PD-1, A Receptor for B7-4, and Uses Therefor

Abstract

Disclosed is a method for modulating an immune response by modulating signaling via PD-1. The immune response may be downregulated by increasing signaling via PD-1, or may be upregulated by decreasing signaling via PD-1. Agents which are useful for stimulating signaling via PD-1 to downregulate an immune response include an activating antibody that recognizes PD-1, a form of B7-4 that binds to an inhibitory receptor, and a small molecule that binds to PD-1. Agents which are useful for inhibiting signaling via PD-1 to upregulate an immune response include a blocking antibody that recognizes PD-1, a non-activating form of B7-4, an antibody that recognizes B7-4, and a soluble form of PD-1. Also disclosed is a method for modulating the interaction of B7-4 with an inhibitory receptor on an immune cell. The method comprises contacting an antigen presenting cell which expresses B7-4 with an agent such as a form of B7-4, a form of PD-1, or an agent that modulates the interaction of B7-4 and PD-1. Also disclosed is a method for inhibiting activation of an immune cell via a non-apoptotic mechanism by increasing the activity or expression of PD-1 in the immune cell. The disclosed methods for modulating an immune response are useful, for instance as therapeutic treatment of a subject with conditions that would benefit from immune response modulation. For instance, a condition such as a tumor, a neurological disease, or an immunosuppressive disease, would be treated by upregulating an immune response, and conditions such as a transplant, an allergy, or an autoimmune disorder would benefit from downregulation of an immune response. Assays for identifying compounds which modulate the activity of, or signaling via, B7-4, or PD-1, especially which modulate the binding of B7-4 or PD-1 to a target molecule are also disclosed. Further disclosed are a vaccine and also other compositions which contain agents that modulate signaling via PD-1.

1 . A method for screening for compounds which modulate PD-1 signaling comprising:
 a) contacting a T cell activated in the presence of a PD-1 ligand with a test compound; and   b) determining the ability of the test compound to modulate phosphorylation of SHP-2;   thereby identifying a compound which modulates PD-1 signaling.   
     
     
         2 . The method of  claim 1  wherein the test compound upmodulates PD-1 signaling and thereby upmodulates SHP-2 phosphorylation. 
     
     
         3 . The method of  claim 1  wherein the test compound downmodulates PD-1 signaling and thereby downmodulates SHP-2 phosphorylation. 
     
     
         4 . A method for screening for compounds which modulate PD-1 signaling comprising:
 a) contacting a T cell activated in the presence of a PD-1 ligand with a test compound; and   b) determining the ability of the test compound to modulate phosphorylation of ERK1 or ERK 2;   
       thereby identifying a compound which modulates PD-1 signaling. 
     
     
         5 . The method of  claim 4  wherein the test compound upmodulates PD-1 signaling and thereby downmodulates ERK 1 or ERK 2 phosphorylation. 
     
     
         6 . The method of  claim 4  wherein the test compound downmodulates PD-1 signaling and thereby upmodulates ERK 1 or ERK 2 phosphorylation. 
     
     
         7 . A method for screening for compounds which modulate PD-1 signaling comprising:
 a) contacting a T cell activated in the presence of a PD-1 ligand with a test compound; and   b) determining the ability of the test compound to modulate phosphorylation of PKC-θ;   
       thereby identifying a compound which modulates PD-1 signaling. 
     
     
         8 . The method of  claim 7  wherein the test compound upmodulates PD-1 signaling and thereby downmodulates PKC-θ phosphorylation. 
     
     
         9 . The method of  claim 7  wherein the test compound downmodulates PD-1 signaling and thereby upmodulates PKC-θ phosphorylation.