Omnipresent suppressive myeloid populations in the tumor microenvironment limit the efficacy of T-cell-directed immunotherapies, become more inhibitory after administration of T-cell checkpoint inhibitors, and are overall associated with worse survival of cancer patients. In early clinical trials, positive outcomes have been demonstrated for therapies aimed at repolarizing suppressive myeloid populations in the tumor microenvironment. We have previously described the key role of P-selectin glycoprotein ligand-1 (PSGL-1) in maintaining an inhibitory state of tumor-associated macrophages (TAMs), most of which express high levels of PSGL-1. Here we describe a novel, first-in-class humanized high-affinity monoclonal antibody VTX-0811 that repolarizes human macrophages from an M2-suppressive phenotype towards an M1 inflammatory phenotype, similar to siRNA-mediated knockdown of PSGL-1. VTX-0811 binds to PSGL-1 of human and cynomolgus macaque origins without inhibiting PSGL-1 interaction with P- and L-Selectins or VISTA. In multi-cellular assays and in patient-derived human tumor cultures, VTX-0811 leads to the induction of pro-inflammatory mediators. RNAseq data from VTX-0811 treated ex vivo tumor cultures and M2c macrophages show similar pathways being modulated, indicating that the mechanism of action translates from isolated macrophages to tumors. A chimeric version of VTX-0811, consisting of the parental murine antibody in a human IgG4 backbone, inhibits tumor growth in a humanized mouse model of cancer. VTX-0811 is exceptionally well tolerated in NHP toxicology assessment and is heading into clinical evaluation after successful IND clearance.
肿瘤微环境中普遍存在的抑制性髓系细胞群限制了T细胞导向免疫疗法的疗效，在接受T细胞检查点抑制剂治疗后其抑制作用进一步增强，且总体与癌症患者较差的生存预后相关。早期临床试验表明，针对肿瘤微环境中抑制性髓系细胞群的重编程治疗已展现出积极疗效。我们先前已阐明P-选择素糖蛋白配体-1（PSGL-1）在维持肿瘤相关巨噬细胞（TAMs）抑制状态中的关键作用——该细胞群体大多高表达PSGL-1。本研究报道了一种首创型人源化高亲和力单克隆抗体VTX-0811，该抗体能够将人巨噬细胞从M2抑制表型重编程为M1炎症表型，其作用机制与siRNA介导的PSGL-1敲低效果相似。VTX-0811可特异性结合人源及食蟹猴源PSGL-1，且不干扰PSGL-1与P-/L-选择素或VISTA的相互作用。在多细胞培养体系及患者来源的人类肿瘤培养模型中，VTX-0811能有效诱导促炎介质产生。对VTX-0811处理的离体肿瘤培养物及M2c巨噬细胞的RNA测序数据显示二者具有相似的通路调控模式，表明该作用机制可从分离的巨噬细胞延伸至肿瘤微环境。将亲本鼠源抗体与人IgG4骨架融合构建的VTX-0811嵌合体，在人源化小鼠肿瘤模型中展现出显著的肿瘤生长抑制效果。非人灵长类毒理学评估显示VTX-0811具有优异的安全性特征，在成功获得新药临床试验许可后，现已进入临床评估阶段。
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