PLA2G2D Antibodies for Cancer Immunotherapy

项目总结/摘要 目前批准的免疫检查点抑制剂（ICI）已经彻底改变了癌症治疗。但大多数 由于原发性或获得性耐药性，患者对这些治疗没有反应。识别新的免疫 调节剂和开发靶向这些分子的治疗剂是免疫肿瘤学的当前焦点。我们 已经发现分泌型磷脂酶A2 PLA 2G 2D在各种人类肿瘤中高度表达， 与经典检查点如CTLA-4、PD-1和PD-L1正相关。PLA 2G 2D强效 减少树突细胞功能，抑制T细胞活性，并促进巨噬细胞M2极化。 因此，使用基因工程改造的功能丧失或获得小鼠的研究表明，PLA 2G 2D 强烈增强肿瘤生长，表明PLA 2G 2D是一种新的、可靶向的肿瘤检查点。 免疫疗法我们已经产生了700多个抗PLA 2G 2D单克隆抗体，并使用一系列 在体外生化和免疫细胞功能测定中，我们已经确定了39种主要的功能阻断剂， 候选人该提案旨在评估5种功能最强的药物的抗肿瘤疗效 候选物（其不与小鼠PLA 2G 2D交叉反应），单独和与现有ICI组合，使用 转基因PLA 2G 2D-人源化小鼠中的同基因肿瘤模型。我们还将评估抗PLA 2G 2D 改变肿瘤免疫谱和组织学评估PLA 2G 2D蛋白在各种人中的表达 肿瘤使用我们的候选药物（目标1）。目标1中确定的最佳候选药物将接受 食蟹猴非GLP最大耐受剂量毒性和毒代动力学评价（目的2）。 总的来说，该提案的成功执行将使我们能够提名我们的最终铅分子， 开始IND赋能研究，作为后续II期SBIR提案的一部分。最终，一种有效的治疗方法 抗PLA 2G 2D抗体将构成对目前可用的ICI具有抗性的患者的新治疗。

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.