Methods of treating vitiligo using pd-1 binding antibodies

Abstract

Provided herein are methods for managing, treating, or preventing vitiligo using proteins that specifically bind to Programmed Death-1 (PD-1) and modulate the expression and/or activity of PD-1.

1 .- 82 . (canceled) 
     
     
         83 . A method of managing, preventing, or treating vitiligo in a subject, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof that
 (A) (a) binds to an epitope of human PD-1 recognized by an antibody comprising a light chain variable region having an amino acid sequence of SEQ ID NO:8 and a heavy chain variable region having an amino acid sequence of SEQ ID NO:13; or
 (b) competes for the binding to human PD-1 with an antibody comprising a light chain variable region having an amino acid sequence of SEQ ID NO:8 and a heavy chain variable region having an amino acid sequence of SEQ ID NO:13; or 
   (B) binds to PD-1, wherein the antibody or antigen-binding fragment thereof comprises:
 (a) a light chain variable region (V L ) comprising V L  complementarity determining region 1 (CDR1), V L  CDR2, and V L  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 heavy chain variable region (V H ) comprising V H  complementarity determining region 1 (CDR1), V H  CDR2, and V H  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. 
   
     
     
         84 . The method of  claim 83 , wherein
 the antibody or antigen-binding fragment thereof comprises:
 (a) a light chain variable region (V L ) further comprising V L  framework 1 (FR1), V L  FR2, V L  FR3, and V L  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 
 (b) a heavy chain variable region (V H ) further comprising V H  framework 1 (FR1), V H  FR2, V H  FR3, and V H  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; 
   (ii) the V L  CDR1, V L  CDR2, and V L  CDR3 that comprise amino acid sequences of SEQ ID NOS:1, 2, and 3, respectively, and the V H  CDR1, V H  CDR2, and V H  CDR3 comprise amino acid sequences of SEQ ID NOS:4, 5, and 6, respectively;   (iii) the V L  CDR1, V L  CDR2, and V L  CDR3 that comprise amino acid sequences of SEQ ID NOS:7, 2, and 3, respectively, and the V H  CDR1, V H  CDR2, and V H  CDR3 comprise amino acid sequences of SEQ ID NOS:4, 5, and 6, respectively;   (iv) the antibody or antigen-binding fragment thereof comprises a V L  comprising an amino acid sequence of SEQ ID NO:8, SEQ ID NO:9 or SEQ ID NO:10;   (v) the antibody or antigen-binding fragment thereof comprises a V H  comprising an amino acid sequence of SEQ ID NO:11, SEQ ID NO:12 or SEQ ID NO:13;   (vi) the antibody or antigen-binding fragment thereof comprises:
 (a) a V L  comprising an amino acid sequence of SEQ ID NO:8; and 
 (b) a V H  comprising an amino acid sequence of SEQ ID NO:11; 
   (vii) the antibody or antigen-binding fragment thereof comprises:
 (a) a V L  comprising an amino acid sequence of SEQ ID NO:9; and 
 (b) a V H  comprising an amino acid sequence of SEQ ID NO:11; 
   (viii) the antibody or antigen-binding fragment thereof comprises:
 (a) a V L  comprising an amino acid sequence of SEQ ID NO:10; and 
 (b) a V H  comprising an amino acid sequence of SEQ ID NO:11; 
   (ix) the antibody or antigen-binding fragment thereof comprises:
 (a) a V L  comprising an amino acid sequence of SEQ ID NO:8; and 
 (b) a V H  comprising an amino acid sequence of SEQ ID NO:12; 
   (x) the antibody or antigen-binding fragment thereof comprises:
 (a) a V L  comprising an amino acid sequence of SEQ ID NO:9; and 
 (b) a V H  comprising an amino acid sequence of SEQ ID NO:12; 
   (xi) the antibody or antigen-binding fragment thereof comprises:
 (a) a V L  comprising an amino acid sequence of SEQ ID NO:10; and 
 (b) a V H  comprising an amino acid sequence of SEQ ID NO:12; 
   (xii) the antibody or antigen-binding fragment thereof comprises:
 (a) a V L  comprising an amino acid sequence of SEQ ID NO:8; and 
 (b) a V H  comprising an amino acid sequence of SEQ ID NO:13; 
   (xiii) the antibody or antigen-binding fragment thereof comprises:
 (a) a V L  comprising an amino acid sequence of SEQ ID NO:9; and 
 (b) a V H  comprising an amino acid sequence of SEQ ID NO:13; or 
   (xiv) the antibody or antigen-binding fragment thereof comprises:
 (a) a V L  comprising an amino acid sequence of SEQ ID NO:10; and 
 (b) a V H  comprising an amino acid sequence of SEQ ID NO:13. 
   
     
     
         85 . The method of  claim 83 , wherein
 (i) the antibody or antigen-binding fragment thereof comprises a human IgG1 Fc region or a variant thereof;   (ii) the antibody or antigen-binding fragment thereof comprises a human IgG1-K322A Fc region;   (iii) the antibody or antigen-binding fragment thereof comprises a heavy chain Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:36-40;
 wherein optionally the antibody or antigen-binding fragment thereof further comprises a light chain constant region comprising an amino acid sequence of SEQ ID NO:41; or 
   (iv) the antibody or antigen-binding fragment thereof comprises:
 (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. 
   
     
     
         86 . The method of  claim 83 , wherein
 (i) the antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence of SEQ ID NO:31;   (ii) the antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:32;   (iii) the antibody or antigen-binding fragment thereof comprises:
 (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; 
   (iv) wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:33;   (v) the antibody or antigen-binding fragment thereof comprises:
 (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; 
   (vi) the antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:34;   (vii) the antibody or antigen-binding fragment thereof comprises:
 (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; 
   (viii) the antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:35; or   (ix) the antibody or antigen-binding fragment thereof comprises:
 (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. 
   
     
     
         87 . The method of  claim 83 , 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;
 wherein optionally, when bound to PD-1, the antibody or antigen-binding fragment binds to at least one of residues 100-105 within an amino acid sequence of SEQ ID NO:42; or 
   (ii) at least one residue selected from the group consisting of N33, T51, S57, L100, N102, G103, R104, D105, H107, and 5109 within an amino acid sequence of SEQ ID NO:42;
 wherein optionally when bound to PD-1, the antibody or antigen-binding fragment binds to 
 (a) N33 within an amino acid sequence of SEQ ID NO:42; 
 (b) T51 within an amino acid sequence of SEQ ID NO:42; 
 (c) S57 within an amino acid sequence of SEQ ID NO:42; 
 (d) L100 within an amino acid sequence of SEQ ID NO:42; 
 (e) N102 within an amino acid sequence of SEQ ID NO:42; 
 (f) G103 within an amino acid sequence of SEQ ID NO:42; 
 (g) R104 within an amino acid sequence of SEQ ID NO:42; 
 (h) D105 within an amino acid sequence of SEQ ID NO:42; 
 (i) H107 within an amino acid sequence of SEQ ID NO:42; 
 (j) 5109 within an amino acid sequence of SEQ ID NO:42; or 
 (k) G103 and R104 within an amino acid sequence of SEQ ID NO:42. 
   
     
     
         88 . The method of  claim 83 , wherein the antibody or antigen-binding fragment thereof specifically binds to human PD-1 and/or monkey PD-1, but not rodent PD-1;
 wherein optionally the K D  for binding to purified human PD-1 is from about 100 pM to about 10 nM, and the K D  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.   
     
     
         89 . The method of  claim 83 , wherein the antibody or antigen-binding fragment thereof has attenuated ADCC activity and/or attenuated CDC activity. 
     
     
         90 . The method of  claim 83 , wherein the antibody or antigen-binding fragment thereof:
 (a) attenuates T cell activity; and/or   (b) downregulates PD-1 expression on the surface of T cells.   
     
     
         91 . The method of  claim 90 , wherein the attenuation of T cell activity is measured by
 (i) inhibition of cytokine production;
 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, IFN-γ, or any combination thereof; 
   (ii) inhibition of T cell proliferation;   (iii) downregulation of T cell activation markers;
 wherein optionally the T cell activation marker is selected from the group consisting of CD25 and CD69; 
   (iv) upregulation of regulatory T cell biomarkers;
 wherein optionally the regulatory T cell biomarker is Foxp3; or 
   (v) increase of regulatory T cells.   
     
     
         92 . The method of  claim 90 , wherein the downregulation of PD-1 expression on the surface of T cells:
 (a) occurs as early as 4 hours after the treatment with the antibody or antigen-binding fragment thereof; and/or   (b) is concurrent with or precedes cytokine inhibition.   
     
     
         93 . The method of  claim 90 , wherein
 (i) the EC 50  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;   (ii) 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%; or   (iii) 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%.   
     
     
         94 . The method of  claim 83 , 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; or 
   (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.   
     
     
         95 . The method of  claim 83 , wherein 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.   
     
     
         96 . The method of  claim 83 , wherein the antibody or antigen-binding fragment thereof further comprises a pharmaceutically acceptable carrier. 
     
     
         97 . The method of  claim 83 , wherein the immune cells in the subject express PD-1.