PD-1 BINDING PROTEINS AND METHODS OF USE THEREOF

• US 20170088618A1
• Filed: 09/28/2016
• Published: 03/30/2017
• Est. Priority Date: 09/29/2015
• Status: Active Grant

• Current Assignee: Celgene Corporation (Bristol-Myers Squibb Company)
• Original Assignee: Celgene Corporation (Bristol-Myers Squibb Company)
• Inventors: Chamberlain, Philip Paul, Khattri, Roli, Leung, Monica, Morrison, Lisa, Torres, Sanaa, Chan, Henry H., Bennett, Brydon, Hariharan, Kandasamy, Jackson, Pilgrim, Kehry, Marilyn, Sun, Jeonghoon
• Granted Patent: US 10,428,145 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/71 Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Provided herein are compositions, methods and uses involving antibodies that specifically bind to Programmed Death-1 (PD-1) and modulate the expression and/or activity of PD-1.

Claims

1-104. -104. (canceled)

105. An antibody or antigen-binding fragment thereof that

(i) binds to an epitope of human PD-1 recognized by an antibody comprising a light chain variable region (VL) having an amino acid sequence of SEQ ID NO:

8 and a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO;

13;

(ii) competes for the binding to human PD-1 with an antibody comprising a VL having an amino acid sequence of SEQ ID NO;

8 and a VH having an amino acid sequence of SEQ ID NO;

13;

or

(iii) binds to PD-1, wherein the antibody or antigen-binding fragment thereof comprises;

(a) a VL comprising VL complementarity determining region 1 (CDR1), VL CDR2, and VL CDR3 of any one of antibodies PD1AB-1, PD1AB-2, PD1AB-3, PD1AB-4, PD1AB-5, or PD1AB-6 as set forth in Table 1; and

/or

(b) a VH comprising VH complementarity determining region 1 (CDR1), VH CDR2, and VH CDR3 of any one of antibodies PD1AB-1, PD1AB-2, PD1AB-3, PD1AB-4, PD1AB-5, or PD1AB-6 as set forth in Table 2;

wherein optionally

(1) the VL further comprising VL framework 1 (FR1), VL FR2, VL FR3, and VL FR4 of any one of antibodies PD1AB-1, PD1AB-2, PD1AB-3, PD1AB-4, PD1AB-5, or PD1AB-6 as set forth in Table 3; and

/or

(2) the VH further comprising VH framework 1 (FR1), VH FR2, VH FR3, and VH FR4 of any one of antibodies PD1AB-1, PD1AB-2, PD1AB-3, PD1AB-4, PD1AB-5, or PD1AB-6 as set forth in Table 4.

106. The antibody or antigen-binding fragment thereof of claim 105 (iii),

(i) wherein the VL CDR1, VL CDR2, and VL CDR3 comprise amino acid sequences of SEQ ID NOS:

1, 2, and 3, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise amino acid sequences of SEQ ID NOS;

4, 5, and 6, respectively;

or

(ii) wherein the VL CDR1, VL CDR2, and VL CDR3 comprise amino acid sequences of SEQ ID NOS;

7, 2, and 3, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise amino acid sequences of SEQ ID NOS;

4, 5, and 6, respectively.

107. The antibody or antigen-binding fragment thereof of claim 105, wherein the antibody or antigen-binding fragment thereof comprises

(i) a VL comprising an amino acid sequence of SEQ ID NO:

8;

(ii) a VL comprising an amino acid sequence of SEQ ID NO;

9;

(iii) a VL comprising an amino acid sequence of SEQ ID NO;

10;

(iv) a VH comprising an amino acid sequence of SEQ ID NO;

11;

(v) a VH comprising an amino acid sequence of SEQ ID NO;

12;

(vi) a VH comprising an amino acid sequence of SEQ ID NO;

13;

(vii) (a) a VL comprising an amino acid sequence of SEQ ID NO;

8; and

(b) a VH comprising an amino acid sequence of SEQ ID NO;

11;

(viii) (a) a VL comprising an amino acid sequence of SEQ ID NO;

9; and

(b) a VH comprising an amino acid sequence of SEQ ID NO;

11;

(ix) (a) a VL comprising an amino acid sequence of SEQ ID NO;

10; and

(b) a VH comprising an amino acid sequence of SEQ ID NO;

11;

(x) (a) a VL comprising an amino acid sequence of SEQ ID NO;

8; and

(b) a VH comprising an amino acid sequence of SEQ ID NO;

12;

(xi) (a) a VL comprising an amino acid sequence of SEQ ID NO;

9; and

(b) a VH comprising an amino acid sequence of SEQ ID NO;

12;

(xii) (a) a VL comprising an amino acid sequence of SEQ ID NO;

10; and

(b) a VH comprising an amino acid sequence of SEQ ID NO;

12;

(xiii) (a) a VL comprising an amino acid sequence of SEQ ID NO;

8; and

(b) a VH comprising an amino acid sequence of SEQ ID NO;

13;

(xiv) (a) a VL comprising an amino acid sequence of SEQ ID NO;

9; and

(b) a VH comprising an amino acid sequence of SEQ ID NO;

13;

or

(xv) (a) a VL comprising an amino acid sequence of SEQ ID NO;

10; and

(b) a VH comprising an amino acid sequence of SEQ ID NO;

13.

108. The antibody or antigen-binding fragment thereof of claim 105, wherein the antibody or antigen-binding fragment thereof comprises

(i) a human IgG1 Fc region or a mutant thereof;

(ii) a human IgG1-K322A Fc region;

(iii) a human IgG4 Fc region or a mutant thereof;

(iv) a human IgG4P Fc region;

(v) a human IgG4PE Fc region;

(vi) a heavy chain Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS;

36-40;

(vii) a light chain constant region comprising an amino acid sequence of SEQ ID NO;

41;

(viii) (a) a light chain constant region comprising an amino acid sequence of SEQ ID NO;

41; and

(b) a heavy chain Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS;

36-40;

(ix) a light chain comprising an amino acid sequence of SEQ ID NO;

31;

(x) a heavy chain comprising an amino acid sequence of SEQ ID NO;

32;

(xi) (a) a light chain comprising an amino acid sequence of SEQ ID NO;

31; and

(b) a heavy chain comprising an amino acid sequence of SEQ ID NO;

32;

(xii) a heavy chain comprising an amino acid sequence of SEQ ID NO;

33;

(xiii) (a) a light chain comprising an amino acid sequence of SEQ ID NO;

31; and

(b) a heavy chain comprising an amino acid sequence of SEQ ID NO;

33;

(xiv) a heavy chain comprising an amino acid sequence of SEQ ID NO;

34;

(xv) (a) a light chain comprising an amino acid sequence of SEQ ID NO;

31; and

(b) a heavy chain comprising an amino acid sequence of SEQ ID NO;

34;

(xvi) a heavy chain comprising an amino acid sequence of SEQ ID NO;

35;

or

(xvii) (a) a light chain comprising an amino acid sequence of SEQ ID NO;

31; and

(b) a heavy chain comprising an amino acid sequence of SEQ ID NO;

35.

109. The antibody or antigen-binding fragment thereof of claim 105, wherein, when bound to PD-1, the antibody or antigen-binding fragment binds to

(i) at least one of residues 100-109 within an amino acid sequence of SEQ ID NO:

42;

(ii) at least one of residues 100-105 within an amino acid sequence of SEQ ID NO;

42;

(iii) at least one residue selected from the group consisting of N33, T51, S57, L100, N102, G103, R104, D105, H107, and S109 within an amino acid sequence of SEQ ID NO;

42;

(iv) N33 within an amino acid sequence of SEQ ID NO;

42;

(v) T51 within an amino acid sequence of SEQ ID NO;

42;

(vi) S57 within an amino acid sequence of SEQ ID NO;

42;

(vii) L100 within an amino acid sequence of SEQ ID NO;

42;

(viii) N102 within an amino acid sequence of SEQ ID NO;

42;

(ix) G103 within an amino acid sequence of SEQ ID NO;

42;

(x) R104 within an amino acid sequence of SEQ ID NO;

42;

(xi) D105 within an amino acid sequence of SEQ ID NO;

42;

(xii) H107 within an amino acid sequence of SEQ ID NO;

42;

(xiii) S109 within an amino acid sequence of SEQ ID NO;

42;

or

(xiv) G103 and R104 within an amino acid sequence of SEQ ID NO;

42.

110. The antibody or antigen-binding fragment thereof of claim 105, wherein the antibody or antigen-binding fragment thereof:

(i) (a) attenuates T cell activity; and

/or

(b) downregulates PD-1 expression on the surface of T cells;

wherein optionally the attenuation of T cell activity occurs in human PBMC or whole blood samples;

wherein optionally the attenuation of T cell activity is measured by inhibition of cytokine production; and

wherein optionally the cytokine that is inhibited by the antibody or antigen-binding fragment thereof comprises IL-1, IL-2, IL-6, IL-12, IL-17, IL-22, IL-23, GM-CSF, TNF-α

, and/or IFN-γ

;

wherein optionally the EC50 for attenuating T cell activity is from about 1 pM to about 10 pM, from about 10 pM to about 100 pM, from about 100 pM to about 1 nM, from about 1 nM to about 10 nM, or from about 10 nM to about 100 nM;

wherein optionally the maximal percent attenuation of T cell activity is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%

wherein optionally the downregulation of PD-1 expression on the surface of T cells;

(1) occurs as early as 4 hours after the treatment with the antibody or antigen-binding fragment thereof; and

/or

(2) is concurrent with or precedes cytokine inhibition;

wherein optionally the maximal percent downregulation of PD-1 expression is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%;

(ii) specifically binds to human PD-1 and/or monkey PD-1, but not rodent PD-1;

wherein optionally the KD for binding to purified human PD-1 is from about 100 pM to about 10 nM, and the KD for binding to human PD-1 expressed on cell surface and monkey PD-1 expressed on cell surface is from about 100 pM to about 10 nM;

or

(iii) has attenuated ADCC activity and/or attenuated CDC activity.

111. The antibody or antigen-binding fragment thereof of claim 105, wherein

(i) the antibody is a monoclonal antibody;

(ii) the antibody is a humanized, human, or chimeric antibody;

wherein optionally the humanized antibody is a deimmunized antibody or a composite human antibody;

(iii) the antibody or antigen-binding fragment thereof is a Fab, a Fab′

, a F(ab′

)2, a Fv, a scFv, a dsFv, a diabody, a triabody, a tetrabody, or a multispecific antibody formed from antibody fragments;

or

(iv) the antibody or antigen-binding fragment thereof is conjugated to an agent;

wherein optionally the agent is selected from the group consisting of a radioisotope, a metal chelator, an enzyme, a fluorescent compound, a bioluminescent compound, and a chemiluminescent compound.

112. A composition comprising the antibody or antigen-binding fragment thereof of claim 105, and a pharmaceutically acceptable carrier.

113. A polynucleotide

(i) comprising nucleotide sequences encoding a VH, a VL, or both a VH and a VL of the antibody of claim 105;

or

(ii) comprising nucleotide sequences encoding a heavy chain, a light chain, or both a heavy chain and a light chain of the antibody of claim 105;

wherein optionally the polynucleotide is operably linked to a promoter.

114. A vector comprising the polynucleotide of claim 113.

115. A cell, wherein:

(i) the cell comprising the polynucleotide of claim 113;

(ii) the cell comprising the vector of claim 114;

or

(iii) the cell producing the antibody or antigen-binding fragment thereof of claim 105.

116. A kit comprising the antibody or antigen-binding fragment thereof of claim 105.

117. A method of making an antibody or antigen-binding fragment thereof which specifically binds to an epitope of human PD-1, comprising

(i) culturing the cell of claim 115 to express the antibody or antigen-binding fragment thereof;

or

(ii) expressing the polynucleotide of claim 113.

118. A method of attenuating activity of a T cell, comprising contacting the T cell with an effective amount of an antibody or antigen binding fragment thereof of claim 105;

wherein optionally the maximal percent attenuation of T cell activity is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%;

wherein optionally the attenuation of T cell activity is measured by inhibition of cytokine production; and

wherein optionally the cytokine is

(i) IL-1, IL-2, IL-6, IL-12, IL-17, IL-22, IL-23, GM-CSF, TNF-α

, IFN-γ

, or any combination thereof;

(ii) IL-2, IL-17, IFN-γ

, or any combination thereof;

(iii) IL-2;

(iv) IL-17;

(v) IFN-γ

;

(vi) IL-1;

(vii) IL-6;

(viii) IL-12;

(ix) IL-22;

(x) IL-23;

(xi) GM-CSF;

or

(xii) TNF-α

;

wherein optionally the inhibition of cytokine production is concurrent with or follows downregulation of PD-1 expression on the surface of the T cell; and

wherein optionally the downregulation of PD-1 expression on the surface of the T cell occurs as early as 4 hours after contact with an effective amount of an antibody or antigen-binding fragment thereof.

119. A method of downregulating PD-1 expression on the surface of a T cell, comprising contacting the T cell with an effective amount of an antibody or antigen binding fragment thereof of claim 105;

wherein optionally the maximal percent downregulation of PD-1 expression by the antibody or antigen-binding fragment thereof is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%;

wherein optionally the downregulation of PD-1 expression on the surface of the T cell occurs as early as 4 hours after contact with the antibody or antigen-binding fragment thereof;

wherein optionally the downregulation of PD-1 expression on the surface of the T cell precedes cytokine inhibition; and

wherein optionally the cytokine is

(i) IL-1, IL-2, IL-6, IL-12, IL-17, IL-22, IL-23, GM-CSF, TNF-α

, IFN-γ

, or any combination thereof;

(ii) IL-2, IL-17, IFN-γ

, or any combination thereof;

(iii) IL-2;

(iv) IL-17;

(v) IFN-γ

;

(vi) IL-1;

(vii) IL-6;

(viii) IL-12;

(ix) IL-22;

(x) IL-23;

(xi) GM-CSF;

or

(xii) TNF-α

.

120. A method of inhibiting cytokine production by a T cell, comprising contacting the T cell with an effective amount of an antibody or antigen binding fragment thereof of claim 105;

wherein optionally the cytokine is

(i) IL-1, IL-2, IL-6, IL-12, IL-17, IL-22, IL-23, GM-CSF, TNF-α

, IFN-γ

, or any combination thereof;

(ii) IL-2, IL-17, IFN-γ

, or any combination thereof;

(iii) IL-2;

(iv) IL-17;

(v) IFN-γ

;

(vi) IL-1;

(vii) IL-6;

(viii) IL-12;

(ix) IL-22;

(x) IL-23;

(xi) GM-CSF;

or

(xii) TNF-α

.