of use thereof
US11786523B2 (en) 2018-01-24 2023-10-17 Beyondspring Pharmaceuticals, Inc. Composition and method for reducing thrombocytopenia
WO2019148089A1 (en) 2018-01-26 2019-08-01 Orionis Biosciences Inc. Xcr1 binding agents and uses thereof
US10988477B2 (en) 2018-01-29 2021-04-27 Merck Patent Gmbh GCN2 inhibitors and uses thereof
US10793563B2 (en) 2018-01-29 2020-10-06 Merck Patent Gmbh GCN2 inhibitors and uses thereof
CN111655730A (en) 2018-01-31 2020-09-11 豪夫迈·罗氏有限公司 Bispecific antibodies comprising an antigen-binding site that binds to LAG3
MA54118A (en) 2018-01-31 2021-09-15 Celgene Corp MULTIPLE THERAPY USING ADOPTIVE CELL THERAPY AND A CHECKPOINT INHIBITOR
CA3090249A1 (en) 2018-01-31 2019-08-08 Novartis Ag Combination therapy using a chimeric antigen receptor
CA3090406A1 (en) 2018-02-05 2019-08-08 Orionis Biosciences, Inc. Fibroblast binding agents and use thereof
US20200405806A1 (en) 2018-02-08 2020-12-31 Bristol-Myers Squibb Company Combination of a tetanus toxoid, anti-ox40 antibody and/or anti-pd-1 antibody to treat tumors
NL2020422B1 (en) 2018-02-12 2019-08-19 Stichting Het Nederlands Kanker Inst Antoni Van Leeuwenhoek Ziekenhuis Methods for Predicting Treatment Outcome and/or for Selecting a Subject Suitable for Immune Checkpoint Therapy.
EP4227302A1 (en) 2018-02-13 2023-08-16 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2019160956A1 (en) 2018-02-13 2019-08-22 Novartis Ag Chimeric antigen receptor therapy in combination with il-15r and il15
WO2019160866A2 (en) 2018-02-13 2019-08-22 Checkmate Pharmaceuticals, Inc. Compositions and methods for tumor immunotherapy
CA3091174A1 (en) 2018-02-21 2019-08-29 Five Prime Therapeutics, Inc. B7-h4 antibody formulations
EP3756012A1 (en) 2018-02-21 2020-12-30 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors
MX2020008791A (en) 2018-02-23 2021-01-08 Bicycletx Ltd Multimeric bicyclic peptide ligands.
WO2019165315A1 (en) 2018-02-23 2019-08-29 Syntrix Biosystems Inc. Method for treating cancer using chemokine antagonists alone or in combination
US20200399376A1 (en) 2018-02-26 2020-12-24 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
TWI877770B (en) 2018-02-27 2025-03-21 美商英塞特公司 Imidazopyrimidines and triazolopyrimidines as a2a / a2b inhibitors
WO2019166951A1 (en) 2018-02-28 2019-09-06 Novartis Ag Indole-2-carbonyl compounds and their use for the treatment of hepatitis b
WO2019169229A1 (en) 2018-03-01 2019-09-06 Nextcure, Inc. Klrg1 binding compositions and methods of use thereof
MA52416A (en) 2018-03-02 2021-04-21 Five Prime Therapeutics Inc B7-H4 ANTIBODIES AND PROCESSES FOR USE
CN112119099A (en) 2018-03-02 2020-12-22 Cdr-生物科技股份有限公司 Trispecific antigen binding proteins
SG11202008113RA (en) 2018-03-05 2020-09-29 Arcus Biosciences Inc Arginase inhibitors
WO2019170727A1 (en) 2018-03-06 2019-09-12 Institut Curie Inhibitor of setdb1 histone methyltransferase for use in cancer combination therapy
CN112218658A (en) 2018-03-12 2021-01-12 国家健康科学研究所 Use of caloric restriction mimetics for enhancing chemoimmunotherapy for cancer treatment
BR112020017709A2 (en) 2018-03-13 2020-12-29 Ose Immunotherapeutics HUMAN ANTI-SIRPA ANTIBODY, ANTIGEN BINDING FRAGMENT OF THE SAME OR MODIFIED ANTIBODY OF THE SAME, PHARMACEUTICAL COMPOSITION, USE OF A POLYPEPTIDE, METHODS OF PREPARING AN ANTI-HUMAN ANTIBODY FOR HUMAN VENTURE PROBABILITY OF EFFECTIVENESS OF A TREATMENT, IN VITRO OR EX VIVO METHOD TO EVALUATE THE PROBABILITY OF EFFECTIVENESS OF A TREATMENT, AND, COMBINATION OF COMPOUNDS
EP3765006A4 (en) 2018-03-13 2022-02-23 Merck Sharp & Dohme Corp. Arginase inhibitors and methods of use
WO2019178269A2 (en) 2018-03-14 2019-09-19 Surface Oncology, Inc. Antibodies that bind cd39 and uses thereof
EP3765517A1 (en) 2018-03-14 2021-01-20 Elstar Therapeutics, Inc. Multifunctional molecules that bind to calreticulin and uses thereof
WO2019178364A2 (en) 2018-03-14 2019-09-19 Elstar Therapeutics, Inc. Multifunctional molecules and uses thereof
WO2019175243A1 (en) 2018-03-14 2019-09-19 Merck Patent Gmbh Compounds and uses thereof to treat tumors in a subject
KR20210003099A (en) * 2018-03-19 2021-01-11 아베오미 코포레이션 High Affinity Neutralizing Monoclonal Antibody to Prospective Cell Death Ligand 1 (PD-L1) and Use thereof
EP3768716A1 (en) 2018-03-21 2021-01-27 Five Prime Therapeutics, Inc. Antibodies binding to vista at acidic ph
TWI723354B (en) * 2018-03-21 2021-04-01 中國醫藥大學 Engineering stem cells for cancer therapy
WO2019183499A1 (en) 2018-03-22 2019-09-26 Surface Oncology, Inc. Anti-il-27 antibodies and uses thereof
WO2019183551A1 (en) 2018-03-23 2019-09-26 Bristol-Myers Squibb Company Antibodies against mica and/or micb and uses thereof
CN110305210B (en) 2018-03-27 2023-02-28 信达生物制药(苏州)有限公司 Novel antibody molecules, methods of making and uses thereof
WO2019184909A1 (en) 2018-03-27 2019-10-03 信达生物制药(苏州)有限公司 Novel antibody molecule, and preparation method and use thereof
CA3094241A1 (en) * 2018-03-27 2019-10-03 Laboratory Corporation Of America Holdings Compositions and methods for identifying subjects who may benefit from treatment with therapeutic agents
WO2019185792A1 (en) 2018-03-29 2019-10-03 Philogen S.P.A Cancer treatment using immunoconjugates and immune check-point inhibitors
AU2019241345A1 (en) * 2018-03-29 2020-10-15 Adagene Inc. Anti-PD-L1 antibodies and use thereof
MX2020010264A (en) 2018-03-29 2020-11-06 Iovance Biotherapeutics Inc Processes for production of tumor infiltrating lymphocytes and uses of same in immunotherapy.
CA3095758A1 (en) 2018-03-30 2019-10-03 Incyte Corporation Heterocyclic compounds as immunomodulators
JP2021519771A (en) 2018-03-30 2021-08-12 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ How to treat a tumor
US11702430B2 (en) 2018-04-03 2023-07-18 Merck Sharp & Dohme Llc Aza-benzothiophene compounds as STING agonists
US10793557B2 (en) 2018-04-03 2020-10-06 Merck Sharp & Dohme Corp. Sting agonist compounds
CN112292399A (en) 2018-04-04 2021-01-29 百时美施贵宝公司 anti-CD27 antibodies and uses thereof
US11874276B2 (en) 2018-04-05 2024-01-16 Dana-Farber Cancer Institute, Inc. STING levels as a biomarker for cancer immunotherapy
WO2019193540A1 (en) 2018-04-06 2019-10-10 Glaxosmithkline Intellectual Property Development Limited Heteroaryl derivatives of formula (i) as atf4 inhibitors
WO2019193541A1 (en) 2018-04-06 2019-10-10 Glaxosmithkline Intellectual Property Development Limited Bicyclic aromatic ring derivatives of formula (i) as atf4 inhibitors
KR20210006905A (en) 2018-04-09 2021-01-19 체크메이트 파마슈티칼스 Packaging of oligonucleotides into virus-like particles
CN115991778A (en) * 2018-04-09 2023-04-21 原启生物科技(上海)有限责任公司 anti-PD-L1 antibodies and uses thereof
BR112020020826A2 (en) 2018-04-12 2021-01-19 Bristol-Myers Squibb Company ANTICANCER COMBINATION THERAPY WITH CD73 ANTAGONIST ANTIBODY AND PD-1 / PD-L1 AXIS ANTIBODY
US20210147547A1 (en) 2018-04-13 2021-05-20 Novartis Ag Dosage Regimens For Anti-Pd-L1 Antibodies And Uses Thereof
CA3096460A1 (en) * 2018-04-15 2019-10-24 Immvira Co., Limited Antibodies binding pd-1 and uses thereof
AU2019255196A1 (en) 2018-04-16 2020-11-12 Arrys Therapeutics, Inc. EP4 inhibitors and use thereof
CN111989095A (en) 2018-04-16 2020-11-24 上海岸阔医药科技有限公司 Methods of preventing or treating side effects of tumor therapy
CA3096894A1 (en) 2018-04-17 2019-10-24 Tempest Therapeutics, Inc. Bicyclic carboxamides and methods of use thereof
SG11202010011RA (en) 2018-04-17 2020-11-27 Celldex Therapeutics Inc Anti-cd27 and anti-pd-l1 antibodies and bispecific constructs
WO2019204272A1 (en) 2018-04-17 2019-10-24 Molecular Templates, Inc. Her2-targeting molecules comprising de-immunized, shiga toxin a subunit scaffolds
JP2021521784A (en) 2018-04-18 2021-08-30 ゼンコア インコーポレイテッド PD-1 targeted heterodimer fusion proteins containing IL-15 / IL-15RaFc fusion proteins and PD-1 antigen binding domains and their use
IL310398A (en) 2018-04-18 2024-03-01 Xencor Inc Il-15/il-15rα heterodimeric fc fusion proteins and uses thereof
CN112041311B (en) 2018-04-19 2023-10-03 吉利德科学公司 PD-1/PD-L1 inhibitors
CN119286871A (en) 2018-04-19 2025-01-10 查美特制药公司 Synthetic RIG-I-like receptor agonists
EP3781687A4 (en) 2018-04-20 2022-02-09 Merck Sharp & Dohme Corp. Novel substituted rig-i agonists: compositions and methods thereof
US11485741B2 (en) 2018-04-24 2022-11-01 Bristol-Myers Squibb Company Macrocyclic toll-like receptor 7 (TLR7) agonists
NZ769136A (en) 2018-04-25 2024-04-26 Innate Tumor Immunity Inc Nlrp3 modulators
TW202012430A (en) 2018-04-26 2020-04-01 美商艾吉納斯公司 Heat shock protein-binding peptide compositions and methods of use thereof
WO2019207030A1 (en) 2018-04-26 2019-10-31 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting a response with an immune checkpoint inhibitor in a patient suffering from a lung cancer
TW202446952A (en) 2018-04-27 2024-12-01 美商艾歐凡斯生物治療公司 Gene editing of tumor infiltrating lymphocytes and uses of same in immunotherapy
WO2019210153A1 (en) 2018-04-27 2019-10-31 Novartis Ag Car t cell therapies with enhanced efficacy
WO2019213282A1 (en) 2018-05-01 2019-11-07 Novartis Ag Biomarkers for evaluating car-t cells to predict clinical outcome
US12048745B2 (en) 2018-05-01 2024-07-30 Augusta University Research Institute, Inc. Methods for detecting and reversing immune therapy resistance
CA3097916A1 (en) 2018-05-03 2019-11-07 Shanghai Epimab Biotherapeutics Co., Ltd. High affinity antibodies to pd-1 and lag-3 and bispecific binding proteins made therefrom
US12037323B2 (en) 2018-05-03 2024-07-16 Bristol-Myers Squibb Company Uracil derivatives as Mer-AXL inhibitors
JP7568512B2 (en) 2018-05-04 2024-10-16 インサイト・コーポレイション Salt of FGFR inhibitor
AU2019264232A1 (en) 2018-05-04 2020-11-12 Tollys TLR3 ligands that activate both epithelial and myeloid cells
JP2021522298A (en) 2018-05-04 2021-08-30 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ Simultaneous inhibition of PD-1 / PD-L1, TGFβ and DNA-PK for cancer treatment
FI3788047T3 (en) 2018-05-04 2024-11-02 Incyte Corp SOLID FORM OF FGFT INHIBITOR AND METHODS FOR THEIR PREPARATION
WO2019217753A1 (en) 2018-05-10 2019-11-14 Iovance Biotherapeutics, Inc. Processes for production of tumor infiltrating lymphocytes and uses of same in immunotherapy
SI4219492T1 (en) 2018-05-11 2025-04-30 Incyte Corporation Heterocyclic compounds as immunomodulators
KR102551319B1 (en) 2018-05-14 2023-07-05 길리애드 사이언시즈, 인코포레이티드 MCL-1 inhibitor
EA202092696A1 (en) 2018-05-15 2021-04-05 Медиммун Лимитед CANCER TREATMENT
GB201807924D0 (en) 2018-05-16 2018-06-27 Ctxt Pty Ltd Compounds
EP3794039A4 (en) * 2018-05-17 2022-05-04 Nanjing Leads Biolabs Co., Ltd. PD-1 BINDING ANTIBODIES AND USES THEREOF
US11168089B2 (en) 2018-05-18 2021-11-09 Incyte Corporation Fused pyrimidine derivatives as A2A / A2B inhibitors
ES2945214T3 (en) 2018-05-23 2023-06-29 Celgene Corp Antiproliferative compounds and bispecific antibody against BCMA and CD3 for combined use
WO2019226770A1 (en) 2018-05-23 2019-11-28 Celgene Corporation Treating multiple myeloma and the use of biomarkers for 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl) piperazin-1-yl)-3-fluorobenzonitrile
JP2021524449A (en) 2018-05-23 2021-09-13 アーデーセー セラピューティクス ソシエテ アノニム Molecular adjuvant
CA3101601A1 (en) 2018-05-29 2019-12-05 Bristol-Myers Squibb Company Modified self-immolating moieties for use in prodrugs and conjugates and methods of using and making
TWI869346B (en) 2018-05-30 2025-01-11 瑞士商諾華公司 Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
WO2019231870A1 (en) 2018-05-31 2019-12-05 Merck Sharp & Dohme Corp. Novel substituted [1.1.1] bicyclo compounds as indoleamine 2,3-dioxygenase inhibitors
US11932681B2 (en) 2018-05-31 2024-03-19 Novartis Ag Hepatitis B antibodies
WO2019232244A2 (en) 2018-05-31 2019-12-05 Novartis Ag Antibody molecules to cd73 and uses thereof
WO2019230919A1 (en) 2018-05-31 2019-12-05 小野薬品工業株式会社 Biomarker for judging efficacy of immune checkpoint inhibitor
TW202017569A (en) 2018-05-31 2020-05-16 美商佩樂敦治療公司 Compositions and methods for inhibiting cd73
WO2019227490A1 (en) * 2018-06-01 2019-12-05 Tayu Huaxia Biotech Medical Group Co., Ltd. Compositions and methods for imaging
EP3802579A1 (en) 2018-06-01 2021-04-14 The Board of Trustees of the Leland Stanford Junior University Il-13/il-4 superkines: immune cell targeting constructs and methods of use thereof
US20210205449A1 (en) 2018-06-01 2021-07-08 Novartis Ag Dosing of a bispecific antibody that bind cd123 and cd3
US11987629B2 (en) 2018-06-01 2024-05-21 Tayu Huaxia Biotech Medical Group Co., Ltd. Compositions and uses thereof for treating disease or condition
US11492409B2 (en) 2018-06-01 2022-11-08 Novartis Ag Binding molecules against BCMA and uses thereof
WO2019234576A1 (en) 2018-06-03 2019-12-12 Lamkap Bio Beta Ltd. Bispecific antibodies against ceacam5 and cd47
CN110563842B (en) 2018-06-06 2022-07-29 浙江博锐生物制药有限公司 Antibodies to programmed death ligand (PD-L1) and uses thereof
KR20210020932A (en) 2018-06-13 2021-02-24 노파르티스 아게 BCMA chimeric antigen receptor and uses thereof
CN112638375A (en) 2018-06-15 2021-04-09 旗舰创业创新五公司 Increasing immune activity through modulation of post-cellular signaling factors
WO2019243252A1 (en) 2018-06-18 2019-12-26 Innate Pharma Compositions and methods for treating cancer
CN112533629A (en) 2018-06-19 2021-03-19 阿尔莫生物科技股份有限公司 Compositions and methods for combined use of IL-10 agents with chimeric antigen receptor cell therapy
WO2019245890A1 (en) 2018-06-20 2019-12-26 Merck Sharp & Dohme Corp. Arginase inhibitors and methods of use
EP4349411A3 (en) 2018-06-20 2024-06-19 Incyte Corporation Anti-pd-1 antibodies and uses thereof
US11180531B2 (en) 2018-06-22 2021-11-23 Bicycletx Limited Bicyclic peptide ligands specific for Nectin-4
SG11202012446UA (en) 2018-06-23 2021-01-28 Genentech Inc Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor
SMT202300466T1 (en) 2018-06-27 2024-01-10 Bristol Myers Squibb Co Substituted naphthyridinone compounds useful as t cell activators
EA202190137A1 (en) 2018-06-27 2021-05-17 Бристол-Маерс Сквибб Компани NAPHTHYRIDINE COMPOUNDS FOR USE AS T-CELL ACTIVATORS
WO2020010250A2 (en) 2018-07-03 2020-01-09 Elstar Therapeutics, Inc. Anti-tcr antibody molecules and uses thereof
CR20240054A (en) 2018-07-05 2024-02-26 Incyte Corp FUSED PYRAZINE DERIVATIVES AS A2A/A2B INHIBITORS (Div. 2021-71)
US11292792B2 (en) 2018-07-06 2022-04-05 Kymera Therapeutics, Inc. Tricyclic CRBN ligands and uses thereof
CA3105942A1 (en) 2018-07-09 2020-01-16 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
JP7411627B2 (en) 2018-07-09 2024-01-11 ファイヴ プライム セラピューティクス インク Antibody that binds to ILT4
TW202035448A (en) * 2018-07-09 2020-10-01 中國大陸商上海岸邁生物科技有限公司 Efficiently expressed egfr and pd-l1 bispecific binding proteins
HRP20231295T1 (en) 2018-07-10 2024-02-02 Novartis Ag 3-(5-HYDROXY-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE DERIVATIVES AND THEIR USE IN THE TREATMENT OF IKAROS FAMILY ZINC FINGER 2 (IKZF2) DEPENDENT DISEASES
AR116109A1 (en) 2018-07-10 2021-03-31 Novartis Ag DERIVATIVES OF 3- (5-AMINO-1-OXOISOINDOLIN-2-IL) PIPERIDINE-2,6-DIONA AND USES OF THE SAME
US12091462B2 (en) 2018-07-11 2024-09-17 Five Prime Therapeutics, Inc. Antibodies binding to vista at acidic pH
EP3820992A2 (en) 2018-07-11 2021-05-19 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof
WO2020011966A1 (en) 2018-07-12 2020-01-16 F-Star Beta Limited Antibody molecules that bind cd137 and ox40
GB201811410D0 (en) 2018-07-12 2018-08-29 F Star Beta Ltd OX40 Binding molecules
GB201811450D0 (en) 2018-07-12 2018-08-29 F Star Delta Ltd Mesothelin and CD137 binding molecules
JP7360440B2 (en) 2018-07-12 2023-10-12 エフ－スター セラピューティクス リミテッド Antibody molecules that bind to PD-L1 and CD137
GB201811408D0 (en) 2018-07-12 2018-08-29 F Star Beta Ltd CD137 Binding Molecules
GB201811415D0 (en) 2018-07-12 2018-08-29 F Star Beta Ltd Anti-Mesothelin Anti bodies
GB201811403D0 (en) 2018-07-12 2018-08-29 F Star Beta Ltd Antibody molecules
SI3618928T1 (en) 2018-07-13 2023-04-28 Alector Llc Anti-sortilin antibodies and methods of use thereof
CA3103286C (en) 2018-07-13 2023-05-09 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
US20210277135A1 (en) 2018-07-13 2021-09-09 Bristol-Myers Squibb Company Ox-40 agonist, pd-1 pathway inhibitor and ctla-4 inhibitor combination for use in a method of treating a cancer or a solid tumor
EP3823614A4 (en) 2018-07-18 2022-03-30 Arcus Biosciences, Inc. SOLID FORMS OF AN AZOLOPYRIMIDINE COMPOUND
AU2019305637A1 (en) 2018-07-18 2021-03-11 Genentech, Inc. Methods of treating lung cancer with a PD-1 axis binding antagonist, an antimetabolite, and a platinum agent
SG11202100373VA (en) 2018-07-20 2021-02-25 Surface Oncology Inc Anti-cd112r compositions and methods
WO2020023355A1 (en) 2018-07-23 2020-01-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2020023356A1 (en) 2018-07-23 2020-01-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN112533677A (en) 2018-07-24 2021-03-19 豪夫迈·罗氏有限公司 Naphthyridine compounds and uses thereof
EP3826722A1 (en) 2018-07-24 2021-06-02 F. Hoffmann-La Roche AG Isoquinoline compounds and uses thereof
US20210301020A1 (en) 2018-07-24 2021-09-30 Amgen Inc. Combination of lilrb1/2 pathway inhibitors and pd-1 pathway inhibitors
CN112041348B (en) 2018-07-25 2023-09-22 天境生物科技(上海)有限公司 Anti-CD73 anti-PD-L1 bispecific antibody
WO2020021061A1 (en) 2018-07-26 2020-01-30 Pieris Pharmaceuticals Gmbh Humanized anti-pd-1 antibodies and uses thereof
EP3826660A1 (en) 2018-07-26 2021-06-02 Bristol-Myers Squibb Company Lag-3 combination therapy for the treatment of cancer
US11554120B2 (en) 2018-08-03 2023-01-17 Bristol-Myers Squibb Company 1H-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (TLR7) agonists and methods and uses therefor
WO2020030634A1 (en) 2018-08-06 2020-02-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers
WO2020031107A1 (en) 2018-08-08 2020-02-13 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
US20210317461A1 (en) 2018-08-09 2021-10-14 Verseau Therapeutics, Inc. Oligonucleotide compositions for targeting ccr2 and csf1r and uses thereof
CN110423757B (en) * 2018-08-11 2021-03-30 广东天科雅生物医药科技有限公司 A kind of engineered nucleic acid, T cell and its application and production method
KR20210046022A (en) 2018-08-16 2021-04-27 인네이트 튜머 이뮤니티, 인코포레이티드 Substituted 4-amino-1H-imidazo[4,5-c]quinoline compound and improved preparation method thereof
EP3837015B1 (en) 2018-08-16 2024-02-14 Innate Tumor Immunity, Inc. Imidazo[4,5-c]quinoline derived nlrp3-modulators
CN113038989A (en) 2018-08-16 2021-06-25 先天肿瘤免疫公司 Imidazo [4,5-C ] quinoline-derived NLRP3 modulators
AU2019324388A1 (en) * 2018-08-20 2021-03-18 1Globe Biomedical Co., Ltd. Novel cancer immunotherapy antibody compositions
US20210246219A1 (en) 2018-08-27 2021-08-12 Pieris Pharmaceuticals Gmbh Combination therapies comprising cd137/her2 bispecific agents and pd-1 axis inhibitors and uses thereof
US10959986B2 (en) 2018-08-29 2021-03-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11253525B2 (en) 2018-08-29 2022-02-22 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2020044206A1 (en) 2018-08-29 2020-03-05 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors for use in the treatment cancer
TW202031273A (en) 2018-08-31 2020-09-01 美商艾歐凡斯生物治療公司 Treatment of nsclc patients refractory for anti-pd-1 antibody
US20210340279A1 (en) 2018-08-31 2021-11-04 Yale University Compositions and methods of using cell-penetrating antibodies in combination with immune checkpoint modulators
JP7535500B2 (en) 2018-09-03 2024-08-16 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Carboxamide and Sulfonamide Derivatives Useful as TEAD Modulators
WO2020048942A1 (en) 2018-09-04 2020-03-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for enhancing cytotoxic t lymphocyte-dependent immune responses
KR102846109B1 (en) 2018-09-07 2025-08-18 화이자 인코포레이티드 Anti-αvβ8 antibody and composition and use thereof
CN113164419A (en) 2018-09-07 2021-07-23 皮克医疗公司 EIF4E inhibitors and uses thereof
WO2020053742A2 (en) 2018-09-10 2020-03-19 Novartis Ag Anti-hla-hbv peptide antibodies
ES3014591T3 (en) 2018-09-11 2025-04-23 Curis Inc Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety
WO2020056008A1 (en) 2018-09-12 2020-03-19 Silverback Therapeutics, Inc. Compositions for the treatment of disease with immune stimulatory conjugates
CN113166113A (en) 2018-09-12 2021-07-23 希沃尔拜克治疗公司 Substituted benzazepine compounds, conjugates and uses thereof
US11072610B2 (en) 2018-09-12 2021-07-27 Novartis Ag Antiviral pyridopyrazinedione compounds
WO2020056194A1 (en) 2018-09-12 2020-03-19 Silverback Therapeutics, Inc. Benzazepine compounds, conjugates, and uses thereof
CN113164774A (en) 2018-09-12 2021-07-23 希沃尔拜克治疗公司 Antibody conjugates of TOLL-like receptor agonists
US20210317214A1 (en) 2018-09-13 2021-10-14 Merck Sharp & Dohme Corp. Combination therapy of a pd-1 antagonist and lag3 antagonist for treating patients with non-microsatellite instability-high or proficient mismatch repair colorectal cancer
CN109053891B (en) * 2018-09-17 2021-12-21 苏州泓迅生物科技股份有限公司 anti-PD-L1 antibody, and preparation method and application thereof
EP3852752A1 (en) 2018-09-19 2021-07-28 F. Hoffmann-La Roche AG Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof
US20220177587A1 (en) 2018-09-19 2022-06-09 Alpine Immune Sciences, Inc. Methods and uses of variant cd80 fusion proteins and related constructs
EP3853611A1 (en) 2018-09-19 2021-07-28 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for bladder cancer
CN113396160A (en) 2018-09-19 2021-09-14 国家医疗保健研究所 Methods and pharmaceutical compositions for treating cancer resistant to immune checkpoint therapy
KR20210064269A (en) 2018-09-20 2021-06-02 이오반스 바이오테라퓨틱스, 인크. Expansion of TILs from cryopreserved tumor samples
US12195544B2 (en) 2018-09-21 2025-01-14 Harpoon Therapeutics, Inc. EGFR binding proteins and methods of use
CA3111809A1 (en) 2018-09-21 2020-03-26 Genentech, Inc. Diagnostic methods for triple-negative breast cancer
CA3114038A1 (en) 2018-09-25 2020-04-02 Harpoon Therapeutics, Inc. Dll3 binding proteins and methods of use
EP3856251B1 (en) 2018-09-26 2024-10-09 Merck Patent GmbH Combination of a pd-1 antagonist, an atr inhibitor and a platinating agent for the treatment of cancer
US20220242957A1 (en) 2018-09-27 2022-08-04 Marengo Therapeutics, Inc. Csf1r/ccr2 multispecific antibodies
US20210347851A1 (en) 2018-09-28 2021-11-11 Novartis Ag Cd19 chimeric antigen receptor (car) and cd22 car combination therapies
EP3856779A1 (en) 2018-09-28 2021-08-04 Novartis AG Cd22 chimeric antigen receptor (car) therapies
SG11202100935TA (en) 2018-09-28 2021-02-25 Massachusetts Inst Technology Collagen-localized immunomodulatory molecules and methods thereof
WO2020065453A1 (en) 2018-09-29 2020-04-02 Novartis Ag Process of manufacture of a compound for inhibiting the activity of shp2
EP3856724A1 (en) 2018-09-30 2021-08-04 F. Hoffmann-La Roche AG Cinnoline compounds and for the treatment of hpk1-dependent disorders such as cancer
US20220040183A1 (en) 2018-10-01 2022-02-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of inhibitors of stress granule formation for targeting the regulation of immune responses
TW202024053A (en) 2018-10-02 2020-07-01 美商建南德克公司 Isoquinoline compounds and uses thereof
MA53822A (en) 2018-10-03 2021-08-11 Xencor Inc IL-12 HETERODIMER FC FUSION PROTEINS
TW202023558A (en) 2018-10-03 2020-07-01 美商建南德克公司 8-aminoisoquinoline compounds and uses thereof
KR20210072059A (en) 2018-10-09 2021-06-16 브리스톨-마이어스 스큅 컴퍼니 Anti-MerTK Antibodies to Treat Cancer
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
TW202446772A (en) 2018-10-11 2024-12-01 日商小野藥品工業股份有限公司 Sting agonist compound
EP3864047A2 (en) 2018-10-12 2021-08-18 Xencor, Inc. Pd-1 targeted il-15/il-15ralpha fc fusion proteins and uses in combination therapies thereof
JP2022502531A (en) 2018-10-12 2022-01-11 ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイションUniversity of Pittsburgh − Of the Commonwealth System of Higher Education Small polymer carrier for delivering the drug
US20210348238A1 (en) 2018-10-16 2021-11-11 Novartis Ag Tumor mutation burden alone or in combination with immune markers as biomarkers for predicting response to targeted therapy
WO2020081493A1 (en) * 2018-10-16 2020-04-23 Molecular Templates, Inc. Pd-l1 binding proteins
WO2020081381A1 (en) 2018-10-17 2020-04-23 Merck Sharp & Dohme Corp. Novel arylalkyl pyrazole compounds as indoleamine 2,3-dioxygenase inhibitors
MX2021004348A (en) 2018-10-18 2021-05-28 Genentech Inc DIAGNOSTIC AND THERAPEUTIC PROCEDURES FOR SARCOMATOID KIDNEY CANCER.
CN112955462B (en) 2018-10-18 2024-05-07 国家医疗保健研究所 Combination of βIG-H3 antagonist and immune checkpoint inhibitor for the treatment of solid tumors
DK3866850T3 (en) 2018-10-19 2024-10-14 Bristol Myers Squibb Co COMBINATION THERAPY AGAINST MELANOMA
BR112021007082A2 (en) 2018-10-22 2021-08-03 Glaxosmithkline Intellectual Property Development Limited dosage
KR20210080460A (en) 2018-10-23 2021-06-30 드래곤플라이 쎄라퓨틱스, 인크. Heterodimeric Fc-fused protein
JP2022505647A (en) 2018-10-23 2022-01-14 ブリストル－マイヤーズ スクイブ カンパニー How to treat a tumor
CN112955435B (en) 2018-10-24 2024-09-06 吉利德科学公司 PD-1/PD-L1 inhibitors
KR20210084552A (en) 2018-10-29 2021-07-07 위스콘신 얼럼나이 리서어치 화운데이션 Dendritic Polymer Complexed with Immune Checkpoint Inhibitors for Enhanced Cancer Immunotherapy
US11564995B2 (en) 2018-10-29 2023-01-31 Wisconsin Alumni Research Foundation Peptide-nanoparticle conjugates
BR112021008012A2 (en) 2018-10-29 2021-11-03 Mersana Therapeutics Inc Engineered cysteine antibody-drug conjugates with peptide-containing linkers
US20230053449A1 (en) 2018-10-31 2023-02-23 Novartis Ag Dc-sign antibody drug conjugates
AU2019372331A1 (en) 2018-11-01 2021-05-27 Juno Therapeutics, Inc. Methods for treatment using chimeric antigen receptors specific for B-cell maturation antigen
US12091405B2 (en) 2018-11-01 2024-09-17 Merck Sharp & Dohme Llc Substituted pyrazole compounds as indoleamine 2,3-dioxygenase inhibitors
CN119569895A (en) 2018-11-01 2025-03-07 朱诺治疗学股份有限公司 G protein coupled receptor class C group 5 member D (GPRC 5D) specific chimeric antigen receptor
JP2022512915A (en) 2018-11-05 2022-02-07 アイオバンス バイオセラピューティクス，インコーポレイテッド Selection of improved tumor-reactive T cells
CR20210295A (en) 2018-11-05 2021-07-09 Iovance Biotherapeutics Inc Processes for production of tumor infiltrating lymphocytes and uses of the same in immunotherapy
SG11202104300PA (en) 2018-11-06 2021-05-28 Genmab As Antibody formulation
US12065438B2 (en) 2018-11-06 2024-08-20 Merck Sharp & Dohme Llc Substituted tricyclic compounds as indoleamine 2,3-dioxygenase inhibitors
WO2020097350A1 (en) 2018-11-08 2020-05-14 Orionis Biosciences, Inc. Modulation of dendritic cell lineages
US20220001026A1 (en) 2018-11-08 2022-01-06 Modernatx, Inc. Use of mrna encoding ox40l to treat cancer in human patients
JP2022512973A (en) 2018-11-09 2022-02-07 ピエリアン バイオサイエンシーズ リミテッド ライアビリティ カンパニー Methods and Compositions for Measuring the Composition of Tumor Microenvironments
EP3880716A4 (en) 2018-11-13 2022-08-03 Compass Therapeutics LLC Multispecific binding constructs against checkpoint molecules and uses thereof
TW202028222A (en) 2018-11-14 2020-08-01 美商Ionis製藥公司 Modulators of foxp3 expression
MX2021005686A (en) 2018-11-14 2021-07-07 Bayer Ag Pharmaceutical combination of anti-ceacam6 and either anti-pd-1 or anti-pd-l1 antibodies for the treatment of cancer.
DK3880186T3 (en) 2018-11-14 2024-06-03 Regeneron Pharma INTRALESIONAL ADMINISTRATION OF PD-1 INHIBITORS FOR THE TREATMENT OF SKIN CANCER
MX2021005651A (en) 2018-11-16 2021-09-10 Arqule Inc Pharmaceutical combination for treatment of cancer.
WO2020102728A1 (en) 2018-11-16 2020-05-22 Neoimmunetech, Inc. Method of treating a tumor with a combination of il-7 protein and an immune checkpoint inhibitor
MY205758A (en) 2018-11-16 2024-11-12 Bristol Myers Squibb Co Anti-nkg2a antibodies and uses thereof
MX2021005734A (en) 2018-11-16 2021-09-10 Juno Therapeutics Inc METHODS OF DOSING MODIFIED T CELLS FOR THE TREATMENT OF B CELL MALIGNANCIES.
KR102718333B1 (en) 2018-11-16 2024-10-17 아르커스 바이오사이언시즈 인코포레이티드 Inhibitors of ARG1 and/or ARG2
WO2020106560A1 (en) 2018-11-20 2020-05-28 Merck Sharp & Dohme Corp. Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use
EP3883964A1 (en) 2018-11-20 2021-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Bispecific antibody targeting transferrin receptor 1 and soluble antigen
MA55142A (en) 2018-11-20 2022-02-23 Merck Sharp & Dohme SUBSTITUTE AMINO-TRIAZOLOPYRIMIDINE AND AMINO-TRIAZOLOPYRAZINE ADENOSINE RECEPTOR ANTAGONIST, PHARMACEUTICAL COMPOSITIONS AND THEIR USE
WO2020104479A1 (en) 2018-11-20 2020-05-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers and resistant cancers with anti transferrin receptor 1 antibodies
EP3886842A1 (en) 2018-11-26 2021-10-06 Debiopharm International SA Combination treatment of hiv infections
KR20210095868A (en) 2018-11-27 2021-08-03 오노 야꾸힝 고교 가부시키가이샤 Cancer treatment by combination with immune checkpoint inhibitor and polpirinox therapy
JP2022513653A (en) 2018-11-28 2022-02-09 ブリストル－マイヤーズ スクイブ カンパニー Antibodies containing modified heavy chain constant regions
WO2020112581A1 (en) 2018-11-28 2020-06-04 Merck Sharp & Dohme Corp. Novel substituted piperazine amide compounds as indoleamine 2, 3-dioxygenase (ido) inhibitors
US20220018828A1 (en) 2018-11-28 2022-01-20 Inserm (Institut National De La Santé Et La Recherche Médicale Methods and kit for assaying lytic potential of immune effector cells
BR112021010484A2 (en) 2018-11-30 2021-08-24 Kymera Therapeutics, Inc. Irak degraders and their uses
SG11202105565UA (en) 2018-11-30 2021-06-29 Bristol Myers Squibb Co Antibody comprising a glutamine-containing light chain c-terminal extension, conjugates thereof, and methods and uses
JOP20210117A1 (en) 2018-11-30 2023-01-30 Merck Sharp & Dohme 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use
MY202884A (en) 2018-11-30 2024-05-28 Univ North Carolina Chapel Hill Compounds useful in hiv therapy
EP3886875B1 (en) 2018-11-30 2024-05-08 Juno Therapeutics, Inc. Methods for treatment using adoptive cell therapy
US12257340B2 (en) 2018-12-03 2025-03-25 Agensys, Inc. Pharmaceutical compositions comprising anti-191P4D12 antibody drug conjugates and methods of use thereof
CN113167802B (en) 2018-12-04 2025-02-07 百时美施贵宝公司 Analytical method using in-sample calibration curves by multi-isotopologue reaction monitoring
CA3119807A1 (en) 2018-12-04 2020-06-11 Sumitomo Dainippon Pharma Oncology, Inc. Cdk9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
KR20210100656A (en) 2018-12-05 2021-08-17 제넨테크, 인크. Diagnostic methods and compositions for cancer immunotherapy
WO2020115262A1 (en) 2018-12-07 2020-06-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of cd26 and cd39 as new phenotypic markers for assessing maturation of foxp3+ t cells and uses thereof for diagnostic purposes
WO2020115261A1 (en) 2018-12-07 2020-06-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
CN113195467A (en) 2018-12-11 2021-07-30 施万生物制药研发Ip有限责任公司 Naphthyridine and quinoline derivatives useful as ALK5 inhibitors
WO2020120592A1 (en) 2018-12-12 2020-06-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating melanoma
EP3894443A2 (en) 2018-12-12 2021-10-20 Bristol-Myers Squibb Company Antibodies modified for transglutaminase conjugation, conjugates thereof, and methods and uses
GB201820288D0 (en) 2018-12-13 2019-01-30 Bicycle Tx Ltd Bicycle peptide ligaands specific for MT1-MMP
GB201820325D0 (en) 2018-12-13 2019-01-30 Bicyclerd Ltd Bicyclic peptide ligands specific for psma
EP3894440A4 (en) 2018-12-13 2022-09-07 Surface Oncology, Inc. ANTI-IL-27 ANTIBODIES AND USES THEREOF
WO2020127059A1 (en) 2018-12-17 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of sulconazole as a furin inhibitor
US12240867B2 (en) 2018-12-18 2025-03-04 Merck Sharp & Dohme Llc Arginase inhibitors and methods of use
EP3898699A1 (en) 2018-12-19 2021-10-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers by immuno-modulation using antibodies against cathespin-d
US12221479B2 (en) 2018-12-19 2025-02-11 Bayer Aktiengesellschaft Pharmaceutical combination of anti CEACAM6 and TIM3 antibodies
AU2019402189B2 (en) 2018-12-20 2023-04-13 Novartis Ag Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2020132646A1 (en) 2018-12-20 2020-06-25 Xencor, Inc. Targeted heterodimeric fc fusion proteins containing il-15/il-15ra and nkg2d antigen binding domains
EP3670659A1 (en) 2018-12-20 2020-06-24 Abivax Biomarkers, and uses in treatment of viral infections, inflammations, or cancer
WO2020128637A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1 binding antibodies in the treatment of a msi-h cancer
CN113166762B (en) 2018-12-21 2025-01-14 瓦莱里奥治疗公司 New coupled nucleic acid molecules and their uses
EP3897613A1 (en) 2018-12-21 2021-10-27 Novartis AG Use of il-1beta binding antibodies
JP2022516850A (en) 2018-12-21 2022-03-03 ノバルティス アーゲー Use of IL-1β antibody in the treatment or prevention of myelodysplastic syndrome
EP4406555A3 (en) 2018-12-21 2024-11-06 Novartis AG Antibodies to pmel17 and conjugates thereof
US20220056123A1 (en) 2018-12-21 2022-02-24 Novartis Ag Use of il-1beta binding antibodies
WO2020127885A1 (en) 2018-12-21 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Compositions for treating cancers and resistant cancers
US20220370606A1 (en) 2018-12-21 2022-11-24 Pfizer Inc. Combination Treatments Of Cancer Comprising A TLR Agonist
SG11202106768RA (en) * 2018-12-27 2021-07-29 Gigagen Inc Anti-pd-l1 binding proteins and methods of use thereof
US12364723B2 (en) 2018-12-27 2025-07-22 Amgen Inc. Thermostable compositions comprising live attenuated herpes simplex virus type 1
US20220073626A1 (en) 2019-01-03 2022-03-10 Institut National De La Santé Et De La Recheche Médicale (Inserm) Methods and pharmaceutical compositions for enhancing cd8+ t cell-dependent immune responses in subjects suffering from cancer
CA3125756A1 (en) 2019-01-09 2020-07-16 Celgene Corporation Solid forms comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and salts thereof, and compositions comprising and methods of using the same
US11779580B2 (en) 2019-01-09 2023-10-10 Celgene Corporation Pharmaceutical compositions comprising (s)-4-(4-(4- (((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrtle and methods of using the
CN114404596A (en) 2019-01-09 2022-04-29 细胞基因公司 Antiproliferative compounds and second agents for the treatment of multiple myeloma
CA3124837A1 (en) 2019-01-14 2020-07-23 Genentech, Inc. Methods of treating cancer with a pd-1 axis binding antagonist and an rna vaccine
US12391675B2 (en) 2019-01-14 2025-08-19 Innate Tumor Immunity, Inc. NLRP3 modulators
JP7506079B2 (en) 2019-01-14 2024-06-25 イネイト・テューマー・イミュニティ・インコーポレイテッド Heterocyclic nlrp3 modulators for use in the treatment of cancer - Patents.com
US12187706B2 (en) 2019-01-14 2025-01-07 Innate Tumor Immunity, Inc. NLRP3 modulators
KR20210114983A (en) 2019-01-14 2021-09-24 인네이트 튜머 이뮤니티, 인코포레이티드 NLRP3 modulators
EP3911670B1 (en) 2019-01-15 2024-12-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Mutated interleukin-34 (il-34) polypeptides and uses thereof in therapy
US11116729B2 (en) 2019-01-17 2021-09-14 Georgia Tech Research Corporation Drug delivery systems containing oxidized cholesterols
US11235032B2 (en) 2019-01-23 2022-02-01 Massachusetts Institute Of Technology Combination immunotherapy dosing regimen for immune checkpoint blockade
JP7538130B2 (en) 2019-01-23 2024-08-21 タユー ファシャ バイオテック メディカル グループ カンパニー， リミテッド Anti-PD-L1 diabodies and uses thereof
JP7678753B2 (en) 2019-01-29 2025-05-16 ジュノー セラピューティクス インコーポレイテッド Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase-like orphan receptor 1 (ROR1)
TWI829857B (en) 2019-01-29 2024-01-21 美商英塞特公司 Pyrazolopyridines and triazolopyridines as a2a / a2b inhibitors
US20220107323A1 (en) 2019-01-30 2022-04-07 Inserm(Institut National De La Santé Et De La Recherche Médicale) Methods and compositions for identifying whether a subject suffering from a cancer will achieve a response with an immune-checkpoint inhibitor
WO2020160365A1 (en) 2019-02-01 2020-08-06 Glaxosmithkline Intellectual Property Development Limited Belantamab mafodotin in combination with pembrolizumab for treating cancer
US20220117911A1 (en) 2019-02-04 2022-04-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating blood-brain barrier
WO2020163589A1 (en) 2019-02-08 2020-08-13 Genentech, Inc. Diagnostic and therapeutic methods for cancer
CN113412262A (en) 2019-02-12 2021-09-17 大日本住友制药肿瘤公司 Formulations comprising heterocyclic protein kinase inhibitors
US20220098674A1 (en) 2019-02-13 2022-03-31 Inserm (Institut National De La Santé Et Dr La Recherch Médicale) Methods and compositions for selecting a cancer treatment in a subject suffering from cancer
JP7483732B2 (en) 2019-02-15 2024-05-15 ノバルティス アーゲー 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
EP3924521A4 (en) 2019-02-15 2023-03-29 IncellDx, Inc. BLADDER-ASSOCIATED SAMPLES TESTING, IDENTIFICATION AND TREATMENT OF BLADDER-ASSOCIATED NEOPLASIA, AND KITS FOR USE THEREON
CA3123519A1 (en) 2019-02-15 2020-08-20 Novartis Ag Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
CA3130210A1 (en) 2019-02-15 2020-08-20 Incyte Corporation Cyclin-dependent kinase 2 biomarkers and uses thereof
WO2020169472A2 (en) 2019-02-18 2020-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of inducing phenotypic changes in macrophages
SG11202109061YA (en) 2019-02-21 2021-09-29 Marengo Therapeutics Inc Multifunctional molecules that bind to t cell related cancer cells and uses thereof
SG11202108955QA (en) 2019-02-21 2021-09-29 Marengo Therapeutics Inc Antibody molecules that bind to nkp30 and uses thereof
MX2021010116A (en) * 2019-02-21 2021-09-23 Eucure Beijing Biopharma Co Ltd Anti-pd-l1 antibody and use thereof.
TWI877141B (en) 2019-02-27 2025-03-21 美商Ionis製藥公司 Modulators of malat1 expression
CA3137361A1 (en) 2019-02-28 2020-09-03 Regeneron Pharmaceuticals, Inc. Administration of pd-1 inhibitors for treating skin cancer
WO2020180959A1 (en) 2019-03-05 2020-09-10 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors
CA3131529A1 (en) 2019-03-05 2020-09-10 Amgen Inc. Use of oncolytic viruses for the treatment of cancer
SG11202109003QA (en) 2019-03-06 2021-09-29 Regeneron Pharma Il-4/il-13 pathway inhibitors for enhanced efficacy in treating cancer
WO2020185532A1 (en) 2019-03-08 2020-09-17 Incyte Corporation Methods of treating cancer with an fgfr inhibitor
US20220241313A1 (en) 2019-03-12 2022-08-04 Arcus Biosciences, Inc. Treatment of oncogene-driven cancers
MX2021010996A (en) 2019-03-14 2021-11-04 Genentech Inc Treatment of cancer with her2xcd3 bispecific antibodies in combination with anti-her2 mab.
TW202102542A (en) 2019-03-19 2021-01-16 瓦爾希伯倫私人腫瘤研究基金會 Combination therapy for the treatment of cancer
WO2020191326A1 (en) 2019-03-20 2020-09-24 Sumitomo Dainippon Pharma Oncology, Inc. Treatment of acute myeloid leukemia (aml) with venetoclax failure
CN113747895A (en) 2019-03-22 2021-12-03 大日本住友制药肿瘤公司 Compositions comprising PKM2 modulators and methods of treatment therewith
US20220041733A1 (en) 2019-03-28 2022-02-10 Bristol-Myers Squibb Company Methods of treating tumor
US20220195046A1 (en) 2019-03-28 2022-06-23 Bristol-Myers Squibb Company Methods of treating tumor
TW202102543A (en) 2019-03-29 2021-01-16 美商安進公司 Use of oncolytic viruses in the neoadjuvant therapy of cancer
JP7743309B2 (en) 2019-03-29 2025-09-24 アーカス バイオサイエンシズ インコーポレイティド Cancer treatment using identified adenosine fingerprints
WO2020205560A1 (en) 2019-03-29 2020-10-08 Incyte Corporation Sulfonylamide compounds as cdk2 inhibitors
AU2020254520A1 (en) 2019-03-29 2021-09-16 Genentech, Inc. Modulators of cell surface protein interactions and methods and compositions related to same
CN109929037B (en) * 2019-04-01 2023-03-17 华博生物医药技术（上海）有限公司 Conjugates to programmed death ligands and uses thereof
EP3947737A2 (en) 2019-04-02 2022-02-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of predicting and preventing cancer in patients having premalignant lesions
AU2020253990A1 (en) 2019-04-02 2021-10-28 Bicycletx Limited Bicycle toxin conjugates and uses thereof
US12281109B2 (en) 2019-04-04 2025-04-22 Merck Sharp & Dohme Llc Inhibitors of histone deacetylase-3 useful for the treatment of cancer, inflammation, neurodegeneration diseases and diabetes
BR112021019748A2 (en) 2019-04-05 2021-12-07 Kymera Therapeutics Inc Stat degraders and their uses
EP3952850A1 (en) 2019-04-09 2022-02-16 Institut National de la Santé et de la Recherche Médicale (INSERM) Use of sk2 inhibitors in combination with immune checkpoint blockade therapy for the treatment of cancer
EP3952903A1 (en) 2019-04-12 2022-02-16 Vascular Biogenics Ltd. Methods of anti-tumor therapy
WO2020212484A1 (en) 2019-04-17 2020-10-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treatment of nlrp3 inflammasome mediated il-1beta dependent disorders
WO2020215020A1 (en) * 2019-04-18 2020-10-22 Qlsf Biotherapeutics Inc. Humanized anti-pd-l1 antibodies
JP7593939B2 (en) 2019-04-19 2024-12-03 ジェネンテック， インコーポレイテッド Anti-MERTK antibodies and methods of use thereof
CA3136698A1 (en) 2019-04-23 2020-10-29 Innate Pharma Cd73 blocking antibodies
WO2020221796A1 (en) 2019-04-30 2020-11-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2020223233A1 (en) 2019-04-30 2020-11-05 Genentech, Inc. Prognostic and therapeutic methods for colorectal cancer
WO2020223469A1 (en) 2019-05-01 2020-11-05 Incyte Corporation N-(1-(methylsulfonyl)piperidin-4-yl)-4,5-di hydro-1h-imidazo[4,5-h]quinazolin-8-amine derivatives and related compounds as cyclin-dependent kinase 2 (cdk2) inhibitors for treating cancer
US20200345820A1 (en) 2019-05-01 2020-11-05 Sensei Biotherapeutics, Inc. Combination therapies for cancer
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
EP3962493A2 (en) 2019-05-03 2022-03-09 Flagship Pioneering Innovations V, Inc. Methods of modulating immune activity/level of irf or sting or of treating cancer, comprising the administration of a sting modulator and/or purinergic receptor modulator or postcellular signaling factor
CN114269376A (en) 2019-05-03 2022-04-01 豪夫迈·罗氏有限公司 Methods of treating cancer with anti-PD-L1 antibodies
EP3965816A1 (en) 2019-05-06 2022-03-16 MedImmune Limited Combination of monalizumab, durvalumab, chemotherapy and bevacizumab or cetuximab for the treatment of colorectal cancer
WO2020226633A1 (en) 2019-05-07 2020-11-12 Immunicom, Inc. Increasing responses to checkpoint inhibitors by extracorporeal apheresis
WO2020232378A1 (en) 2019-05-16 2020-11-19 Silicon Swat, Inc. Benzo[b][1,8]naphthyridine acetic acid derivatives and methods of use
WO2020232375A1 (en) 2019-05-16 2020-11-19 Silicon Swat, Inc. Oxoacridinyl acetic acid derivatives and methods of use
KR20220010525A (en) 2019-05-20 2022-01-25 메사추세츠 인스티튜트 오브 테크놀로지 Boronic acid ester prodrugs and uses thereof
US20220241412A1 (en) 2019-05-24 2022-08-04 Pfizer Inc. Combination therapies using cdk inhibitors
JP2022534967A (en) 2019-05-30 2022-08-04 ブリストル－マイヤーズ スクイブ カンパニー Multiple tumor gene signatures and their uses
EP3976832A1 (en) 2019-05-30 2022-04-06 Bristol-Myers Squibb Company Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy
CN114174537A (en) 2019-05-30 2022-03-11 百时美施贵宝公司 Cell localization features and combination therapies
MX2021014441A (en) 2019-05-31 2022-01-06 Ikena Oncology Inc Tead inhibitors and uses thereof.
WO2020248926A1 (en) 2019-06-10 2020-12-17 山东博安生物技术有限公司 BIFUNCTIONAL FUSION PROTEIN AGAINST PDL1 AND TGFβ AND USE THEREOF
US20210038684A1 (en) 2019-06-11 2021-02-11 Alkermes Pharma Ireland Limited Compositions and Methods for Cancer Immunotherapy
AU2020291012B2 (en) 2019-06-12 2025-09-25 AskGene Pharma, Inc. Novel IL-15 prodrugs and methods of use thereof
WO2020248156A1 (en) * 2019-06-12 2020-12-17 苏州工业园区唯可达生物科技有限公司 Pd-l1-targeting binding agent and use thereof
EP3986454A1 (en) 2019-06-18 2022-04-27 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and anti-pd-1 or anti-pd-l1 antibody
EP3986460A2 (en) 2019-06-18 2022-04-27 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and anti-pd-1 antibody
EP3991745A1 (en) 2019-06-25 2022-05-04 Innovent Biologics (Suzhou) Co., Ltd. Formulations containing anti-cd47/pd-l1 bispecific antibody and preparation method therefor and use thereof
US20230295313A1 (en) 2019-06-26 2023-09-21 Glaxosmithkline Intellectual Property Development Limited Il1rap binding proteins
EP3990491A1 (en) 2019-06-26 2022-05-04 Massachusetts Institute of Technology Immunomodulatory fusion protein-metal hydroxide complexes and methods thereof
WO2020260547A1 (en) 2019-06-27 2020-12-30 Rigontec Gmbh Design method for optimized rig-i ligands
CN114729383A (en) 2019-07-02 2022-07-08 弗莱德哈钦森癌症研究中心 Recombinant AD35 vector and related gene therapy improvement
JP2022539208A (en) 2019-07-03 2022-09-07 スミトモ ファーマ オンコロジー， インコーポレイテッド Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US20220356255A1 (en) * 2019-07-15 2022-11-10 Capella Bioscience Ltd Anti-pd-l1 antibodies
GB201910304D0 (en) 2019-07-18 2019-09-04 Ctxt Pty Ltd Compounds
GB201910305D0 (en) 2019-07-18 2019-09-04 Ctxt Pty Ltd Compounds
US12036204B2 (en) 2019-07-26 2024-07-16 Eisai R&D Management Co., Ltd. Pharmaceutical composition for treating tumor
US11083705B2 (en) 2019-07-26 2021-08-10 Eisai R&D Management Co., Ltd. Pharmaceutical composition for treating tumor
JP2022542437A (en) 2019-08-02 2022-10-03 ランティオペプ ベスローテン ヴェンノーツハップ Angiotensin type 2 (AT2) receptor agonists for treating cancer
JP7662156B2 (en) 2019-08-05 2025-04-15 小野薬品工業株式会社 Biomarkers for determining efficacy of immune checkpoint inhibitors
WO2021024020A1 (en) 2019-08-06 2021-02-11 Astellas Pharma Inc. Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer
US12098212B2 (en) 2019-08-12 2024-09-24 Purinomia Biotech, Inc. Methods and compositions for promoting and potentiating T-cell mediated immune responses through ADCC targeting of CD39 expressing cells
WO2021030537A1 (en) 2019-08-14 2021-02-18 Incyte Corporation Imidazolyl pyrimidinylamine compounds as cdk2 inhibitors
KR20220058555A (en) 2019-08-15 2022-05-09 실버백 테라퓨틱스, 인크. Formulations of benzazepine conjugates and uses thereof
GB201912107D0 (en) 2019-08-22 2019-10-09 Amazentis Sa Combination
US20220332827A1 (en) * 2019-08-23 2022-10-20 WuXi Biologics Ireland Limited Humanized antibodies against pd-l1
WO2021041532A1 (en) 2019-08-26 2021-03-04 Dana-Farber Cancer Institute, Inc. Use of heparin to promote type 1 interferon signaling
AR119821A1 (en) 2019-08-28 2022-01-12 Bristol Myers Squibb Co SUBSTITUTED PYRIDOPYRIMIDINOL COMPOUNDS USEFUL AS T-CELL ACTIVATORS
KR20220012856A (en) * 2019-08-29 2022-02-04 레메젠 코, 리미티드 Anti-PD-L1 antibody and uses thereof
PE20221151A1 (en) 2019-08-30 2022-07-18 Agenus Inc ANTI-CD96 ANTIBODIES AND THEIR METHODS OF USE
WO2021043961A1 (en) 2019-09-06 2021-03-11 Glaxosmithkline Intellectual Property Development Limited Dosing regimen for the treatment of cancer with an anti icos agonistic antibody and chemotherapy
WO2021048292A1 (en) 2019-09-11 2021-03-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
PH12022550605A1 (en) 2019-09-13 2023-09-25 Nimbus Saturn Inc Hpk1 antagonists and uses thereof
US20240377413A1 (en) 2019-09-16 2024-11-14 Bristol-Myers Squibb Company Dual capture method for analysis of antibody-drug conjugates
WO2021055329A1 (en) 2019-09-16 2021-03-25 Surface Oncology, Inc. Anti-cd39 antibody compositions and methods
US20220380314A1 (en) 2019-09-17 2022-12-01 Bial - R&D Investments, S.A. Substituted, saturated and unsaturated n-heterocyclic carboxamides and related compounds for their use in the treatment of medical disorders
AU2020349519A1 (en) 2019-09-17 2022-03-17 Bial-R&D Investments, S.A. Substituted N-heterocyclic carboxamides as acid ceramidase inhibitors and their use as medicaments
JP2022549228A (en) 2019-09-17 2022-11-24 バイアル－アールアンドディー インベストメンツ ソシエダッド アノニマ Substituted imidazole carboxamides and their use in the treatment of medical disorders
CN114786776A (en) 2019-09-18 2022-07-22 拉姆卡普生物阿尔法股份公司 Bispecific antibodies against CEACAM5 and CD3
WO2021053559A1 (en) 2019-09-18 2021-03-25 Novartis Ag Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
KR20220081977A (en) 2019-09-18 2022-06-16 몰레큘러 템플레이츠, 인코퍼레이션. PD-L1 Binding Molecules Containing Shiga Toxin A Subunit Scaffolds (PD-L1 BINDING MOLECULES COMPRISING SHIGA TOXIN A SUBUNIT SCAFFOLDS)
WO2021055816A1 (en) 2019-09-18 2021-03-25 Molecular Templates, Inc. Pd-l1 binding molecules comprising shiga toxin a subunit scaffolds
CN114401998A (en) 2019-09-18 2022-04-26 诺华股份有限公司 NKG2D fusion protein and its use
TW202124446A (en) 2019-09-18 2021-07-01 瑞士商諾華公司 Combination therapies with entpd2 antibodies
BR112022004831A2 (en) 2019-09-19 2022-06-07 Bristol Myers Squibb Co Antibodies that bind to seen at acidic pH
KR20220068242A (en) 2019-09-20 2022-05-25 트랜스진 Combination of an anti-PD-L1 antibody with a poxvirus encoding HPV polypeptide and IL-2
BR112022004316A2 (en) 2019-09-22 2022-06-21 Bristol Myers Squibb Co Quantitative spatial characterization for lag-3 antagonist therapy
CA3151078A1 (en) 2019-09-25 2021-04-01 Surface Oncology, Inc. Anti-il-27 antibodies and uses thereof
WO2021062018A1 (en) 2019-09-25 2021-04-01 Bristol-Myers Squibb Company Composite biomarker for cancer therapy
KR20220070005A (en) 2019-09-26 2022-05-27 노파르티스 아게 Antiviral pyrazolopyridinone compounds
JP7280387B2 (en) 2019-09-27 2023-05-23 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド antigen binding protein
JP2022548978A (en) 2019-09-27 2022-11-22 ジェネンテック， インコーポレイテッド Dosing for Treatment with Drugs Anti-TIGIT and Anti-PD-L1 Antagonist Antibodies
AU2020353235A1 (en) 2019-09-28 2022-03-31 AskGene Pharma, Inc. Cytokine prodrugs and dual-prodrugs
BR112022005826A2 (en) 2019-09-30 2022-06-21 Incyte Corp Pyrido[3,2-d]pyrimidine compounds as immunomodulators
WO2021064567A1 (en) 2019-09-30 2021-04-08 Astrazeneca Ab Combination treatment for cancer
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
EP3800201A1 (en) 2019-10-01 2021-04-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Cd28h stimulation enhances nk cell killing activities
AU2020358726A1 (en) 2019-10-01 2022-04-07 Silverback Therapeutics, Inc. Combination therapy with immune stimulatory conjugates
EP4037714A1 (en) 2019-10-03 2022-08-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating macrophages polarization
US11851466B2 (en) 2019-10-03 2023-12-26 Xencor, Inc. Targeted IL-12 heterodimeric Fc-fusion proteins
AU2020358859A1 (en) * 2019-10-04 2022-05-12 Seagen Inc. Anti-PD-L1 antibodies and antibody-drug conjugates
WO2021064184A1 (en) 2019-10-04 2021-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of ovarian cancer, breast cancer or pancreatic cancer
TW202128757A (en) 2019-10-11 2021-08-01 美商建南德克公司 Pd-1 targeted il-15/il-15ralpha fc fusion proteins with improved properties
MX2022004390A (en) 2019-10-11 2022-08-08 Incyte Corp Bicyclic amines as cdk2 inhibitors.
WO2021076602A1 (en) 2019-10-14 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
US11781138B2 (en) 2019-10-14 2023-10-10 Aro Biotherapeutics Company FN3 domain-siRNA conjugates and uses thereof
WO2021076546A1 (en) 2019-10-14 2021-04-22 Aro Biotherapeutics Company Cd71 binding fibronectin type iii domains
WO2021074683A1 (en) 2019-10-16 2021-04-22 Avacta Life Sciences Limited Bispecific anti-pd-l1 and anti-fcrn polypeptides
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
WO2021074391A1 (en) 2019-10-17 2021-04-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing nasal intestinal type adenocarcinomas
BR112022007376A2 (en) 2019-10-21 2022-07-05 Novartis Ag COMBINATION THERAPIES WITH VENETOCLAX AND TIM-3 INHIBITORS
US20240301054A1 (en) 2019-10-21 2024-09-12 Novartis Ag Tim-3 inhibitors and uses thereof
CA3155202A1 (en) 2019-10-23 2021-04-29 Arthur M. Krieg Synthetic rig-i-like receptor agonists
WO2021080682A1 (en) 2019-10-24 2021-04-29 Massachusetts Institute Of Technology Monoclonal antibodies that bind human cd161 and uses thereof
JP2022553389A (en) 2019-10-25 2022-12-22 アイオバンス バイオセラピューティクス，インコーポレイテッド Gene editing of tumor-infiltrating lymphocytes and its use in immunotherapy
EP4053124A1 (en) 2019-10-28 2022-09-07 Shanghai Institute of Materia Medica, Chinese Academy of Sciences Five-membered heterocyclic oxocarboxylic acid compound and medical use thereof
JP7691418B2 (en) 2019-10-29 2025-06-11 エーザイ・アール・アンド・ディー・マネジメント株式会社 Combination of a pd-1 antagonist, a vegfr/fgfr/ret tyrosine kinase inhibitor, and a cbp/beta-catenin inhibitor for treating cancer - Patents.com
WO2021083959A1 (en) 2019-10-29 2021-05-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating uveal melanoma
CN114599372A (en) 2019-11-04 2022-06-07 阿斯利康(瑞典)有限公司 Combination therapy for the treatment of cancer
CR20220244A (en) 2019-11-04 2022-06-28 Alector Llc SIGLEC-9 ECD FUSION MOLECULES AND METHODS OF USING THESE
MX2022005371A (en) 2019-11-05 2022-08-04 Celgene Corp Combination therapy with 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiper idin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide.
WO2021092220A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
WO2021092221A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
US20220389103A1 (en) 2019-11-06 2022-12-08 Genentech, Inc. Diagnostic and therapeutic methods for treatment of hematologic cancers
JP2023500054A (en) 2019-11-07 2023-01-04 オンクセルナ セラピューティクス，インコーポレイテッド Classification of the tumor microenvironment
BR112022008191A2 (en) 2019-11-08 2022-07-12 Bristol Myers Squibb Co LAG-3 ANTAGONIST THERAPY FOR MELANOMA
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
WO2021096888A1 (en) 2019-11-12 2021-05-20 Foundation Medicine, Inc. Methods of detecting a fusion gene encoding a neoantigen
EP4058435A1 (en) 2019-11-13 2022-09-21 Genentech, Inc. Therapeutic compounds and methods of use
US20220395553A1 (en) 2019-11-14 2022-12-15 Cohbar, Inc. Cxcr4 antagonist peptides
KR20220103753A (en) 2019-11-19 2022-07-22 브리스톨-마이어스 스큅 컴퍼니 Compounds useful as inhibitors of helios proteins
WO2021102343A1 (en) 2019-11-22 2021-05-27 Sumitomo Dainippon Pharma Oncology, Inc. Solid dose pharmaceutical composition
US11590116B2 (en) 2019-11-22 2023-02-28 Theravance Biopharma R&D Ip, Llc Substituted pyridines and methods of use
WO2021108025A1 (en) 2019-11-26 2021-06-03 Massachusetts Institute Of Technology Cell-based cancer vaccines and cancer therapies
ES3028099T3 (en) 2019-11-26 2025-06-18 Ikena Oncology Inc Polymorphic carbazole derivatives and uses thereof
EP4065157A1 (en) 2019-11-26 2022-10-05 Novartis AG Cd19 and cd22 chimeric antigen receptors and uses thereof
AU2020393854A1 (en) 2019-11-26 2022-06-09 Bristol-Myers Squibb Company Salts/cocrystals of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide
GB201917254D0 (en) 2019-11-27 2020-01-08 Adc Therapeutics Sa Combination therapy
EP3831849A1 (en) 2019-12-02 2021-06-09 LamKap Bio beta AG Bispecific antibodies against ceacam5 and cd47
CA3163875A1 (en) 2019-12-04 2021-06-10 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
AU2020395185A1 (en) 2019-12-04 2022-06-02 Incyte Corporation Derivatives of an FGFR inhibitor
EP4069683A1 (en) 2019-12-06 2022-10-12 Mersana Therapeutics, Inc. Dimeric compounds as sting agonists
US11897950B2 (en) 2019-12-06 2024-02-13 Augusta University Research Institute, Inc. Osteopontin monoclonal antibodies
EP4073236A1 (en) 2019-12-11 2022-10-19 Iovance Biotherapeutics, Inc. Processes for the production of tumor infiltrating lymphocytes (tils) and methods of using the same
WO2021119429A1 (en) 2019-12-13 2021-06-17 Cugene Inc. Novel interleukin-15 (il-15) fusion proteins and uses thereof
BR112022011651A2 (en) 2019-12-17 2022-08-23 Kymera Therapeutics Inc IRAK DEGRADATORS AND USES THEREOF
EP4076524A4 (en) 2019-12-17 2023-11-29 Kymera Therapeutics, Inc. IRAQ DEGRADERS AND USES THEREOF
US20230114107A1 (en) 2019-12-17 2023-04-13 Flagship Pioneering Innovations V, Inc. Combination anti-cancer therapies with inducers of iron-dependent cellular disassembly
EP4076443B1 (en) 2019-12-17 2025-09-10 Merck Sharp & Dohme LLC Substituted 1,3,8-triazaspiro[4,5]decane-2,4-dione compound as indoleamine 2,3-dioxygenase (ido) and/or tryptophan 2,3-dioxygenase (tdo) inhibitors
CA3164751A1 (en) 2019-12-18 2021-06-24 Benjamin Joseph MORROW Compounds
EP4076529A1 (en) 2019-12-19 2022-10-26 Bristol-Myers Squibb Company Combinations of dgk inhibitors and checkpoint antagonists
EP4076508A1 (en) 2019-12-19 2022-10-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and vaccine compositions to treat cancers
US20230056470A1 (en) 2019-12-20 2023-02-23 Novartis Ag Uses of anti-tgf-beta antibodies and checkpoint inhibitors for the treatment of proliferative diseases
IL294270A (en) 2019-12-23 2022-08-01 Bristol Myers Squibb Co Substituted piperazine derivatives are useful as t-cell activators
AU2020415377A1 (en) 2019-12-23 2022-08-18 Bristol-Myers Squibb Company Substituted quinazolinyl compounds useful as T cell activators
ES3013568T3 (en) 2019-12-23 2025-04-14 Bristol Myers Squibb Co Substituted heteroaryl compounds useful as t cell activators
AR120823A1 (en) 2019-12-23 2022-03-23 Bristol Myers Squibb Co SUBSTITUTED BICYCLIC COMPOUNDS USEFUL AS T-CELL ACTIVATORS
CN115297931A (en) 2019-12-23 2022-11-04 凯麦拉医疗公司 SMARCA degraders and their uses
MX2022007369A (en) 2019-12-23 2022-07-12 Bristol Myers Squibb Co SUBSTITUTED PIPERAZINE QUINOLINONYL COMPOUNDS USEFUL AS T CELL ACTIVATORS.
CN113045655A (en) 2019-12-27 2021-06-29 高诚生物医药(香港)有限公司 anti-OX 40 antibodies and uses thereof
TW202135824A (en) 2020-01-03 2021-10-01 美商英塞特公司 Combination therapy comprising a2a/a2b and pd-1/pd-l1 inhibitors
EP4084821A4 (en) 2020-01-03 2024-04-24 Marengo Therapeutics, Inc. CD33-BINDING MULTIFUNCTIONAL MOLECULES AND THEIR USES
BR112022013424A2 (en) 2020-01-06 2022-12-13 Hifibio Hk Ltd ANTI-TNFR2 ANTIBODY AND ITS USES
JP2023510737A (en) 2020-01-06 2023-03-15 ブリストル－マイヤーズ スクイブ カンパニー Immunomodulator
CN115210261B (en) 2020-01-07 2025-07-18 高诚生物医药公司 Anti-galectin-9 antibodies and uses thereof
WO2021141751A1 (en) 2020-01-07 2021-07-15 Merck Sharp & Dohme Corp. Arginase inhibitors and methods of use
WO2021142203A1 (en) 2020-01-10 2021-07-15 Innate Tumor Immunity, Inc. Nlrp3 modulators
WO2021146424A1 (en) 2020-01-15 2021-07-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
US11534441B2 (en) 2020-01-15 2022-12-27 Blueprint Medicines Corporation MAP4K1 inhibitors
US20230076415A1 (en) 2020-01-17 2023-03-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
BR112022012310A2 (en) 2020-01-17 2022-09-06 Novartis Ag A COMBINATION COMPRISING A TIM-3 INHIBITOR AND A HYPOMETYLING AGENT FOR USE IN THE TREATMENT OF MYELODYSPLASTIC SYNDROME OR CHRONIC MYELOMONOCYTIC LEUKEMIA
WO2022050954A1 (en) 2020-09-04 2022-03-10 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021194481A1 (en) 2020-03-24 2021-09-30 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
BR112022014562A2 (en) 2020-01-28 2022-09-13 Glaxosmithkline Ip Dev Ltd COMBINATION TREATMENTS, USES AND METHODS THEREOF
KR20220132598A (en) 2020-01-28 2022-09-30 제넨테크, 인크. IL15/IL15R alpha heterodimer Fc-fusion protein for cancer treatment
WO2021152400A1 (en) 2020-01-30 2021-08-05 Gnubiotics Sciences Sa Compositions comprising pig stomach mucins and uses thereof
BR112022014962A2 (en) 2020-01-30 2022-09-20 Ona Therapeutics S L COMBINATION THERAPY FOR TREATMENT OF CANCER AND CANCER METASTASIS
MX2022009391A (en) 2020-01-31 2022-09-26 Genentech Inc Methods of inducing neoepitope-specific t cells with a pd-1 axis binding antagonist and an rna vaccine.
WO2021156360A1 (en) 2020-02-05 2021-08-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for discontinuing a treatment with a tyrosine kinase inhibitor (tki)
KR20220139915A (en) 2020-02-06 2022-10-17 브리스톨-마이어스 스큅 컴퍼니 IL-10 and its uses
TW202140028A (en) 2020-02-07 2021-11-01 美商Ａｉ治療公司 Anti-viral compositions and methods of use
BR112022016368A2 (en) 2020-02-18 2023-01-10 Alector Llc PILRA ANTIBODIES AND THEIR METHODS OF USE
JP7735291B2 (en) 2020-02-21 2025-09-08 エーアールエス ファーマシューティカルズ、インコーポレイテッド Nectin-4 antibody conjugates and uses thereof
CA3173257A1 (en) 2020-02-26 2021-09-02 Biograph 55, Inc. C19 c38 bispecific antibodies
US20230113705A1 (en) 2020-02-28 2023-04-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing, prognosing and managing treatment of breast cancer
WO2021171264A1 (en) 2020-02-28 2021-09-02 Novartis Ag Dosing of a bispecific antibody that binds cd123 and cd3
US20240277878A1 (en) 2020-02-28 2024-08-22 Bristol-Myers Squibb Company Radiolabeled fibronectin based scaffolds and antibodies and theranostic uses thereof
EP4114529A1 (en) 2020-03-03 2023-01-11 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
KR20220150353A (en) 2020-03-05 2022-11-10 네오티엑스 테라퓨틱스 엘티디. Methods and compositions for treating cancer using immune cells
US20230114276A1 (en) 2020-03-06 2023-04-13 Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Modulating anti-tumor immunity
EP4114398A1 (en) 2020-03-06 2023-01-11 Celgene Quanticel Research, Inc. Combination of an lsd-1 inhibitor and nivolumab for use in treating sclc or sqnsclc
IL295979A (en) 2020-03-06 2022-10-01 Ona Therapeutics S L Anti-cd36 antibodies and their use to treat cancer
WO2021177980A1 (en) 2020-03-06 2021-09-10 Genentech, Inc. Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist
CN115697343A (en) 2020-03-06 2023-02-03 因赛特公司 Combination therapy comprising AXL/MER and PD-1/PD-L1 inhibitors
WO2021183318A2 (en) 2020-03-09 2021-09-16 President And Fellows Of Harvard College Methods and compositions relating to improved combination therapies
KR20220151189A (en) 2020-03-09 2022-11-14 브리스톨-마이어스 스큅 컴퍼니 Antibodies to CD40 with enhanced agonist activity
US11407712B2 (en) 2020-03-19 2022-08-09 Arcus Biosciences, Inc. Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2α
US20240424110A1 (en) 2020-03-19 2024-12-26 Kymera Therapeutics, Inc. Mdm2 degraders and uses thereof
PE20230821A1 (en) 2020-03-23 2023-05-19 Bristol Myers Squibb Co ANTI-CCR8 ANTIBODIES FOR THE TREATMENT OF CANCER
TW202140441A (en) 2020-03-23 2021-11-01 美商必治妥美雅史谷比公司 Substituted oxoisoindoline compounds
CN115362166A (en) 2020-03-30 2022-11-18 百时美施贵宝公司 Immunomodulator
US11673879B2 (en) 2020-03-31 2023-06-13 Theravance Biopharma R&D Ip, Llc Substituted pyrimidines and methods of use
WO2021202959A1 (en) 2020-04-03 2021-10-07 Genentech, Inc. Therapeutic and diagnostic methods for cancer
EP4134098A4 (en) 2020-04-10 2024-05-15 ONO Pharmaceutical Co., Ltd. Method of cancer therapy
US20230149462A1 (en) 2020-04-10 2023-05-18 Juno Therapeutics, Inc. Methods and uses related to cell therapy engineered with a chimeric antigen receptor targeting b-cell maturation antigen
JPWO2021205631A1 (en) 2020-04-10 2021-10-14
WO2021209358A1 (en) 2020-04-14 2021-10-21 Glaxosmithkline Intellectual Property Development Limited Combination treatment for cancer based upon an icos antibody and a pd-l1 antibody tgf-beta-receptor fusion protein
BR112022020841A2 (en) 2020-04-16 2023-05-02 Incyte Corp CAST TRICYCLIC KRAS INHIBITORS
WO2021216572A1 (en) 2020-04-20 2021-10-28 Massachusetts Institute Of Technology Lipid compositions for delivery of sting agonist compounds and uses thereof
EP4139341A1 (en) 2020-04-21 2023-03-01 Regeneron Pharmaceuticals, Inc. Il-2 variants with reduced binding to il-2 receptor alpha and uses thereof
JP7644777B2 (en) 2020-04-22 2025-03-12 ドラゴンフライ セラピューティクス， インコーポレイテッド Formulations, Dosage Regimens, and Manufacturing Processes for Heterodimeric Fc-Fusion Proteins
CN115997008A (en) 2020-04-22 2023-04-21 艾欧凡斯生物治疗公司 Systems and methods for coordinating the manufacture of cells for patient-specific immunotherapy
TW202206100A (en) 2020-04-27 2022-02-16 美商西健公司 Treatment for cancer
EP4143345A1 (en) 2020-04-28 2023-03-08 Genentech, Inc. Methods and compositions for non-small cell lung cancer immunotherapy
US20230181756A1 (en) 2020-04-30 2023-06-15 Novartis Ag Ccr7 antibody drug conjugates for treating cancer
JP2023526783A (en) 2020-05-05 2023-06-23 テオン セラピューティクス，インク． Cannabinoid receptor type 2 (CB2) modulators and uses thereof
JP2023524257A (en) 2020-05-05 2023-06-09 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Prediction of response to PD-1 axis inhibitors
IL297781A (en) 2020-05-06 2022-12-01 Merck Sharp & Dohme Llc il4i1 inhibitors and methods of use
IL297980A (en) 2020-05-08 2023-01-01 Alpine Immune Sciences Inc April and baff inhibitory immunomodulatory proteins and methods of use thereof
WO2021231773A1 (en) 2020-05-13 2021-11-18 Good Therapeutics, Inc. Compositions of protein complexes and methods of use thereof
WO2021231526A1 (en) 2020-05-13 2021-11-18 Incyte Corporation Fused pyrimidine compounds as kras inhibitors
MX2022014191A (en) 2020-05-13 2022-12-07 Massachusetts Inst Technology Compositions of polymeric microdevices and their use in cancer immunotherapy.
US20230192867A1 (en) 2020-05-15 2023-06-22 Bristol-Myers Squibb Company Antibodies to garp
AU2021280245A1 (en) 2020-05-26 2022-12-08 Regeneron Pharmaceuticals, Inc. Methods of treating cervical cancer by administering a PD-1 inhibitor
CA3184802A1 (en) 2020-05-26 2021-12-02 Inserm (Institut National De La Sante Et De La Recherche Medicale) Severe acute respiratory syndrome coronavirus 2 (sars-cov-2) polypeptides and uses thereof for vaccine purposes
WO2021243207A1 (en) 2020-05-28 2021-12-02 Modernatx, Inc. Use of mrnas encoding ox40l, il-23 and il-36gamma for treating cancer
EP4157923A2 (en) 2020-05-29 2023-04-05 President And Fellows Of Harvard College Living cells engineered with polyphenol-functionalized biologically active nanocomplexes
CR20220611A (en) 2020-06-02 2023-06-07 Arcus Biosciences Inc ANTI-TIGIT ANTIBODIES
EP4161521A4 (en) 2020-06-03 2024-07-10 Kymera Therapeutics, Inc. Deuterated irak degraders and uses thereof
TW202210483A (en) 2020-06-03 2022-03-16 美商凱麥拉醫療公司 Crystalline forms of irak degraders
US11767353B2 (en) 2020-06-05 2023-09-26 Theraly Fibrosis, Inc. Trail compositions with reduced immunogenicity
TW202214623A (en) 2020-06-10 2022-04-16 美商施萬生物製藥研發 Ip有限責任公司 Crystalline alk5 inhibitors and uses thereof
WO2021249969A1 (en) 2020-06-10 2021-12-16 Merck Patent Gmbh Combination product for the treatment of cancer diseases
WO2021252977A1 (en) 2020-06-12 2021-12-16 Genentech, Inc. Methods and compositions for cancer immunotherapy
MX2022015877A (en) 2020-06-16 2023-01-24 Genentech Inc Methods and compositions for treating triple-negative breast cancer.
KR20230024368A (en) 2020-06-18 2023-02-20 제넨테크, 인크. Treatment with anti-TIGIT antibodies and PD-1 axis binding antagonists
WO2021258010A1 (en) 2020-06-19 2021-12-23 Gossamer Bio Services, Inc. Oxime compounds useful as t cell activators
AR122644A1 (en) 2020-06-19 2022-09-28 Onxeo NEW CONJUGATED NUCLEIC ACID MOLECULES AND THEIR USES
CN111925434B (en) * 2020-06-22 2023-06-27 南昌大学 A screening method for monoclonal antibodies
BR112022026202A2 (en) 2020-06-23 2023-01-17 Novartis Ag DOSAGE REGIMEN COMPRISING 3-(1-OXOISOINDOLIN-2-IL)PIPERIDINE-2,6-DIONE DERIVATIVES
WO2021262969A1 (en) 2020-06-24 2021-12-30 The General Hospital Corporation Materials and methods of treating cancer
IL299293A (en) 2020-06-25 2023-02-01 Celgene Corp Methods for treating cancer with combination therapies
CN116209459A (en) 2020-06-26 2023-06-02 美国安进公司 IL-10 muteins and fusion proteins thereof
WO2022006179A1 (en) 2020-06-29 2022-01-06 Flagship Pioneering Innovations V, Inc. Viruses engineered to promote thanotransmission and their use in treating cancer
EP4172621A1 (en) 2020-06-30 2023-05-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the risk of recurrence and/or death of patients suffering from a solid cancer after preoperative adjuvant therapies
JP7741831B2 (en) 2020-06-30 2025-09-18 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル Method for predicting the risk of recurrence and/or death in patients with solid tumors after neoadjuvant therapy and curative surgery - Patent Application 20070122997
AU2021300362A1 (en) 2020-07-01 2023-02-23 ARS Pharmaceuticals, Inc. Anti-ASGR1 antibody conjugates and uses thereof
US20230250173A1 (en) 2020-07-01 2023-08-10 Pfizer Inc. Biomarkers for pd-1 axis binding antagonist therapy
MX2023000197A (en) 2020-07-07 2023-02-22 BioNTech SE THERAPEUTIC RNA FOR HPV POSITIVE CANCER.
PT4178548T (en) 2020-07-07 2024-10-22 Celgene Corp Pharmaceutical compositions comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)m ethyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and methods of using the same
TW202216778A (en) 2020-07-15 2022-05-01 美商安進公司 Tigit and cd112r blockade
US11787775B2 (en) 2020-07-24 2023-10-17 Genentech, Inc. Therapeutic compounds and methods of use
WO2022023379A1 (en) 2020-07-28 2022-02-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for preventing and treating a cancer
TW202221031A (en) 2020-07-30 2022-06-01 英商阿法克塔生命科學有限公司 Serum half-life extended pd-l1 inhibitory polypeptides
CN116133692A (en) 2020-07-30 2023-05-16 凯麦拉医疗公司 Methods of treating mutant lymphomas
CN116134027B (en) 2020-08-03 2025-01-24 诺华股份有限公司 Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US12297281B2 (en) 2020-08-05 2025-05-13 Synthekine, Inc. IL10RA binding molecules and methods of use
US20230272094A1 (en) 2020-08-05 2023-08-31 Synthekine, Inc. Il2rb/il2rg synthetic cytokines
CA3190430A1 (en) 2020-08-05 2022-02-10 Synthekine, Inc. Il10rb binding molecules and methods of use
US20240199737A1 (en) 2020-08-05 2024-06-20 Synthekine, Inc. GP130 Binding Molecules and Methods of Use
EP4192880A4 (en) 2020-08-05 2025-04-30 Synthekine, Inc. Il10 receptor binding molecules and methods of use
MX2023001707A (en) 2020-08-10 2023-05-04 Shanghai Xunbaihui Biotechnology Co Ltd Compositions and methods for treating autoimmune diseases and cancers by targeting igsf8.
EP4196612A1 (en) 2020-08-12 2023-06-21 Genentech, Inc. Diagnostic and therapeutic methods for cancer
JP2023538906A (en) 2020-08-17 2023-09-12 バイシクルティーエクス・リミテッド Bicyclic conjugates specific for nectin-4 and uses thereof
EP4204592A1 (en) 2020-08-26 2023-07-05 Regeneron Pharmaceuticals, Inc. Methods of treating cancer by administering a pd-1 inhibitor
KR20230074487A (en) 2020-08-26 2023-05-30 마렝고 테라퓨틱스, 인크. How to detect TRBC1 or TRBC2
WO2022047093A1 (en) 2020-08-28 2022-03-03 Incyte Corporation Vinyl imidazole compounds as inhibitors of kras
US20230265188A1 (en) 2020-08-28 2023-08-24 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hepatocellular carcinoma
US20230303700A1 (en) 2020-08-31 2023-09-28 Bristol-Myers Squibb Company Cell localization signature and immunotherapy
US20230265196A1 (en) 2020-09-02 2023-08-24 Pharmabcine Inc. Combination Therapy of a PD-1 Antagonist and an Antagonist for VEGFR-2 for Treating Patients with Cancer
IL300975A (en) 2020-09-03 2023-04-01 Regeneron Pharma Methods for treating cancer pain by administering a PD-1 inhibitor
CN114316045B (en) * 2020-09-29 2024-07-12 英诺欧奇生物医药(苏州)有限公司 Anti-PD-L1 antibodies and uses thereof
WO2022072783A1 (en) 2020-10-02 2022-04-07 Incyte Corporation Bicyclic dione compounds as inhibitors of kras
WO2022076318A1 (en) 2020-10-05 2022-04-14 Bristol-Myers Squibb Company Methods for concentrating proteins
US20230364127A1 (en) 2020-10-06 2023-11-16 Codiak Biosciences, Inc. Extracellular vesicle-aso constructs targeting stat6
WO2022084210A1 (en) 2020-10-20 2022-04-28 F. Hoffmann-La Roche Ag Combination therapy of pd-1 axis binding antagonists and lrrk2 inhitibors
AR123855A1 (en) 2020-10-20 2023-01-18 Genentech Inc PEG-CONJUGATED ANTI-MERTK ANTIBODIES AND METHODS OF USE
WO2022087402A1 (en) 2020-10-23 2022-04-28 Bristol-Myers Squibb Company Lag-3 antagonist therapy for lung cancer
WO2022084531A1 (en) 2020-10-23 2022-04-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating glioma
EP4236960A1 (en) 2020-10-28 2023-09-06 Ikena Oncology, Inc. Combination of an ahr inhibitor with a pdx inhibitor or doxorubicine
WO2022093981A1 (en) 2020-10-28 2022-05-05 Genentech, Inc. Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists
US12351643B2 (en) 2020-11-04 2025-07-08 Genentech, Inc. Dosing for treatment with anti-CD20/anti-CD3 bispecific antibodies
JP2023548859A (en) 2020-11-06 2023-11-21 インサイト・コーポレイション Process for making PD-1/PD-L1 inhibitors and their salts and crystalline forms
WO2022099018A1 (en) 2020-11-06 2022-05-12 Incyte Corporation Process of preparing a pd-1/pd-l1 inhibitor
KR20230104651A (en) 2020-11-06 2023-07-10 노파르티스 아게 CD19 Binding Molecules and Uses Thereof
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
WO2022098972A1 (en) 2020-11-08 2022-05-12 Seagen Inc. Combination-therapy antibody drug conjugate with immune cell inhibitor
MX2023005570A (en) 2020-11-12 2023-05-29 Inst Nat Sante Rech Med Antibodies conjugated or fused to the receptor-binding domain of the sars-cov-2 spike protein and uses thereof for vaccine purposes.
CA3201519A1 (en) 2020-11-13 2022-05-19 Genentech, Inc. Methods and compositions comprising a krasg12c inhibitor and a pd-l1 binding antagonist for treating lung cancer
EP4245301A4 (en) 2020-11-13 2024-08-21 ONO Pharmaceutical Co., Ltd. CANCER TREATMENT BY COMBINED USE OF AN EP4 ANTAGONIST AND AN IMMUNE CHECKPOINT INHIBITOR
WO2022101463A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of the last c-terminal residues m31/41 of zikv m ectodomain for triggering apoptotic cell death
US20230416830A1 (en) 2020-11-16 2023-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating uveal melanoma
EP4244392A1 (en) 2020-11-16 2023-09-20 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and compositions for predicting and treating uveal melanoma
US20240024320A1 (en) 2020-11-17 2024-01-25 Seagen Inc. Methods of treating cancer with a combination of tucatinib and an anti-pd-1/anti-pd-l1 antibody
IL303376A (en) 2020-12-02 2023-08-01 Ikena Oncology Inc TEAD inhibitors and their uses
WO2022120353A1 (en) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Tead inhibitors and uses thereof
EP4255481A1 (en) 2020-12-02 2023-10-11 Genentech, Inc. Methods and compositions for neoadjuvant and adjuvant urothelial carcinoma therapy
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
PH12023500013A1 (en) 2020-12-04 2024-03-11 Tidal Therapeutics Inc Ionizable cationic lipids and lipi nanoparticles, and methods of synthesis and use thereof
WO2022121846A1 (en) * 2020-12-08 2022-06-16 博际生物医药科技(杭州)有限公司 Pd-l1 antibody and application thereof
US20240050432A1 (en) 2020-12-08 2024-02-15 Infinity Pharmaceuticals, Inc. Eganelisib for use in the treatment of pd-l1 negative cancer
TW202237119A (en) 2020-12-10 2022-10-01 美商住友製藥腫瘤公司 Alk-5 inhibitors and uses thereof
US12180284B2 (en) 2020-12-16 2024-12-31 Molecular Templates, Inc. Clinical methods for use of a PD-L1-binding molecule comprising a Shiga toxin effector
CN116964050A (en) 2020-12-16 2023-10-27 戈萨默生物服务公司 Compounds that can be used as T cell activators
US11753481B2 (en) 2020-12-18 2023-09-12 Lamkap Bio Beta Ltd Bispecific antibodies against CEACAM5 and CD47
TW202245808A (en) 2020-12-21 2022-12-01 德商拜恩迪克公司 Therapeutic rna for treating cancer
WO2022135667A1 (en) 2020-12-21 2022-06-30 BioNTech SE Therapeutic rna for treating cancer
WO2022135666A1 (en) 2020-12-21 2022-06-30 BioNTech SE Treatment schedule for cytokine proteins
ES3023507T3 (en) 2020-12-28 2025-06-02 Bristol Myers Squibb Co Antibody compositions and methods of use thereof
JP2024501029A (en) 2020-12-28 2024-01-10 ブリストル－マイヤーズ スクイブ カンパニー Subcutaneous administration of PD1/PD-L1 antibodies
WO2022147092A1 (en) 2020-12-29 2022-07-07 Incyte Corporation Combination therapy comprising a2a/a2b inhibitors, pd-1/pd-l1 inhibitors, and anti-cd73 antibodies
AU2021413371A1 (en) 2020-12-30 2023-07-13 Kymera Therapeutics, Inc. Irak degraders and uses thereof
JP2024501894A (en) 2021-01-04 2024-01-16 メルサナ セラピューティクス インコーポレイテッド B7H4 targeting antibody-drug conjugates and methods of use thereof
EP4274616A2 (en) 2021-01-11 2023-11-15 Synthekine, Inc. Compositions and methods related to receptor pairing
US20250186539A2 (en) 2021-01-11 2025-06-12 Bicycletx Limited Methods for treating cancer
WO2022155541A1 (en) 2021-01-14 2022-07-21 AskGene Pharma, Inc. Interferon prodrugs and methods of making and using the same
CN116963773A (en) 2021-01-21 2023-10-27 浙江养生堂天然药物研究所有限公司 Compositions and methods for treating tumors
JP2024505049A (en) 2021-01-29 2024-02-02 ノバルティス アーゲー Administration modes for anti-CD73 and anti-ENTPD2 antibodies and their uses
WO2022165403A1 (en) 2021-02-01 2022-08-04 Yale University Chemotherapeutic bioadhesive particles with immunostimulatory molecules for cancer treatment
AU2022215844A1 (en) 2021-02-02 2023-09-14 Liminal Biosciences Limited Gpr84 antagonists and uses thereof
CA3206501A1 (en) 2021-02-02 2022-08-11 Shaun Abbott Gpr84 antagonists and uses thereof
AR124800A1 (en) 2021-02-03 2023-05-03 Genentech Inc LACTAMS AS CBL-B INHIBITORS
EP4288428A1 (en) 2021-02-03 2023-12-13 Genentech, Inc. Amides as cbl-b inhibitors
CN115105600B (en) 2021-02-10 2024-07-19 同润生物医药(上海)有限公司 Pharmaceutical composition of PI3K delta/gamma and method for treating tumor by using pharmaceutical composition
US20250277038A1 (en) * 2021-02-10 2025-09-04 Shanghai Jemincare Pharmaceutical Co., Ltd. Anti-pd-l1 antibody and use thereof
MX2023009379A (en) 2021-02-12 2023-10-10 Hoffmann La Roche Bicyclic tetrahydroazepine derivatives for the treatment of cancer.
US12252488B2 (en) 2021-02-12 2025-03-18 Nimbus Saturn, Inc. HPK1 antagonists and uses thereof
MX2023009527A (en) 2021-02-15 2023-08-24 Kymera Therapeutics Inc Irak4 degraders and uses thereof.
AU2022220869A1 (en) 2021-02-15 2023-08-24 Kymera Therapeutics, Inc. Irak4 degraders and uses thereof
GB202102396D0 (en) 2021-02-19 2021-04-07 Adc Therapeutics Sa Molecular adjuvant
WO2022185160A1 (en) 2021-03-02 2022-09-09 Glaxosmithkline Intellectual Property Development Limited Substituted pyridines as dnmt1 inhibitors
JP2024509192A (en) 2021-03-05 2024-02-29 ニンバス サターン， インコーポレイテッド HPK1 antagonists and their uses
JP2024510947A (en) 2021-03-05 2024-03-12 レアダルティス、ソシエダッド リミターダ Trimeric polypeptides and their use in cancer therapy
JP2024510176A (en) 2021-03-08 2024-03-06 ブループリント メディシンズ コーポレイション MAP4K1 inhibitor
US11918582B2 (en) 2021-03-15 2024-03-05 Rapt Therapeutics, Inc. Pyrazole pyrimidine compounds and uses thereof
CN115073599B (en) * 2021-03-16 2023-04-28 北京天广实生物技术股份有限公司 Antibodies that bind PD-L1 and uses thereof
EP4308118A1 (en) 2021-03-17 2024-01-24 Institut National de la Santé et de la Recherche Médicale (INSERM) Methods and compositions for treating melanoma
US20240310266A1 (en) 2021-03-18 2024-09-19 Novartis Ag Biomarkers for cancer and methods of use thereof
US11859021B2 (en) 2021-03-19 2024-01-02 Icahn School Of Medicine At Mount Sinai Compounds for regulating trained immunity, and their methods of use
JP2024511106A (en) 2021-03-23 2024-03-12 リジェネロン・ファーマシューティカルズ・インコーポレイテッド Method of treating cancer in immunosuppressed or immunocompromised patients by administering PD-1 inhibitors
TW202304506A (en) 2021-03-25 2023-02-01 日商安斯泰來製藥公司 Combination therapy involving antibodies against claudin 18.2 for treatment of cancer
AU2022245322A1 (en) 2021-03-25 2023-10-05 Oncxerna Therapeutics, Inc. Targeted therapies in cancer
IL305847A (en) 2021-03-26 2023-11-01 Innate Pharma Multispecific proteins comprising an nkp46-binding site, a cancer antgienge binding site fused to a cytokine for nk cell engaging
AU2022246593A1 (en) 2021-03-29 2023-10-12 Juno Therapeutics, Inc. Methods for dosing and treatment with a combination of a checkpoint inhibitor therapy and a car t cell therapy
JP2024513011A (en) 2021-03-29 2024-03-21 ニンバス サターン， インコーポレイテッド HPK1 antagonists and their uses
EP4313109A1 (en) 2021-03-31 2024-02-07 Flagship Pioneering Innovations V, Inc. Thanotransmission polypeptides and their use in treating cancer
JP2024511831A (en) 2021-03-31 2024-03-15 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド Antigen binding proteins and combinations thereof
JP2024514530A (en) 2021-04-02 2024-04-02 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Antibodies against truncated CDCP1 and uses thereof
JP2024515545A (en) 2021-04-05 2024-04-10 ブリストル－マイヤーズ スクイブ カンパニー Pyridinyl-substituted oxoisoindoline compounds for cancer treatment
PL4320112T3 (en) 2021-04-06 2025-07-21 Bristol-Myers Squibb Company Pyridinyl substituted oxoisoindoline compounds
TW202304979A (en) 2021-04-07 2023-02-01 瑞士商諾華公司 USES OF ANTI-TGFβ ANTIBODIES AND OTHER THERAPEUTIC AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
US12016860B2 (en) 2021-04-08 2024-06-25 Nurix Therapeutics, Inc. Combination therapies with Cbl-b inhibitor compounds
GB2623199A (en) 2021-04-08 2024-04-10 Marengo Therapeutics Inc Multifunctional molecules binding to TCR and uses thereof
US20240197723A1 (en) 2021-04-09 2024-06-20 Beyondspring Pharmaceuticals, Inc. Therapeutic compositions and methods for treating tumors
EP4320156A1 (en) 2021-04-09 2024-02-14 Ose Immunotherapeutics Scaffold for bifunctioanl molecules comprising pd-1 or cd28 and sirp binding domains
KR20230167097A (en) 2021-04-09 2023-12-07 제넨테크, 인크. Combination therapy with RAF inhibitors and PD-1 axis inhibitors
WO2022217026A1 (en) 2021-04-09 2022-10-13 Seagen Inc. Methods of treating cancer with anti-tigit antibodies
MX2023011964A (en) 2021-04-09 2024-01-08 Ose Immunotherapeutics New scaffold for bifunctional molecules with improved properties.
IL307479A (en) 2021-04-09 2023-12-01 Nimbus Clio Inc Modulators of CBL-B and their uses
TW202304459A (en) 2021-04-12 2023-02-01 美商英塞特公司 Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent
US12037346B2 (en) 2021-04-13 2024-07-16 Nuvalent, Inc. Amino-substituted heteroaryls for treating cancers with EGFR mutations
WO2022221550A1 (en) 2021-04-14 2022-10-20 Aro Biotherapeutics Company Fn3 domain-sirna conjugates and uses thereof
US20240228659A1 (en) 2021-04-14 2024-07-11 INSERM (Institut National de la Santé et de la Recherche Médicale) New method to improve nk cells cytotoxicity
KR20240034160A (en) 2021-04-14 2024-03-13 에이알오 바이오테라퓨틱스 컴패니 CD71 binding fibronectin type 3 domain
CN113150153B (en) * 2021-04-15 2022-05-10 博奥信生物技术（南京）有限公司 Anti-human PDL1 monoclonal antibody and application thereof
WO2022221720A1 (en) 2021-04-16 2022-10-20 Novartis Ag Antibody drug conjugates and methods for making thereof
EP4323066A1 (en) 2021-04-16 2024-02-21 Ikena Oncology, Inc. Mek inhibitors and uses thereof
CA3212610A1 (en) 2021-04-20 2022-10-27 Philip MOQUIST Modulation of antibody-dependent cellular cytotoxicity
WO2022223791A1 (en) 2021-04-23 2022-10-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cell senescence accumulation related disease
WO2022227015A1 (en) 2021-04-30 2022-11-03 Merck Sharp & Dohme Corp. Il4i1 inhibitors and methods of use
JP2024516230A (en) 2021-04-30 2024-04-12 ジェネンテック， インコーポレイテッド Therapeutic and diagnostic methods and compositions for cancer
CN117321078A (en) 2021-04-30 2023-12-29 豪夫迈·罗氏有限公司 Administration for combination therapy with anti-CD 20/anti-CD 3 bispecific antibody and anti-CD 79B antibody drug conjugates
PH12023500023A1 (en) 2021-05-07 2024-03-11 Kymera Therapeutics Inc Cdk2 degraders and uses thereof
AU2022270170A1 (en) 2021-05-07 2023-09-21 Surface Oncology, LLC Anti-il-27 antibodies and uses thereof
WO2022241235A1 (en) 2021-05-14 2022-11-17 Genentech, Inc. Methods for treatment of cd20-positive proliferative disorder with mosunetuzumab and polatuzumab vedotin
AR125874A1 (en) 2021-05-18 2023-08-23 Novartis Ag COMBINATION THERAPIES
TW202313682A (en) 2021-05-18 2023-04-01 英商凱麥博有限公司 Uses of anti-icos antibodies
WO2022246177A1 (en) 2021-05-21 2022-11-24 Arcus Biosciences, Inc. Axl compounds
WO2022242737A1 (en) 2021-05-21 2022-11-24 天津立博美华基因科技有限责任公司 Pharmaceutical combination and use thereof
JP2024521712A (en) 2021-05-21 2024-06-04 アーカス バイオサイエンシーズ，インコーポレーテッド AXL Inhibitor Compounds
CN117412767A (en) 2021-05-25 2024-01-16 雪绒花免疫公司 C-X-C motif chemokine receptor 6 (CXCR 6) binding molecules and methods of use thereof
EP4349863A2 (en) 2021-05-26 2024-04-10 Centro de Inmunologia Molecular Use of therapeutic compositions for the treatment of patients with tumours of epithelial origin
WO2022251359A1 (en) 2021-05-26 2022-12-01 Theravance Biopharma R&D Ip, Llc Bicyclic inhibitors of alk5 and methods of use
TW202307210A (en) 2021-06-01 2023-02-16 瑞士商諾華公司 Cd19 and cd22 chimeric antigen receptors and uses thereof
WO2022256534A1 (en) 2021-06-03 2022-12-08 Synthorx, Inc. Head and neck cancer combination therapy comprising an il-2 conjugate and pembrolizumab
CN113234152B (en) * 2021-06-03 2023-05-02 天津科技大学 Programmed death receptor-ligand 1 (PD-L1) specific binding polypeptide and application thereof
GB202107994D0 (en) 2021-06-04 2021-07-21 Kymab Ltd Treatment of cancer
MX2023014389A (en) 2021-06-04 2024-03-04 Boehringer Ingelheim Int Anti-sirp-alpha antibodies.
EP4351595A1 (en) 2021-06-07 2024-04-17 Providence Health & Services - Oregon Cxcr5, pd-1, and icos expressing tumor reactive cd4 t cells and their use
WO2022258691A1 (en) 2021-06-09 2022-12-15 Innate Pharma Multispecific proteins binding to nkg2d, a cytokine receptor, a tumour antigen and cd16a
MX2023014647A (en) 2021-06-09 2024-01-31 Innate Pharma MULTI-SPECIFIC NKP46 BINDING PROTEINS.
EP4352060A1 (en) 2021-06-09 2024-04-17 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
TW202313611A (en) 2021-06-09 2023-04-01 美商英塞特公司 Tricyclic heterocycles as fgfr inhibitors
WO2022258678A1 (en) 2021-06-09 2022-12-15 Innate Pharma Multispecific proteins binding to nkp30, a cytokine receptor, a tumour antigen and cd16a
WO2022260132A1 (en) 2021-06-10 2022-12-15 小野薬品工業株式会社 Method for treating cancer through combination of cd47 inhibitor, immune checkpoint inhibitor, and standard therapy
US20230034659A1 (en) * 2021-06-17 2023-02-02 Sparx Bioscience Limited Anti-pdl1 antibodies and uses thereof
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
JP2024525475A (en) 2021-06-29 2024-07-12 フラグシップ パイオニアリング イノベーションズ ブイ，インコーポレーテッド Engineered immune cells to promote tanotransmission and uses thereof
MX2023015416A (en) 2021-07-02 2024-04-30 Genentech Inc Methods and compositions for treating cancer.
EP4367269A1 (en) 2021-07-05 2024-05-15 Inserm (Institut National De La Sante Et De La Recherche Medicale) Gene signatures for predicting survival time in patients suffering from renal cell carcinoma
WO2023283213A1 (en) 2021-07-07 2023-01-12 Incyte Corporation Tricyclic compounds as inhibitors of kras
MX2024000674A (en) 2021-07-13 2024-02-07 BioNTech SE Multispecific binding agents against cd40 and cd137 in combination therapy for cancer.
JP2024529347A (en) 2021-07-14 2024-08-06 インサイト・コーポレイション Tricyclic Compounds as Inhibitors of KRAS
EP4370523A1 (en) 2021-07-14 2024-05-22 Blueprint Medicines Corporation Heterocyclic compounds as map4k1 inhibitors
CA3226163A1 (en) 2021-07-14 2023-01-19 Synthekine, Inc. Methods and compositions for use in cell therapy of neoplastic disease
TW202321238A (en) 2021-07-15 2023-06-01 美商纜圖藥品公司 Map4k1 inhibitors
EP4373505A1 (en) 2021-07-19 2024-05-29 Regeneron Pharmaceuticals, Inc. Combination of checkpoint inhibitors and an oncolytic virus for treating cancer
MX2024001075A (en) * 2021-07-23 2024-04-03 Univ Columbia Characterization of potent and broadly neutralizing monoclonal antibodies against sars-cov-2, its variants, and related coronaviruses and methods of use.
IL309120A (en) 2021-07-28 2024-02-01 Hoffmann La Roche Methods and compositions for treating cancer
JP2024527049A (en) 2021-07-28 2024-07-19 ジェネンテック， インコーポレイテッド Methods and Compositions for Treating Cancer
IL309934A (en) 2021-07-30 2024-03-01 Ona Therapeutics S L Anti-CD36 antibodies and their use for cancer treatment
EP4377348A1 (en) 2021-07-30 2024-06-05 Seagen Inc. Treatment for cancer
EP4380980A1 (en) 2021-08-03 2024-06-12 F. Hoffmann-La Roche AG Bispecific antibodies and methods of use
WO2023015198A1 (en) 2021-08-04 2023-02-09 Genentech, Inc. Il15/il15r alpha heterodimeric fc-fusion proteins for the expansion of nk cells in the treatment of solid tumours
WO2023028501A1 (en) 2021-08-23 2023-03-02 Immunitas Therapeutics, Inc. Anti-cd161 antibodies and uses thereof
JP2024534127A (en) 2021-08-25 2024-09-18 ピク セラピューティクス， インコーポレイテッド eIF4E inhibitors and uses thereof
JP2024532276A (en) 2021-08-25 2024-09-05 ピク セラピューティクス， インコーポレイテッド eIF4E inhibitors and uses thereof
JP2024534187A (en) 2021-08-31 2024-09-18 インサイト・コーポレイション Naphthyridine Compounds as Inhibitors of KRAS - Patent application
TW202325306A (en) 2021-09-02 2023-07-01 美商天恩治療有限公司 Methods of improving growth and function of immune cells
WO2023031366A1 (en) 2021-09-02 2023-03-09 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Anti-cecam6 antibodies with reduced side-effects
WO2023039089A1 (en) 2021-09-08 2023-03-16 Twentyeight-Seven, Inc. Papd5 and/or papd7 inhibiting 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives
US12030883B2 (en) 2021-09-21 2024-07-09 Incyte Corporation Hetero-tricyclic compounds as inhibitors of KRAS
WO2023051926A1 (en) 2021-09-30 2023-04-06 BioNTech SE Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists
WO2023056403A1 (en) 2021-09-30 2023-04-06 Genentech, Inc. Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists
EP4408536A1 (en) 2021-10-01 2024-08-07 Incyte Corporation Pyrazoloquinoline kras inhibitors
TW202327595A (en) 2021-10-05 2023-07-16 美商輝瑞大藥廠 Combinations of azalactam compounds for the treatment of cancer
TW202333802A (en) 2021-10-11 2023-09-01 德商拜恩迪克公司 Therapeutic rna for lung cancer
AU2022367432A1 (en) 2021-10-14 2024-05-02 Incyte Corporation Quinoline compounds as inhibitors of kras
MX2024004763A (en) 2021-10-20 2024-05-08 Synthekine Inc Heterodimeric fc cytokines and uses thereof.
TW202328198A (en) 2021-10-21 2023-07-16 大陸商杭州阿諾生物醫藥科技有限公司 A fusion polypeptide and application thereof
AU2022377637A1 (en) 2021-10-28 2024-05-02 Lyell Immunopharma, Inc. Methods for culturing immune cells
WO2023077090A1 (en) 2021-10-29 2023-05-04 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hematological cancer
CN116072211A (en) * 2021-10-29 2023-05-05 京东方科技集团股份有限公司 Method for alignment of antibody complementarity determinant sequences and its device and electronic equipment
JP2024540080A (en) 2021-10-29 2024-10-31 カイメラ セラピューティクス， インコーポレイテッド IRAK4 degraders and their synthesis
WO2023079428A1 (en) 2021-11-03 2023-05-11 Pfizer Inc. Combination therapies using tlr7/8 agonist
WO2023078900A1 (en) 2021-11-03 2023-05-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating triple negative breast cancer (tnbc)
WO2023081730A1 (en) 2021-11-03 2023-05-11 Teon Therapeutics, Inc. 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide derivatives as cannabinoid cb2 receptor modulators for the treatment of cancer
WO2023080900A1 (en) 2021-11-05 2023-05-11 Genentech, Inc. Methods and compositions for classifying and treating kidney cancer
WO2023086835A1 (en) 2021-11-09 2023-05-19 Sensei Biotherapeutics, Inc. Anti-vista antibodies and uses thereof
WO2023083439A1 (en) 2021-11-09 2023-05-19 BioNTech SE Tlr7 agonist and combinations for cancer treatment
KR20240103030A (en) 2021-11-17 2024-07-03 인스티튜트 내셔날 드 라 싼테 에 드 라 리셰르셰 메디칼르 Universal Sarbecovirus Vaccine
TW202320792A (en) 2021-11-22 2023-06-01 美商英塞特公司 Combination therapy comprising an fgfr inhibitor and a kras inhibitor
EP4436969A2 (en) 2021-11-24 2024-10-02 Genentech, Inc. Bicyclic therapeutic compounds and methods of use in the treatment of cancer
TW202332429A (en) 2021-11-24 2023-08-16 美商建南德克公司 Therapeutic compounds and methods of use
WO2023097211A1 (en) 2021-11-24 2023-06-01 The University Of Southern California Methods for enhancing immune checkpoint inhibitor therapy
WO2023102184A1 (en) 2021-12-03 2023-06-08 Incyte Corporation Bicyclic amine compounds as cdk12 inhibitors
US12084453B2 (en) 2021-12-10 2024-09-10 Incyte Corporation Bicyclic amines as CDK12 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors
CN118660964A (en) 2021-12-16 2024-09-17 瓦莱里奥治疗公司 Novel conjugated nucleic acid molecules and uses thereof
WO2023114984A1 (en) 2021-12-17 2023-06-22 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2023122573A1 (en) 2021-12-20 2023-06-29 Synthorx, Inc. Head and neck cancer combination therapy comprising an il-2 conjugate and pembrolizumab
WO2023118165A1 (en) 2021-12-21 2023-06-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
AR128043A1 (en) 2021-12-22 2024-03-20 Incyte Corp SALTS AND SOLID FORMS OF AN FGFR INHIBITOR AND PROCESSES FOR THEIR PREPARATION
WO2023122777A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
WO2023122772A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
WO2023122778A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Pyridazinone derivatives useful as t cell activators
WO2023129438A1 (en) 2021-12-28 2023-07-06 Wisconsin Alumni Research Foundation Hydrogel compositions for use for depletion of tumor associated macrophages
JP2025501238A (en) 2021-12-30 2025-01-17 ネオイミューンテック， インコーポレイテッド Method for treating tumors using a combination of IL-7 protein and VEGF antagonist
WO2023137161A1 (en) 2022-01-14 2023-07-20 Amgen Inc. Triple blockade of tigit, cd112r, and pd-l1
EP4469477A1 (en) 2022-01-26 2024-12-04 Bristol-Myers Squibb Company Combination therapy for hepatocellular carcinoma
WO2023147470A2 (en) 2022-01-28 2023-08-03 Georgiamune Inc. Antibodies to programmed cell death protein 1 that are pd-1 agonists
CN118742325A (en) 2022-01-28 2024-10-01 上海岸阔医药科技有限公司 Methods for preventing or treating diseases or conditions associated with anti-tumor agents
TW202339738A (en) 2022-01-31 2023-10-16 美商凱麥拉醫療公司 Irak degraders and uses thereof
JP2025504955A (en) 2022-01-31 2025-02-19 センテッサ ファーマシューティカルズ （ユーケー） リミテッド Activatable bispecific anti-cd47 and anti-pd-l1 proteins and uses thereof
WO2023150186A1 (en) 2022-02-01 2023-08-10 Arvinas Operations, Inc. Dgk targeting compounds and uses thereof
WO2023154905A1 (en) 2022-02-14 2023-08-17 Gilead Sciences, Inc. Antiviral pyrazolopyridinone compounds
WO2023154799A1 (en) 2022-02-14 2023-08-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Combination immunotherapy for treating cancer
US12052261B2 (en) 2022-02-15 2024-07-30 Bank Of America Corporation System and method for authenticating the receiving end of data transmission via LiFi and holochain network
US12074641B2 (en) 2022-02-15 2024-08-27 Bank Of America Corporation System and method for secured data transmission using LiFi and holochain network
KR20240149434A (en) 2022-02-17 2024-10-14 리제너론 파마슈티칼스 인코포레이티드 Combination of checkpoint inhibitors and oncolytic viruses to treat cancer
KR20240150493A (en) 2022-02-21 2024-10-15 온퀄리티 파마슈티컬스 차이나 리미티드 Compounds and their uses
WO2023161453A1 (en) 2022-02-24 2023-08-31 Amazentis Sa Uses of urolithins
JP2025507694A (en) 2022-02-25 2025-03-21 ブリストル－マイヤーズ スクイブ カンパニー Combination Therapy for Colorectal Cancer
IL315262A (en) 2022-03-03 2024-10-01 Pfizer Multispecific antibodies binding to il-4, il-13 and/or tslp and uses thereof
WO2023168404A1 (en) 2022-03-04 2023-09-07 Bristol-Myers Squibb Company Methods of treating a tumor
EP4490151A1 (en) 2022-03-07 2025-01-15 Incyte Corporation Solid forms, salts, and processes of preparation of a cdk2 inhibitor
US20250179170A1 (en) 2022-03-08 2025-06-05 Alentis Therapeutics Ag Use of anti-claudin-1 antibodies to increase t cell availability
WO2023173053A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023173057A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023174210A1 (en) 2022-03-14 2023-09-21 Laekna Limited Combination treatment for cancer
EP4493575A1 (en) 2022-03-18 2025-01-22 Bristol-Myers Squibb Company Methods of isolating polypeptides
IL315768A (en) 2022-03-30 2024-11-01 Centessa Pharmaceuticals Uk Ltd Activatable bispecific anti-cd3 and anti-pd-l1 proteins and uses thereof
WO2023192478A1 (en) 2022-04-01 2023-10-05 Bristol-Myers Squibb Company Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer
WO2023191816A1 (en) 2022-04-01 2023-10-05 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023196987A1 (en) 2022-04-07 2023-10-12 Bristol-Myers Squibb Company Methods of treating tumor
WO2023196988A1 (en) 2022-04-07 2023-10-12 Modernatx, Inc. Methods of use of mrnas encoding il-12
WO2023194656A1 (en) 2022-04-08 2023-10-12 Tilt Biotherapeutics Oy Monoclonal pd-l1 antibodies
JP2025517869A (en) 2022-04-08 2025-06-12 ブリストル－マイヤーズ スクイブ カンパニー Machine learning identification, classification, and quantification of tertiary lymphoid tissue-like structures
TW202519266A (en) 2022-04-13 2025-05-16 美商建南德克公司 Pharmaceutical compositions of mosunetuzumab and methods of use
US20230406930A1 (en) 2022-04-13 2023-12-21 Genentech, Inc. Pharmaceutical compositions of therapeutic proteins and methods of use
EP4507704A1 (en) 2022-04-15 2025-02-19 Iovance Biotherapeutics, Inc. Til expansion processes using specific cytokine combinations and/or akti treatment
WO2023211889A1 (en) 2022-04-25 2023-11-02 Ikena Oncology, Inc. Polymorphic compounds and uses thereof
WO2023214325A1 (en) 2022-05-05 2023-11-09 Novartis Ag Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors
IL316738A (en) 2022-05-11 2024-12-01 Genentech Inc Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
AR129314A1 (en) 2022-05-12 2024-08-14 Genentech Inc PROCEDURES AND COMPOSITIONS COMPRISING AN SHP2 INHIBITOR AND A PD-L1 BINDING ANTAGONIST
EP4525991A1 (en) 2022-05-18 2025-03-26 Kymab Limited Uses of anti-icos antibodies
JP2025519119A (en) 2022-05-25 2025-06-24 イケナ オンコロジー， インコーポレイテッド MEK inhibitors and their uses
WO2023230554A1 (en) 2022-05-25 2023-11-30 Pfizer Inc. Combination of a braf inhibitor, an egfr inhibitor, and a pd-1 antagonist for the treatment of braf v600e-mutant, msi-h/dmmr colorectal cancer
AR129423A1 (en) 2022-05-27 2024-08-21 Viiv Healthcare Co USEFUL COMPOUNDS IN HIV THERAPY
JP2025518785A (en) 2022-06-02 2025-06-19 ブリストル－マイヤーズ スクイブ カンパニー Antibody compositions and methods of use thereof
KR20250022049A (en) 2022-06-07 2025-02-14 제넨테크, 인크. Method for determining the efficacy of a treatment for lung cancer comprising an anti-PD-L1 antagonist and an anti-TIGIT antagonist antibody
JP2025523403A (en) 2022-06-08 2025-07-23 タイダル・セラビューティクス・インコーポレイテッド Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and uses thereof
AU2023284958A1 (en) 2022-06-08 2025-01-02 Incyte Corporation Tricyclic triazolo compounds as dgk inhibitors
JP2025523424A (en) 2022-06-16 2025-07-23 ランカプ バイオ ベータ リミテッド Combination therapy with bispecific antibodies against CEACAM5 and CD47 and bispecific antibodies against CEACAM5 and CD3
KR20250029137A (en) 2022-06-22 2025-03-04 주노 쎄러퓨티크스 인코퍼레이티드 Treatment methods for second-line therapy with CD19-targeted CAR T cells
WO2023250430A1 (en) 2022-06-22 2023-12-28 Incyte Corporation Bicyclic amine cdk12 inhibitors
US20240101557A1 (en) 2022-07-11 2024-03-28 Incyte Corporation Fused tricyclic compounds as inhibitors of kras g12v mutants
EP4555093A2 (en) 2022-07-11 2025-05-21 Autonomous Therapeutics, Inc. Encrypted rna and methods of its use
EP4554586A1 (en) 2022-07-12 2025-05-21 Hotspot Therapeutics, Inc. Cbl-b inhibitors and anti-pd1/anti-pd-l1 for use in the treatment of cancer
AU2023305619A1 (en) 2022-07-13 2025-01-23 F. Hoffmann-La Roche Ag Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024015372A1 (en) 2022-07-14 2024-01-18 Teon Therapeutics, Inc. Adenosine receptor antagonists and uses thereof
EP4558524A1 (en) 2022-07-19 2025-05-28 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
JP2025526369A (en) 2022-07-27 2025-08-13 アストラゼネカ・アクチエボラーグ Combination of recombinant viruses expressing interleukin-12 with PD-1/PD-L1 inhibitors
CN120051456A (en) 2022-08-02 2025-05-27 里米诺生物科学有限公司 Substituted pyridone GPR84 antagonists and uses thereof
AU2023317740A1 (en) 2022-08-02 2025-03-13 Liminal Biosciences Limited Heteroaryl carboxamide and related gpr84 antagonists and uses thereof
TW202415650A (en) 2022-08-02 2024-04-16 英商利米那生物科技有限公司 Aryl-triazolyl and related gpr84 antagonists and uses thereof
IL318416A (en) 2022-08-05 2025-03-01 Juno Therapeutics Inc Chimeric antigen receptors specific for gprc5d and bcma
EP4568950A1 (en) 2022-08-08 2025-06-18 Bristol-Myers Squibb Company Substituted tetrazolyl compounds useful as t cell activators
WO2024036101A1 (en) 2022-08-09 2024-02-15 Bristol-Myers Squibb Company Tertiary amine substituted bicyclic compounds useful as t cell activators
WO2024033400A1 (en) 2022-08-10 2024-02-15 Institut National de la Santé et de la Recherche Médicale Sk2 inhibitor for the treatment of pancreatic cancer
WO2024033399A1 (en) 2022-08-10 2024-02-15 Institut National de la Santé et de la Recherche Médicale Sigmar1 ligand for the treatment of pancreatic cancer
JP2025526683A (en) 2022-08-11 2025-08-15 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Bicyclic tetrahydrothiazepine derivatives
AU2023322638A1 (en) 2022-08-11 2024-11-28 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
EP4568960A1 (en) 2022-08-11 2025-06-18 F. Hoffmann-La Roche AG Bicyclic tetrahydroazepine derivatives
PE20251399A1 (en) 2022-08-11 2025-05-22 Hoffmann La Roche Bicyclic tetrahydrothiazepine derivatives
JP2025527578A (en) 2022-08-18 2025-08-22 パルマトリックス オペレーティング カンパニー，インコーポレイテッド Methods for treating cancer with inhaled angiogenesis inhibitors
WO2024040264A1 (en) 2022-08-19 2024-02-22 Massachusetts Institute Of Technology Compositions and methods for targeting dendritic cell lectins
JPWO2024043227A1 (en) 2022-08-23 2024-02-29
JP2025529210A (en) 2022-09-01 2025-09-04 ユニバーシティ・オブ・ジョージア・リサーチ・ファウンデイション・インコーポレイテッド Compositions and methods for channeling apolipoprotein L1 to induce mammalian cell death - Patents.com
WO2024049949A1 (en) 2022-09-01 2024-03-07 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
WO2024052356A1 (en) 2022-09-06 2024-03-14 Institut National de la Santé et de la Recherche Médicale Inhibitors of the ceramide metabolic pathway for overcoming immunotherapy resistance in cancer
EP4587040A1 (en) 2022-09-14 2025-07-23 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for the treatment of dilated cardiomyopathy
EP4593961A1 (en) 2022-09-30 2025-08-06 Alentis Therapeutics AG Treatment of drug-resistant hepatocellular carcinoma
US20240174732A1 (en) 2022-10-05 2024-05-30 Flagship Pioneering Innovations V, Inc. Nucleic acid molecules encoding trif and additional polypeptides and their use in treating cancer
EP4599089A1 (en) 2022-10-05 2025-08-13 Genentech, Inc. Methods and compositions for classifying and treating bladder cancer
EP4599088A1 (en) 2022-10-05 2025-08-13 Genentech, Inc. Methods and compositions for classifying and treating lung cancer
AU2023361162A1 (en) 2022-10-11 2025-05-29 Yale University Compositions and methods of using cell-penetrating antibodies
JP7730432B2 (en) 2022-10-19 2025-08-27 アステラス製薬株式会社 Use of anti-cldn4-anti-cd137 bispecific antibodies in combination with pd-1 signal inhibitors in cancer treatment
EP4604939A1 (en) 2022-10-20 2025-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Combination therapy for the treatment of cancer
WO2024086739A1 (en) 2022-10-20 2024-04-25 Synthekine, Inc. Methods and compositions of il12 muteins and il2 muteins
EP4605422A2 (en) 2022-10-20 2025-08-27 Repertoire Immune Medicines, Inc. Cd8 t cell targeted il2
WO2024084034A1 (en) 2022-10-21 2024-04-25 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for the treatment of osteoarthritis
EP4608995A1 (en) 2022-10-24 2025-09-03 Memorial Sloan-Kettering Cancer Center Tumour stratification for responsiveness to an immune checkpoint inhibitor
AU2023369055A1 (en) 2022-10-24 2025-05-15 Cancer Research Technology Limited Tumour sensitisation to checkpoint inhibitors with redox status modifier
WO2024091991A1 (en) 2022-10-25 2024-05-02 Genentech, Inc. Therapeutic and diagnostic methods for multiple myeloma
WO2024102722A1 (en) 2022-11-07 2024-05-16 Neoimmunetech, Inc. Methods of treating a tumor with an unmethylated mgmt promoter
WO2024102635A1 (en) 2022-11-07 2024-05-16 Alector Llc Uses of siglec-9 ecd fusion molecules in cancer treatment
WO2024108100A1 (en) 2022-11-18 2024-05-23 Incyte Corporation Heteroaryl fluoroalkenes as dgk inhibitors
CN120584182A (en) 2022-11-21 2025-09-02 艾欧凡斯生物治疗公司 Two-dimensional process of tumor-infiltrating lymphocyte expansion and its therapy
US20240208961A1 (en) 2022-11-22 2024-06-27 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
EP4622631A1 (en) 2022-11-23 2025-10-01 University of Georgia Research Foundation, Inc. Compositions and methods of use thereof for increasing immune responses
EP4613780A1 (en) 2022-11-29 2025-09-10 Adlai Nortye Biopharma Co., Ltd. Fusion polypeptide and use thereof
WO2024118836A1 (en) 2022-11-30 2024-06-06 Iovance Biotherapeutics, Inc. Processes for production of tumor infiltrating lymphocytes with shortened rep step
AU2023402712A1 (en) 2022-12-01 2025-05-08 Innate Pharma Compositions and methods for neoadjuvant treatment in cancer comprising anti-cd39 antibodies
CN120302979A (en) 2022-12-01 2025-07-11 生物技术公司 Combination therapy of multispecific antibodies targeting CD40 and CD137 with anti-PD1 Ab and chemotherapy
WO2024116140A1 (en) 2022-12-01 2024-06-06 Medimmune Limited Combination therapy for treatment of cancer comprising anti-pd-l1 and anti-cd73 antibodies
WO2024129778A2 (en) 2022-12-13 2024-06-20 Juno Therapeutics, Inc. Chimeric antigen receptors specific for baff-r and cd19 and methods and uses thereof
WO2024126457A1 (en) 2022-12-14 2024-06-20 Astellas Pharma Europe Bv Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and immune checkpoint inhibitors
KR20250122520A (en) 2022-12-20 2025-08-13 제넨테크, 인크. Method for treating pancreatic cancer using a PD-1 axis binding antagonist and an RNA vaccine
IL321575A (en) 2022-12-21 2025-08-01 Bristol Myers Squibb Co Combination therapy for lung cancer
WO2024137865A1 (en) 2022-12-22 2024-06-27 Gossamer Bio Services, Inc. Compounds useful as t cell activators
IL321948A (en) 2023-01-06 2025-09-01 Lassen Therapeutics Inc Anti-il-18bp antibodies
TW202430560A (en) 2023-01-06 2024-08-01 美商拉森醫療公司 Anti-il-18bp antibodies
US20240269251A1 (en) 2023-01-09 2024-08-15 Flagship Pioneering Innovations V, Inc. Genetic switches and their use in treating cancer
WO2024150177A1 (en) 2023-01-11 2024-07-18 Advesya Treatment methods for solid tumors
TW202428575A (en) 2023-01-12 2024-07-16 美商英塞特公司 Heteroaryl fluoroalkenes as dgk inhibitors
WO2024150017A1 (en) 2023-01-13 2024-07-18 Akrivia Biomedics Limited Method of profiling diseases
WO2024151885A1 (en) 2023-01-13 2024-07-18 Iovance Biotherapeutics, Inc. Use of til as maintenance therapy for nsclc patients who achieved pr/cr after prior therapy
US20240294651A1 (en) 2023-01-30 2024-09-05 Kymab Limited Antibodies
WO2024163477A1 (en) 2023-01-31 2024-08-08 University Of Rochester Immune checkpoint blockade therapy for treating staphylococcus aureus infections
WO2024196952A1 (en) 2023-03-20 2024-09-26 Bristol-Myers Squibb Company Tumor subtype assessment for cancer therapy
AU2024239150A1 (en) 2023-03-21 2025-10-02 Biograph 55, Inc. Cd19/cd38 multispecific antibodies
WO2024200571A1 (en) 2023-03-28 2024-10-03 Institut National de la Santé et de la Recherche Médicale Method for discriminating mono-immunotherapy from combined immunotherapy in cancers
US20240336608A1 (en) 2023-03-29 2024-10-10 Merck Sharp & Dohme Llc Il4i1 inhibitors and methods of use
WO2024208818A1 (en) 2023-04-04 2024-10-10 Innate Pharma Modular chimeric antigen receptor
WO2024216028A1 (en) 2023-04-12 2024-10-17 Agenus Inc. Methods of treating cancer using an anti-ctla4 antibody and an enpp1 inhibitor
WO2024213767A1 (en) 2023-04-14 2024-10-17 Institut National de la Santé et de la Recherche Médicale Engraftment of mesenchymal stromal cells engineered to stimulate immune infiltration in tumors
US20240390340A1 (en) 2023-04-18 2024-11-28 Incyte Corporation Pyrrolidine kras inhibitors
WO2024218512A1 (en) * 2023-04-19 2024-10-24 Centessa Pharmaceuticals (Uk) Limited Activatable bispecific anti-cd89 and anti-pd-l1 proteins and uses thereof
WO2024224323A1 (en) 2023-04-24 2024-10-31 King Abdullah University Of Science Of Technology Compositions, systems and methods for multiplex detection of target biomarkers in a sample
WO2024223299A2 (en) 2023-04-26 2024-10-31 Isa Pharmaceuticals B.V. Methods of treating cancer by administering immunogenic compositions and a pd-1 inhibitor
WO2024228167A1 (en) 2023-05-03 2024-11-07 Iox Therapeutics Inc. Inkt cell modulator liposomal compositions and methods of use
TW202509069A (en) 2023-05-04 2025-03-01 美商諾瓦森塔股份有限公司 Anti-cd161 antibodies and methods of use thereof
WO2024233341A1 (en) 2023-05-05 2024-11-14 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024231384A1 (en) 2023-05-10 2024-11-14 Institut National de la Santé et de la Recherche Médicale Compositions for treating senescence related disease
WO2024233646A1 (en) 2023-05-10 2024-11-14 Genentech, Inc. Methods and compositions for treating cancer
TW202509014A (en) 2023-05-10 2025-03-01 美商纜圖藥品公司 Gsk3α inhibitors and methods of use thereof
WO2024245951A1 (en) 2023-05-26 2024-12-05 Institut National de la Santé et de la Recherche Médicale Combination of slc8a1 inhibitor and mitochondria-targeted antioxidant for treating melanoma
WO2024254227A1 (en) 2023-06-07 2024-12-12 Bristol-Myers Squibb Company Spirocyclic substituted oxoisoindolinyl piperidine-2,6-dione compound
WO2024254245A1 (en) 2023-06-09 2024-12-12 Incyte Corporation Bicyclic amines as cdk2 inhibitors
WO2024256635A1 (en) 2023-06-15 2024-12-19 Institut National de la Santé et de la Recherche Médicale Dpm1 inhibitor for treating cancer
WO2024261302A1 (en) 2023-06-22 2024-12-26 Institut National de la Santé et de la Recherche Médicale Nlrp3 inhibitors, pak1/2 inhibitors and/or caspase 1 inhibitors for use in the treatment of rac2 monogenic disorders
US20250059164A1 (en) 2023-06-23 2025-02-20 Kymera Therapeutics, Inc. Irak degraders and uses thereof
WO2024263195A1 (en) 2023-06-23 2024-12-26 Genentech, Inc. Methods for treatment of liver cancer
WO2024263904A1 (en) 2023-06-23 2024-12-26 Genentech, Inc. Methods for treatment of liver cancer
WO2024263853A1 (en) 2023-06-23 2024-12-26 Bristol-Myers Squibb Company Substituted oxoisoindolinyl piperidine-2,6-dione compound as anticancer agent
WO2025003193A1 (en) 2023-06-26 2025-01-02 Institut National de la Santé et de la Recherche Médicale Sertraline and indatraline for disrupting intracellular cholesterol trafficking and subsequently inducing lysosomal damage and anti-tumor immunity
WO2025006811A1 (en) 2023-06-27 2025-01-02 Lyell Immunopharma, Inc. Methods for culturing immune cells
WO2025012417A1 (en) 2023-07-13 2025-01-16 Institut National de la Santé et de la Recherche Médicale Anti-neurotensin long fragment and anti-neuromedin n long fragment antibodies and uses thereof
WO2025024257A1 (en) 2023-07-21 2025-01-30 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2025030002A2 (en) 2023-08-02 2025-02-06 Arvinas Operations, Inc. Dgk targeting compounds and uses thereof
WO2025038763A1 (en) 2023-08-15 2025-02-20 Bristol-Myers Squibb Company Ceramic hydroxyapatite chromatography flow through method
WO2025042742A1 (en) 2023-08-18 2025-02-27 Bristol-Myers Squibb Company Compositions comprising antibodies that bind bcma and cd3 and methods of treatment
US20250066363A1 (en) 2023-08-24 2025-02-27 Incyte Corporation Bicyclic DGK Inhibitors
TW202515614A (en) 2023-08-25 2025-04-16 美商建南德克公司 Methods and compositions for treating non-small cell lung cancer
WO2025064197A1 (en) 2023-09-02 2025-03-27 Bristol-Myers Squibb Company Substituted azetidinyl oxoisoindolinyl piperidine-2,6-dione compounds
WO2025056180A1 (en) 2023-09-15 2025-03-20 BioNTech SE Methods of treatment using agents binding to epcam and cd137 in combination with pd-1 axis binding antagonists
WO2025073765A1 (en) 2023-10-03 2025-04-10 Institut National de la Santé et de la Recherche Médicale Methods of prognosis and treatment of patients suffering from melanoma
US20250114346A1 (en) 2023-10-09 2025-04-10 Incyte Corporation Combination therapy using a kras g12d inhibitor and pd-1 inhibitor or pd-l1 inhibitor
WO2025080538A1 (en) 2023-10-09 2025-04-17 Regeneron Pharmaceuticals, Inc. Methods of treating cancer with a combination of a pd1 inhibitor and a targeted immunocytokine
TW202515903A (en) 2023-10-12 2025-04-16 瑞士商百濟神州瑞士有限責任公司 Anti-pd-1-based treatment before and after surgery
WO2025078632A1 (en) 2023-10-12 2025-04-17 Institut National de la Santé et de la Recherche Médicale Methods of prognosis and treatment of patients suffering from cancer
WO2025085404A1 (en) 2023-10-16 2025-04-24 Genentech, Inc. Diagnostic and therapeutic methods for treating lung cancer
WO2025085781A1 (en) 2023-10-19 2025-04-24 Genentech, Inc. Combinations of il15/il15r alpha heterodimeric fc-fusion proteins and her2xcd3 bispecific antibodies for the treatment of her2-positive cancers
WO2025096494A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
US20250145590A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
WO2025096490A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
WO2025096489A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
WO2025096488A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
WO2025096487A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
WO2025096505A1 (en) 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Ubiquitin specific processing protease 1 (usp1) compounds
WO2025096738A1 (en) 2023-11-01 2025-05-08 Incyte Corporation Kras inhibitors
WO2025096843A1 (en) 2023-11-03 2025-05-08 Amgen Inc. Bispecific molecules
WO2025106278A1 (en) 2023-11-17 2025-05-22 Mersana Therapeutics, Inc. Treatment of cancer using b7-h4-targeted antibody-drug conjugates
TW202523667A (en) 2023-12-05 2025-06-16 美商英塞特公司 Tricyclic triazolo compounds as dgk inhibitors
US20250186450A1 (en) 2023-12-06 2025-06-12 Incyte Corporation COMBINATION THERAPY COMPRISING DGK INHIBITORS and PD-1/PD-L1 INHIBITORS
WO2025121445A1 (en) 2023-12-08 2025-06-12 Astellas Pharma Inc. Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and agents stabilizing or increasing expression of cldn18.2
WO2025120867A1 (en) 2023-12-08 2025-06-12 Astellas Pharma Inc. Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and anti-vegfr2 antibodies
WO2025120866A1 (en) 2023-12-08 2025-06-12 Astellas Pharma Inc. Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and agents stabilizing or increasing expression of cldn18.2
WO2025129002A1 (en) 2023-12-13 2025-06-19 Incyte Corporation Bicyclooctane kras inhibitors
WO2025132479A1 (en) 2023-12-18 2025-06-26 Institut National de la Santé et de la Recherche Médicale Flt3 inhibitor for modulating macrophages polarization
WO2025132770A1 (en) 2023-12-22 2025-06-26 Institut National de la Santé et de la Recherche Médicale Affitins for the treatment of cancer
WO2025145207A1 (en) 2023-12-29 2025-07-03 Bristol-Myers Squibb Company Combination therapy of kras inhibitor and treg-depleting agent
WO2025155607A1 (en) 2024-01-16 2025-07-24 Genentech, Inc. Methods of treating urothelial carcinoma with a pd-1 axis binding antagonist and an rna vaccine
WO2025153834A1 (en) 2024-01-19 2025-07-24 Institut National de la Santé et de la Recherche Médicale Methods of predicting the risk of recurrence and/or death of patients suffering from a hepatocellular carcinoma (hcc)
WO2025163468A1 (en) 2024-01-30 2025-08-07 Seagen Inc. Anti-pd-l1 antibodies and antibody-drug conjugates and their use in the treatment of cancer
WO2025174825A2 (en) 2024-02-12 2025-08-21 Aera Therapeutics, Inc. Delivery compositions
WO2025174933A1 (en) 2024-02-14 2025-08-21 Genentech, Inc. Methods for treatment of pancreatic cancer with anti-pd-l1 ab, anti-tigit ab, gemcitabine and nab-placlitaxel
WO2025184208A1 (en) 2024-02-27 2025-09-04 Bristol-Myers Squibb Company Anti-ceacam5 antibodies and uses thereof
US20250269052A1 (en) 2024-02-27 2025-08-28 Bristol-Myers Squibb Company Anti-ceacam5 antibody drug conjugates
US20250282786A1 (en) 2024-03-05 2025-09-11 Bristol-Myers Squibb Company Tricyclic TLR7 Agonists and Uses Thereof
WO2025188693A1 (en) 2024-03-05 2025-09-12 Bristol-Myers Squibb Company Bicyclic tlr7 agonists and uses thereof
WO2025186778A1 (en) 2024-03-08 2025-09-12 Janssen Biotech, Inc. Combinations of oncolytic viruses and immunomodulators
WO2025191498A1 (en) 2024-03-12 2025-09-18 Adaptam Therapeutics, S.L. Anti-siglec-15 antibodies and uses thereof
WO2025191529A1 (en) 2024-03-14 2025-09-18 Biohaven Therapeutics Ltd. Next generation riluzole prodrugs
WO2025202213A1 (en) 2024-03-26 2025-10-02 Institut National de la Santé et de la Recherche Médicale Lipid nanoparticle loaded with antitumoral agent and functionnalized to target immosuppressive cells

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7794710B2 (en) * 2001-04-20 2010-09-14 Mayo Foundation For Medical Education And Research Methods of enhancing T cell responsiveness
US9102725B2 (en) * 2005-07-01 2015-08-11 E. R. Squibb & Sons, L. L. C. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
US20170137514A1 (en) * 2012-07-02 2017-05-18 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US20180155429A1 (en) * 2015-05-28 2018-06-07 Bristol-Myers Squibb Company Treatment of pd-l1 positive lung cancer using an anti-pd-1 antibody
US20180162942A1 (en) * 2015-05-29 2018-06-14 Bristol-Myers Squibb Company Treatment of renal cell carcinoma
US20180179282A1 (en) * 2015-06-12 2018-06-28 Bristol-Myers Squibb Company Treatment of cancer by combined blockade of the pd-1 and cxcr4 signaling pathways

Family Cites Families (135)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4399216A (en) 1980-02-25 1983-08-16 The Trustees Of Columbia University Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4634665A (en) 1980-02-25 1987-01-06 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US5179017A (en) 1980-02-25 1993-01-12 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4475196A (en) 1981-03-06 1984-10-02 Zor Clair G Instrument for locating faults in aircraft passenger reading light and attendant call control system
US4447233A (en) 1981-04-10 1984-05-08 Parker-Hannifin Corporation Medication infusion pump
US4439196A (en) 1982-03-18 1984-03-27 Merck & Co., Inc. Osmotic drug delivery system
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US4447224A (en) 1982-09-20 1984-05-08 Infusaid Corporation Variable flow implantable infusion apparatus
US4487603A (en) 1982-11-26 1984-12-11 Cordis Corporation Implantable microinfusion pump system
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4486194A (en) 1983-06-08 1984-12-04 James Ferrara Therapeutic device for administering medicaments through the skin
EP0154316B1 (en) 1984-03-06 1989-09-13 Takeda Chemical Industries, Ltd. Chemically modified lymphokine and production thereof
US4596556A (en) 1985-03-25 1986-06-24 Bioject, Inc. Hypodermic injection apparatus
US5374548A (en) 1986-05-02 1994-12-20 Genentech, Inc. Methods and compositions for the attachment of proteins to liposomes using a glycophospholipid anchor
MX9203291A (en) 1985-06-26 1992-08-01 Liposome Co Inc LIPOSOMAS COUPLING METHOD.
GB8601597D0 (en) 1986-01-23 1986-02-26 Wilson R H Nucleotide sequences
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US4954617A (en) 1986-07-07 1990-09-04 Trustees Of Dartmouth College Monoclonal antibodies to FC receptors for immunoglobulin G on human mononuclear phagocytes
US5260203A (en) 1986-09-02 1993-11-09 Enzon, Inc. Single polypeptide chain binding molecules
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US4881175A (en) 1986-09-02 1989-11-14 Genex Corporation Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides
EP0307434B2 (en) 1987-03-18 1998-07-29 Scotgen Biopharmaceuticals, Inc. Altered antibodies
US5013653A (en) 1987-03-20 1991-05-07 Creative Biomolecules, Inc. Product and process for introduction of a hinge region into a fusion protein to facilitate cleavage
US5091513A (en) 1987-05-21 1992-02-25 Creative Biomolecules, Inc. Biosynthetic antibody binding sites
WO1988009344A1 (en) 1987-05-21 1988-12-01 Creative Biomolecules, Inc. Targeted multifunctional proteins
US5258498A (en) 1987-05-21 1993-11-02 Creative Biomolecules, Inc. Polypeptide linkers for production of biosynthetic proteins
US5132405A (en) 1987-05-21 1992-07-21 Creative Biomolecules, Inc. Biosynthetic antibody binding sites
US4941880A (en) 1987-06-19 1990-07-17 Bioject, Inc. Pre-filled ampule and non-invasive hypodermic injection device assembly
US4790824A (en) 1987-06-19 1988-12-13 Bioject, Inc. Non-invasive hypodermic injection device
GB8717430D0 (en) 1987-07-23 1987-08-26 Celltech Ltd Recombinant dna product
US5677425A (en) 1987-09-04 1997-10-14 Celltech Therapeutics Limited Recombinant antibody
GB8809129D0 (en) 1988-04-18 1988-05-18 Celltech Ltd Recombinant dna methods vectors and host cells
US5476996A (en) 1988-06-14 1995-12-19 Lidak Pharmaceuticals Human immune system in non-human animal
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
GB8823869D0 (en) 1988-10-12 1988-11-16 Medical Res Council Production of antibodies
DE68925966T2 (en) 1988-12-22 1996-08-29 Kirin Amgen Inc CHEMICALLY MODIFIED GRANULOCYTE COLONY EXCITING FACTOR
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5108921A (en) 1989-04-03 1992-04-28 Purdue Research Foundation Method for enhanced transmembrane transport of exogenous molecules
US5064413A (en) 1989-11-09 1991-11-12 Bioject, Inc. Needleless hypodermic injection device
US5312335A (en) 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
US5859205A (en) * 1989-12-21 1999-01-12 Celltech Limited Humanised antibodies
US6673986B1 (en) 1990-01-12 2004-01-06 Abgenix, Inc. Generation of xenogeneic antibodies
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
DK0463151T3 (en) 1990-01-12 1996-07-01 Cell Genesys Inc Generation of xenogenic antibodies
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
US6172197B1 (en) 1991-07-10 2001-01-09 Medical Research Council Methods for producing members of specific binding pairs
GB9015198D0 (en) 1990-07-10 1990-08-29 Brien Caroline J O Binding substance
US5877397A (en) 1990-08-29 1999-03-02 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
US5789650A (en) 1990-08-29 1998-08-04 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
KR100272077B1 (en) 1990-08-29 2000-11-15 젠팜인터내셔날,인코포레이티드 Transgenic non-human animals capable of producing heterologous antibodies
US5874299A (en) 1990-08-29 1999-02-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5770429A (en) 1990-08-29 1998-06-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US6255458B1 (en) 1990-08-29 2001-07-03 Genpharm International High affinity human antibodies and human antibodies against digoxin
US6300129B1 (en) 1990-08-29 2001-10-09 Genpharm International Transgenic non-human animals for producing heterologous antibodies
ES2227512T3 (en) 1991-12-02 2005-04-01 Medical Research Council PRODUCTION OF ANTIBODIES AGAINST SELF-ANTIGENS FROM REPERTORIES OF ANTIBODY SEGMENTS FIXED IN A PHOTO.
AU3328493A (en) 1991-12-17 1993-07-19 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5714350A (en) 1992-03-09 1998-02-03 Protein Design Labs, Inc. Increasing antibody affinity by altering glycosylation in the immunoglobulin variable region
EP0640094A1 (en) 1992-04-24 1995-03-01 The Board Of Regents, The University Of Texas System Recombinant production of immunoglobulin-like domains in prokaryotic cells
US5260074A (en) 1992-06-22 1993-11-09 Digestive Care Inc. Compositions of digestive enzymes and salts of bile acids and process for preparation thereof
US5383851A (en) 1992-07-24 1995-01-24 Bioject Inc. Needleless hypodermic injection device
GB9223377D0 (en) 1992-11-04 1992-12-23 Medarex Inc Humanized antibodies to fc receptors for immunoglobulin on human mononuclear phagocytes
JPH08509612A (en) 1993-04-26 1996-10-15 ジェンファーム インターナショナル インコーポレイテッド Transgenic non-human animal capable of producing heterologous antibody
JPH08511420A (en) 1993-06-16 1996-12-03 セルテック・セラピューテイクス・リミテッド Body
IL108501A (en) 1994-01-31 1998-10-30 Mor Research Applic Ltd Antibodies and pharmaceutical compositions containing them
CA2143491C (en) 1994-03-01 2011-02-22 Yasumasa Ishida A novel peptide related to human programmed cell death and dna encoding it
US5869046A (en) 1995-04-14 1999-02-09 Genentech, Inc. Altered polypeptides with increased half-life
US6121022A (en) 1995-04-14 2000-09-19 Genentech, Inc. Altered polypeptides with increased half-life
US6410690B1 (en) 1995-06-07 2002-06-25 Medarex, Inc. Therapeutic compounds comprised of anti-Fc receptor antibodies
US5811097A (en) 1995-07-25 1998-09-22 The Regents Of The University Of California Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US6051227A (en) 1995-07-25 2000-04-18 The Regents Of The University Of California, Office Of Technology Transfer Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
JP4436457B2 (en) 1995-08-18 2010-03-24 モルフォシス アイピー ゲーエムベーハー Protein / (poly) peptide library
ATE352613T1 (en) 1995-08-29 2007-02-15 Kirin Brewery CHIMERIC ANIMAL AND METHOD OF PRODUCING SAME
US6632976B1 (en) 1995-08-29 2003-10-14 Kirin Beer Kabushiki Kaisha Chimeric mice that are produced by microcell mediated chromosome transfer and that retain a human antibody gene
US5922845A (en) 1996-07-11 1999-07-13 Medarex, Inc. Therapeutic multispecific compounds comprised of anti-Fcα receptor antibodies
US6277375B1 (en) 1997-03-03 2001-08-21 Board Of Regents, The University Of Texas System Immunoglobulin-like domains with increased half-lives
US7368531B2 (en) 1997-03-07 2008-05-06 Human Genome Sciences, Inc. Human secreted proteins
US6261791B1 (en) 1997-03-10 2001-07-17 The Regents Of The University Of California Method for diagnosing cancer using specific PSCA antibodies
ATE319745T1 (en) 1997-05-21 2006-03-15 Biovation Ltd METHOD FOR PRODUCING NON-IMMUNOGENIC PROTEINS
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
WO1999054342A1 (en) 1998-04-20 1999-10-28 Pablo Umana Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity
ATE397457T1 (en) 1998-12-03 2008-06-15 Univ California STIMULATION OF T-CELLS AGAINST SELF-ANTIGENS USING CTLA-4 INHIBITING AGENTS
US7041474B2 (en) 1998-12-30 2006-05-09 Millennium Pharmaceuticals, Inc. Nucleic acid encoding human tango 509
US20080213778A1 (en) 1998-12-30 2008-09-04 Millennium Pharmaceuticals, Inc. Novel genes encoding proteins having prognostic, diagnostic, preventive, therapeutic, and other uses
HUP0104865A3 (en) 1999-01-15 2004-07-28 Genentech Inc Polypeptide variants with altered effector function
EP3031917A1 (en) 1999-04-09 2016-06-15 Kyowa Hakko Kirin Co., Ltd. Method for controlling the activity of immunologically functional molecule
FR2794025A1 (en) 1999-05-25 2000-12-01 Transgene Sa COMPOSITION FOR IMPLEMENTING ANTI-TUMOR OR ANTIVIRAL TREATMENT IN A MAMMAL
JP2003516718A (en) 1999-07-29 2003-05-20 メダレックス インク Human monoclonal antibody against HER2 / neu
EP2360254A1 (en) 1999-08-23 2011-08-24 Dana-Farber Cancer Institute, Inc. Assays for screening anti-pd-1 antibodies and uses thereof
ATE353365T1 (en) 1999-08-23 2007-02-15 Dana Farber Cancer Inst Inc NEW B7-4 MOLECULES AND THEIR USES
KR20020047132A (en) 1999-08-24 2002-06-21 메다렉스, 인코포레이티드 Human ctla-4 antibodies and their uses
AU1448701A (en) 1999-11-09 2001-06-06 Human Genome Sciences, Inc. 15 human secreted proteins
EP1234031B2 (en) 1999-11-30 2021-11-24 Mayo Foundation For Medical Education And Research B7-h1, a novel immunoregulatory molecule
US6803192B1 (en) 1999-11-30 2004-10-12 Mayo Foundation For Medical Education And Research B7-H1, a novel immunoregulatory molecule
US7030219B2 (en) 2000-04-28 2006-04-18 Johns Hopkins University B7-DC, Dendritic cell co-stimulatory molecules
US20030031675A1 (en) 2000-06-06 2003-02-13 Mikesell Glen E. B7-related nucleic acids and polypeptides useful for immunomodulation
AU2001275285A1 (en) 2000-06-06 2001-12-17 Bristol-Myers Squibb Company B7-related nucleic acids and polypeptides and their uses for immunomodulation
NZ543512A (en) 2000-06-28 2008-12-24 Genetics Inst Llc Interaction of PD-L2 with PD-1 transmits a negative signal to immune cells, downregulating immune responses
US20020025317A1 (en) 2000-07-20 2002-02-28 Schering Ag Bispecific monoclonal antibodies to IL-12 and IL-18
AU2599002A (en) 2000-10-20 2002-04-29 Tsuneya Ohno Fusion cells and cytokine compositions for treatment of disease
US7132109B1 (en) 2000-10-20 2006-11-07 University Of Connecticut Health Center Using heat shock proteins to increase immune response
ES2405944T3 (en) 2000-11-30 2013-06-04 Medarex, Inc. Nucleic acids encoding reorganized human immunoglobulin sequences from transgenic transchromosomal mice zadas
US7396917B2 (en) * 2000-12-05 2008-07-08 Alexion Pharmaceuticals, Inc. Rationally designed antibodies
AR036993A1 (en) 2001-04-02 2004-10-20 Wyeth Corp USE OF AGENTS THAT MODULATE THE INTERACTION BETWEEN PD-1 AND ITS LINKS IN THE SUBMODULATION OF IMMUNOLOGICAL ANSWERS
CA2442066C (en) 2001-04-02 2005-11-01 Wyeth Pd-1, a receptor for b7-4, and uses therefor
JP2004532038A (en) 2001-05-17 2004-10-21 ディヴァーサ コーポレイション Application of novel antigen-binding molecules to therapeutic, diagnostic, prophylactic, enzymatic, industrial and agricultural fields, and methods for producing and screening novel antigen-binding molecules therefor
WO2003006636A1 (en) 2001-07-12 2003-01-23 Genethor Gmbh Reduction of the stimulatory capacity of antigen-presenting cells
WO2004006955A1 (en) 2001-07-12 2004-01-22 Jefferson Foote Super humanized antibodies
JP4249013B2 (en) 2001-07-31 2009-04-02 佑 本庶 Substance with specificity for PD-1
IL145926A0 (en) 2001-10-15 2002-07-25 Mor Research Applic Ltd Peptide epitopes of mimotopes useful in immunomodulation
PL213948B1 (en) 2001-10-25 2013-05-31 Genentech Inc Glycoprotein compositions
CA2466279A1 (en) * 2001-11-13 2003-05-22 Dana-Farber Cancer Institute, Inc. Agents that modulate immune cell activation and methods of use thereof
WO2003074679A2 (en) 2002-03-01 2003-09-12 Xencor Antibody optimization
KR100708398B1 (en) 2002-03-22 2007-04-18 (주) 에이프로젠 Humanized antibody and process for preparing same
PL373256A1 (en) 2002-04-09 2005-08-22 Kyowa Hakko Kogyo Co, Ltd. Cells with modified genome
IL149820A0 (en) 2002-05-23 2002-11-10 Curetech Ltd Humanized immunomodulatory monoclonal antibodies for the treatment of neoplastic disease or immunodeficiency
US7304149B2 (en) 2002-06-20 2007-12-04 Washington University In St. Louis BTLA nucleic acids
DK2206517T3 (en) 2002-07-03 2023-11-06 Ono Pharmaceutical Co Immunopotentiating compositions comprising anti-PD-L1 antibodies
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
US7563869B2 (en) 2003-01-23 2009-07-21 Ono Pharmaceutical Co., Ltd. Substance specific to human PD-1
US7465446B2 (en) 2003-05-30 2008-12-16 Medarex, Inc. Surrogate therapeutic endpoint for anti-CTLA4-based immunotherapy of disease
WO2006021955A2 (en) 2004-08-23 2006-03-02 Mor Research Applications Ltd. Use of bat monoclonal antibody for immunotherapy
TWI309240B (en) * 2004-09-17 2009-05-01 Hoffmann La Roche Anti-ox40l antibodies
EP1810026B1 (en) 2004-10-06 2018-04-18 Mayo Foundation For Medical Education And Research B7-h1 and pd-1 in treatment of renal cell carcinoma
CA3151350A1 (en) 2005-05-09 2006-11-16 E. R. Squibb & Sons, L.L.C. Human monoclonal antibodies to programmed death 1 (pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
WO2006124269A2 (en) 2005-05-16 2006-11-23 Amgen Fremont Inc. Human monoclonal antibodies that bind to very late antigen-1 for the treatment of inflammation and other disorders
AU2012344260B2 (en) * 2011-11-28 2017-09-07 Merck Patent Gmbh Anti-PD-L1 antibodies and uses thereof
RU2016128726A (en) * 2013-12-17 2018-01-23 Дженентек, Инк. METHODS FOR TREATING MALIGNANT TUMORS USING PD-1 BINDING ANTAGONISTS AND ANTIBODIES AGAINST CD20
SG11201807474SA (en) * 2016-04-25 2018-11-29 Medimmune Llc Compositions comprising coformulation of anti-pd-l1 and anti-ctla-4 antibodies
KR102602137B1 (en) * 2016-07-06 2023-11-13 브리스톨-마이어스 스큅 컴퍼니 Combinations and methods of use of TIM-4 antagonists and PD-1 antagonists

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7794710B2 (en) * 2001-04-20 2010-09-14 Mayo Foundation For Medical Education And Research Methods of enhancing T cell responsiveness
US9102725B2 (en) * 2005-07-01 2015-08-11 E. R. Squibb & Sons, L. L. C. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
US9273135B2 (en) * 2005-07-01 2016-03-01 E. R. Squibb & Sons, L. L. C. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
US20170137514A1 (en) * 2012-07-02 2017-05-18 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US20180371087A1 (en) * 2012-07-02 2018-12-27 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US20180155429A1 (en) * 2015-05-28 2018-06-07 Bristol-Myers Squibb Company Treatment of pd-l1 positive lung cancer using an anti-pd-1 antibody
US20180162942A1 (en) * 2015-05-29 2018-06-14 Bristol-Myers Squibb Company Treatment of renal cell carcinoma
US20180179282A1 (en) * 2015-06-12 2018-06-28 Bristol-Myers Squibb Company Treatment of cancer by combined blockade of the pd-1 and cxcr4 signaling pathways

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
Abdiche et al. mAbs (2016) 8: 264–277. *
Boyd et al. Current Opinion in Immunology 2016, 40: 103–109. *
Conroy et al. Methods (2017) 116: 12–22. *
Damschroder et al. Molecular Immunology (2004) 41: 985–1000. *
Ferrara et al. mAbs (2015) 7: 32-41. *
Hirano et al. (Cancer Res 2005; 65(3): 1089-1096). *
Khan et al. Sci. Rep. (2017) 7, 45163; doi: 10.1038/srep45163 (12 pages). *
Konitzer et al. mAbs (2017) 9: 536-549. *
Lee et al. Nature Medicine (2016) 22: 1456–1464. *
Parola et al. Immunology (2018) 153: 31-41. *
Sheehan et al. Microbiol. Spectr. (2015) 3(1): AID-0028-2014; 17 pages. *
Van Regenmortel MHV. Front. Immunol. (2018) Vol. 8, Article 2009 (11 pages). *
Zhu et al. Cell (2015) 161: 1280–1292. *
Zou W. Nature Reviews Cancer (2005) 5: 263–274. *

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11236165B2 (en) 2008-08-11 2022-02-01 E.R. Squibb & Sons, L.L.C. Human antibodies that bind Lymphocyte Activation Gene-3 (LAG-3), and uses thereof
US11512130B2 (en) 2008-08-11 2022-11-29 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11530267B2 (en) 2008-08-11 2022-12-20 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11236163B2 (en) 2008-08-11 2022-02-01 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11236164B2 (en) 2008-08-11 2022-02-01 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US10344089B2 (en) 2008-08-11 2019-07-09 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US10988535B2 (en) 2008-08-11 2021-04-27 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US10988536B2 (en) 2008-08-11 2021-04-27 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11001630B2 (en) 2008-08-11 2021-05-11 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation Gene-3 (LAG-3), and uses thereof
US11345752B2 (en) 2012-07-02 2022-05-31 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
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US10081681B2 (en) 2013-09-20 2018-09-25 Bristol-Myers Squibb Company Combination of anti-LAG-3 antibodies and anti-PD-1 antibodies to treat tumors
US11274152B2 (en) 2013-09-20 2022-03-15 Bristol-Myers Squibb Company Combination of anti-LAG-3 antibodies and anti-PD-1 antibodies to treat tumors
US11174316B2 (en) 2015-03-13 2021-11-16 Cytomx Therapeutics, Inc. Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of use thereof
US10669339B2 (en) 2015-03-13 2020-06-02 Cytomx Therapeutics, Inc. Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of use thereof
US10336824B2 (en) 2015-03-13 2019-07-02 Cytomx Therapeutics, Inc. Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of thereof
US10512689B2 (en) 2015-04-17 2019-12-24 Bristol-Myers Squibb Company Compositions comprising a combination of nivolumab and ipilimumab
US11612654B2 (en) 2015-04-17 2023-03-28 Bristol-Myers Squibb Company Combination therapy comprising nivolumab and ipilimumab
US11078278B2 (en) 2015-05-29 2021-08-03 Bristol-Myers Squibb Company Treatment of renal cell carcinoma
US12152075B2 (en) 2015-05-29 2024-11-26 Bristol-Myers Squibb Company Treatment of renal cell carcinoma
US11542332B2 (en) 2016-03-26 2023-01-03 Bioatla, Inc. Anti-CTLA4 antibodies, antibody fragments, their immunoconjugates and uses thereof
WO2017220602A1 (en) 2016-06-21 2017-12-28 Herlev Hospital Pdl1 peptides for use in cancer vaccines
US11807686B2 (en) 2017-05-30 2023-11-07 Bristol-Myers Squibb Company Treatment of LAG-3 positive tumors
US12049503B2 (en) 2017-05-30 2024-07-30 Bristol-Myers Squibb Company Treatment of LAG-3 positive tumors
US11723975B2 (en) 2017-05-30 2023-08-15 Bristol-Myers Squibb Company Compositions comprising an anti-LAG-3 antibody or an anti-LAG-3 antibody and an anti-PD-1 or anti-PD-L1 antibody
US11168144B2 (en) 2017-06-01 2021-11-09 Cytomx Therapeutics, Inc. Activatable anti-PDL1 antibodies, and methods of use thereof
EP4116327A1 (en) * 2017-10-11 2023-01-11 Board Of Regents, The University Of Texas System Human pd-l1 antibodies and methods of use therefor
US11525002B2 (en) 2017-10-11 2022-12-13 Board Of Regents, The University Of Texas System Human PD-L1 antibodies and methods of use therefor
WO2019075097A1 (en) * 2017-10-11 2019-04-18 Board Of Regents, The University Of Texas System Human pd-l1 antibodies and methods of use therefor
US12325747B2 (en) 2017-10-11 2025-06-10 Board Of Regents, The University Of Texas System Human PD-L1 antibodies and methods of use therefor
US11976128B2 (en) 2018-03-23 2024-05-07 Board Of Regents, The University Of Texas System Human PD-L2 antibodies and methods of use therefor
US12134648B2 (en) 2018-03-23 2024-11-05 Board Of Regents, The University Of Texas System Dual specificity antibodies to human PD-L1 and PD-L2 and methods of use therefor
US12187799B2 (en) 2018-03-23 2025-01-07 Board Of Regents, The University Of Texas System Dual specificity antibodies to PD-L1 and PD-L2 and methods of use therefor
US12428489B2 (en) 2018-03-23 2025-09-30 Board Of Regents, The University Of Texas System Human PD-L2 antibodies and methods of use therefor
US10995141B2 (en) 2019-04-19 2021-05-04 ImmunoBrain Checkpoint, Inc. Modified anti-PD-L1 antibody and methods and uses for treating a neurodegenerative disease
WO2020215049A1 (en) * 2019-04-19 2020-10-22 ImmunoBrain Checkpoint, Inc. Modified anti-pd-l1 antibodies and methods and uses for treating a neurodegenerative disease
WO2021062184A1 (en) * 2019-09-26 2021-04-01 Orionis Biosciences, Inc. Pd-l1 targeted chimeric proteins and uses thereof

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