PLA2G2D Antibodies for Cancer Immunotherapy

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PROJECT SUMMARY / ABSTRACT Currently approved immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, most patients do not respond to these treatments because of primary or acquired resistance. Identifying new immune regulators and developing therapeutics targeting such molecules is a current focus in immuno-oncology. We have found that the secreted phospholipase A2 PLA2G2D is highly expressed in various human tumors and positively correlated with that of classic checkpoints such as CTLA-4, PD-1, and PD-L1. PLA2G2D potently diminishes dendritic cell function, suppresses T cell activity, and promotes macrophage M2 polarization. Accordingly, studies using genetically-engineered loss- or gain-of-function mice demonstrate that PLA2G2D strongly enhances tumor growth, indicating that PLA2G2D is a novel, targetable checkpoint for tumor immunotherapy. We have generated more than 700 anti-PLA2G2D monoclonal antibodies, and using a series of in vitro biochemical and immune cell functional assays we have identified 39 leading function-blocking candidates. This proposal seeks to evaluate the anti-tumor efficacy of the 5 most functionally potent drug candidates (which do not cross-react with mouse PLA2G2D), alone and in combination with existing ICIs, using syngeneic tumor models in transgenic PLA2G2D-humanized mice. We will also assess how anti-PLA2G2D changes the tumor immune profile and histologically evaluate PLA2G2D protein expression in various human tumors using our drug candidate (Aim 1). The best drug candidate identified in Aim 1 will then be subjected to non-GLP maximum tolerated dose toxicity and toxicokinetic evaluation in cynomolgus monkeys (Aim 2). Collectively, the successful execution of this proposal will enable us to nominate our final lead molecule and begin IND-enabling studies as part of a follow-up phase II SBIR proposal. Ultimately, an efficacious therapeutic anti-PLA2G2D antibody will comprise a new treatment for patients resistant to currently available ICIs.