Abstract 2370: Revitalizing anti-tumor immunity through PLT012 monoclonal antibody, targeting CD36 for metabolic rewiring in the tumor microenvironment

Abstract The accumulation of lipid metabolic products in the TME has been extensively documented to exacerbate cancer malignancy by suppressing anti-tumor immunity. This phenomenon is characterized by the induction of immunosuppressive features in various immune cells and the development of exhausted phenotypes in T cells, creating formidable obstacles for effective immunotherapies. Notably, CD36, a fatty acid transporter, has been identified as up-regulated in both malignant cells and various tumor-associated immune cells, including regulatory T cells, tumor-associated macrophages, and CD8+ T cells. This upregulation serves to adjust the metabolic preferences of these cells, enabling adaptation to the lipid-enriched TME. CD36-mediated adaptation not only instigates alterations in metabolic regulations but also significantly influences immune cell properties, contributing to the establishment of an immunosuppressive TME. Consequently, it has been proposed that inhibiting CD36-mediated fatty acid uptake could strategically reshape the host's anti-tumor immunity within the TME, resulting in the reduction of tumor-infiltrating regulatory T cells and the restoration of both survival and functionality in CD8 T cells. These findings underscore the therapeutic potential of anti-CD36 antibodies as a targeted approach to mitigate the immunosuppressive milieu within the TME. Hence, PLT012, a humanized anti-CD36 antibody, was developed via phage display, followed by affinity maturation and developability optimization, and possesses cross-reactivity among species, including murine, non-human primates, and human. Through CryoEM-based structural analysis, we found that PLT012 recognizes the lipid binding domain of CD36 without interfering with the TSP-1 binding site. Moreover, administration of PLT012 significantly reduced oxLDL-mediated M2 macrophage polarization and fatty acid uptake in CD8+ TILs. Notably, HCC-bearing mice treated with PLT012 exhibited a significant reduction in tumor growth with an increased CD8/Treg ratio and CD8 effector functions, consistent with the ex vivo observations of PLT012 treatments in human HCC samples. In addition to murine studies, PLT012 also demonstrated excellent tolerability in NHP studies without any adverse effects. Ongoing studies in translational medicine will further bridge our findings and proposed mechanism of action with clinical observations, highlighting the potential therapeutic outcome in HCC patients particularly. Taken together, these results reveal that blocking CD36-mediated metabolic alterations in Treg and CD8+ TILs with PLT012 treatment can elicit robust tumor growth inhibition and shift the immunosuppressive nature within the TME toward an immunosupportive one. This study further provides the pillar for harnessing immunometabolic targeting in cancer immunotherapy. Citation Format: Yi-Ru Yu, Sheue-Fen Tzeng, Huey-Wen Hsiao, Jaeoh Park, Lana Kandalaft, Yun-Han Lin, Chin-Hsien Tsai, Ping-Chih Ho. Revitalizing anti-tumor immunity through PLT012 monoclonal antibody, targeting CD36 for metabolic rewiring in the tumor microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2370.