Targeting Immune Checkpoints with JTX-8064: Reprogramming Tumor-Associated Macrophages for Cancer Immunotherapy

Jounce Therapeutics has developed cell-specific gene signatures to analyze large-scale cancer datasets, identifying potential immune checkpoint targets. A connection was found between tumor-associated macrophages (TAMs) and LILRB2, a receptor that inhibits immune responses when bound to MHC I molecules, including the immunosuppressive HLA-G. Given the role of TAMs in dampening anti-cancer immunity, LILRB2 presents a compelling target.

A panel of monoclonal antibodies was created to specifically bind LILRB2, blocking its interaction with MHC I molecules. These antibodies were shown to shift macrophages towards a more inflammatory state in vitro, as indicated by increased secretion of TNF-α and IL-6 and decreased IL-10 and CCL2 production. mRNA analysis confirmed an M1-like, inflammatory polarization in macrophages treated with anti-LILRB2 antibodies. In human tumor histocultures, these antibodies induced responses suggestive of macrophage and T cell activation across various cancer types. Although mice do not express LILRB2, they do express a similar molecule, Pirb, and Pirb-deficient mice showed reduced tumor growth, indicating the pathway's role as an immune checkpoint.

From these findings, JTX-8064, a high-affinity, humanized antagonist monoclonal antibody against LILRB2, is being advanced as a new immunotherapy. It aims to reprogram tumor-associated suppressive macrophages to enhance the immune response within the tumor microenvironment.