Therapies based on control of regulatory t cell stability and function via a neuropilin-1:semaphorin axis

Abstract

The invention is directed to treatment of cancer, infections and various inflammatory and autoimmune conditions by affecting regulatory T cell stability and function via a Neuropilin-1:Semaphorin axis.

1 .- 116 . (canceled) 
     
     
         117 . A method of treating a cancer in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of a neuropilin-1 (Nrp1):semaphorin axis in regulatory T cell (Treg) of the subject, wherein the inhibitor of Nrp1:semaphorin axis is an anti-NRP-1 antibody. 
     
     
         118 . The method of  claim 117 , comprising inhibiting interaction between a transmembrane semaphorin on cells expressing such transmembrane semaphorin and Nrp1 on the Treg of the subject. 
     
     
         119 . The method of  claim 118 , wherein the transmembrane semaphorin is a class IV semaphorin. 
     
     
         120 . The method of  claim 119 , wherein the class IV semaphorin is Sema4a. 
     
     
         121 . The method of  claim 118 , wherein the cells expressing the transmembrane semaphorin are selected from the group consisting of conventional T cells (Tconv), conventional dendritic cells (cDCs), and plasmacytoid dendritic cells (pDCs). 
     
     
         122 . The method of  claim 117 , wherein the cancer is melanoma or glioblastoma. 
     
     
         123 . The method of  claim 117 , wherein the anti-NRP-1 antibody does not affect Nrp1-vascular endothelial growth factor (VEGF) interaction in the Treg of the subject. 
     
     
         124 . The method of  claim 117 , wherein the anti-NRP-1 antibody inhibits expression of Nrp1 protein in the Tregs of the subject. 
     
     
         125 . The method of  claim 117 , wherein the anti-NRP-1 antibody is administered to the Treg in vivo. 
     
     
         126 . The method of  claim 117 , wherein the anti-NRP-1 antibody is administered to the Treg in vitro, wherein the Treg is extracted from a subject, is expanded ex vivo in the presence of the anti-NRP-1 antibody and then (i) is reintroduced back into the subject or (ii) is administered to a different subject. 
     
     
         127 . The method of  claim 117 , wherein the anti-NRP-1 antibody prevents NRP-1 from engaging with its downstream signaling pathway(s). 
     
     
         128 . The method of  claim 117 , wherein the anti-NRP-1 antibody is capable of binding to an extracellular domain of a NRP-1 polypeptide. 
     
     
         129 . The method of  claim 117 , wherein the Treg is an activated Treg. 
     
     
         130 . The method of  claim 117 , wherein the administering does not induce an inflammatory or autoimmune disease in the subject. 
     
     
         131 . The method of  claim 117 , wherein the administering inhibits suppression of anti-tumor immunity in the subject. 
     
     
         132 . The method of  claim 117 , wherein the anti-NRP-1 antibody binds to a portion of NRP-1 that is contacted by semaphorin-4. 
     
     
         133 . The method of  claim 117 , further comprising administering to the subject an additional immunomodulatory treatment. 
     
     
         134 . The method of  claim 133 , wherein the additional immunomodulatory treatment comprises administering a therapeutic vaccine, an immune checkpoint inhibitor, or an immune activator. 
     
     
         135 . The method of  claim 117 , further comprising administering to the subject a chemotherapy or radiation therapy.