1401 PLT012, a monoclonal antibody targeting CD36, unleashes anti-tumor immunity via metabolic reprogramming in tumor microenvironment

• DOI: 10.1136/jitc-2023-sitc2023.1401
• Publication Date: 2023-10-31T14:50:39Z
• Authors: Yi-Ru Yu; Chin-Hsien Tsai; Huey-Wen Hsiao; Jaeoh Park; Pandelakis Koni; Hung-Kai Chen; Lana Kandalaft; Claudia Lengerke
• Keywords: CD36; Cancer Immunotherapy

<h3>Background</h3> Accumulation of lipid metabolic products in tumor microenvironment (TME) has been documented to augment the malignancy cancer by dampening anti-tumor immunity, including increased immunosuppressive features various immune cells and development exhausted phenotypes T cells, which further orchestrates hurdles for immunotherapies. Previously, CD36, a fatty acid transporter, reported be up-regulated both malignant tumor-associated regulatory macrophages CD8⁺ adjust preference, allow adapt lipid-enriched TME. This CD36-mediated adaption not only alters regulations, but also impacts cell properties construct an It suggested that blocking uptake rewires host immunity within TME, reducing abundance tumor-infiltrating Treg restoring survival functions CD8 highlighting therapeutic potential anti-CD36 antibodies. <h3>Methods</h3> PLT012, humanized antibody, was developed via phage display, followed affinity maturation developability optimization. Binding epitope PLT012 revealed CryoEM structural analysis. Biological analyses blockade were validated isolated cells. The efficacy assessed genetically-induced melanoma hydrodynamic injection-mediated hepatocellular carcinoma (HCC) murine model. Mechanism action (MOA) confirmed human HCC samples on <i>ex vivo</i> culture platform. <h3>Results</h3> Firstly, generated with no concerns ADCC/CDC effects possessed cross-reactivity among species, murine, non-human primates human. We found recognizes binding domain CD36 without interfering TSP-1 site Administration significantly reduced M2 macrophage differentiation TILs. Importantly, HCC-bearing mice treated exhibited significant reduction growth CD8/Treg ratio, lines vivo</i>observations treatments samples. <h3>Conclusions</h3> These results demonstrate alterations TILs treatment can elicit robust inhibition shift nature TME toward immunosupportive one. study provides pillar harnessing immunometabolic targeting immunotherapy.