Methods of reducing liver pd-1-expressing cd8+ t cells using pd-1 fc fusion proteins that bind fc receptors

Abstract

The present invention relates to methods of reducing liver PD-1-expressing CD8+ T cells using PD-1 Fc fusion proteins that bind Fc receptors, as well as diagnostic, prognostic, therapeutic methods and compositions related thereto.

1 . A method of reducing CD8+ T cells expressing PD-1 in the liver of a subject comprising administering to the subject a therapeutically effective amount of an Fc fusion protein that specifically binds to PD-1 and binds to at least one Fc receptor, optionally wherein the PD-1 is listed in Table 1, is mouse PD-1, or is human PD-1. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the Fc fusion protein inhibits or blocks the activity of PD-1 on the CD8+ T cells expressing PD-1. 
     
     
         5 . The method of  claim 1 , wherein the at least one Fc receptor is an activating human FcγR, optionally selected from the group consisting of human FcγRI, human FcγRIIa, human FcγRIIc, human FcγRIIIa, and human FcγRIIIb. 
     
     
         6 . The method of  claim 5 , wherein i the human FcγRIIa is an H131 allotype human FcγRIIa or an R131 allotype human FcγRIIa or ii) the human FcγRIIIa is a V158 allotype human FcγRIIIa or an F158 allotype human FcγRIIa. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the at least one Fc receptor is an inhibitory human FcγR, optionally wherein the inhibitory human FcγR is human FcγRIIb. 
     
     
         9 . The method of  claim 1 , wherein the at least one Fc receptor is an activating mouse FcγR, optionally selected from the group consisting of mouse FcγRI, mouse FcγRII, and mouse FcγRIV. 
     
     
         10 . The method of  claim 1 , wherein the at least one Fc receptor is an inhibitory mouse FcγR, optionally wherein the inhibitory mouse FcγR is mouse FcγRIIb. 
     
     
         11 . The method of  claim 1 , wherein
 a) the Fc fusion protein mediates antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), or a combination thereof;   b) the affinity of association (K A ) between the Fc fusion protein and the at least one Fc receptor is at least 0.5×10 5  M −1 ;   c) the Fc fusion protein is an anti-PD-1 antibody, or an anti-PD-1 binding fragment thereof;   d) the Fc fusion protein or effector domain thereof is a human IgG1, human IgG2, human IgG3, or human IgG4 isotype;   e) the Fc fusion protein or effector domain thereof is a mouse IgG1, mouse IgG2a, mouse IgG3, or mouse IgG2b isotype;   f) the Fc fusion protein is administered with at least one additional agent that reduces liver CD8+ T cells expressing PD-1;   g) the Fc fusion protein is administered with at least one additional agent that reduces liver immunopathology   h) the Fc fusion protein and/or at least one additional agent is administered in a pharmaceutically acceptable formulation;   i) the Fc fusion protein is administered systemically;   j) the Fc fusion protein is administered intraperitoneally, subcutaneously, intramuscularly, or intravenously;   k) the Fc fusion protein is administered as a single dose or as a series of doses.   
     
     
         12 - 13 . (canceled) 
     
     
         14 . The method of  claim 11 , wherein
 i) the antibody is a monoclonal antibody, or comprises an antigen binding fragment thereof;   ii) the antibody is a bispecific or multispecific antibody, or antigen binding fragment thereof;   iii) the antibody, or antigen binding fragment thereof, is murine, chimeric, humanized, or human;   iv) the antibody, or antigen binding fragment thereof, is detectably labeled;   v) the antibody, or antigen binding fragment thereof, comprises an effector domain;   vi) the antibody, or antigen binding fragment thereof, comprises an Fc domain;   vii) the antibody, or antigen binding fragment thereof, is an Fv, Fav, F(ab′)2), Fab′, dsFv, scFv, sc(Fv)2, or diabody fragment; and/or   viii) the antibody, or antigen binding fragment thereof, is conjugated to an agent that promotes reduction of CD8+ T cells expressing PD-1 in the liver, optionally wherein the agent is a cytotoxic agent, chemotherapeutic agent, a biologic agent, a toxin, a radioactive isotope, or a combination thereof.   
     
     
         15 - 22 . (canceled) 
     
     
         23 . The method of claim  13 , wherein the at least one additional agent inhibits or blocks an immune checkpoint, optionally wherein the immune checkpoint is selected from the group consisting of PD-L1, PD-L2, LAG-3, TIM-1, CTLA-4, VISTA, B7-H2, B7-H3, B7-H4, B7-H6, 2B4, ICOS, HVEM, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-4, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, and A2aR. 
     
     
         24 . The method of claim  13 , wherein the at least one additional agent is selected from the group consisting of a small molecule, an RNA interfering agent, an antisense oligonucleotide, a peptide, a peptidomimetic, a fusion protein, an antibody or antigen-binding fragment thereof, and an aptamers. 
     
     
         25 . The method of  claim 1 , further comprising a step of transient or complete lymphodepletion. 
     
     
         26 . The method of  claim 25 , wherein
 a) sublethal whole body irradiation is used for transient lymphodepletion;   b) lethal whole body irradiation is used for complete lymphodepletion; and/or   c) the step of lymphodepletion occurs before, concurrently with, or after the step of agent administration.   
     
     
         27 - 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein the CD8+ T cells expressing PD-1 are i) effector T cells, ii) antigen-specific, and/or iii) highly express PD-1. 
     
     
         30 - 34 . (canceled) 
     
     
         35 . The method of  claim 1 , wherein the CD8+ T cells expressing PD-1 are reduced by at least 30 fold in the liver after administration of the Fc fusion protein relative to the number of CD8+ T cells expressing PD-1 in the liver before administration of the Fc fusion protein. 
     
     
         36 . The method of  claim 1 , wherein the CD8+ T cells expressing PD-1 are reduced by at least 6 fold in the liver after administration of the Fc fusion protein relative to the number of CD8+ T cells expressing PD-1 in another tissue of the subject after administration of the Fc fusion protein. 
     
     
         37 . The method of  claim 1 , wherein the CD8+ T cells expressing PD-1 in the liver are reduced after 24 hours of administration. 
     
     
         38 . The method of  claim 1 , wherein the subject is afflicted with a liver sensitivity disorder. 
     
     
         39 . The method of  claim 38 , wherein the liver sensitivity disorder is selected from the group consisting of chronic viral infection, organ transplant, acute infection, chronic infection, cancer, allergy, drug-induced liver injury, alcoholic liver disease, metabolic disease, ischemia/reperfusion injury, graft rejection, graft-versus-host disease, liver failure, congenital disease, stroke, acute liver disease, septic shock, endocrine disease, and autoimmune disease. 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 1 , wherein the subject is a mammal, a mouse, a human, or an animal model of a liver sensitivity disorder. 
     
     
         42 - 43 . (canceled)