Novobrantseva Tatiana, Manfra Denise, Ritter Jessica, Razlog Maja, O'Nuallain Brian, Zafari Mohammad, Nowakowska Dominika, Basinski Sara, Phennicie Ryan T, Nguyen Phuong A, Brehm Michael A, Sazinsky Stephen, Feldman Igor
Verseau Therapeutics, 2000 Commonwealth Ave, Newton, MA 02466, USA.
Diabetes Center of Excellence, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA.
Cancers (Basel). 2024 Aug 6;16(16):2778. doi: 10.3390/cancers16162778.
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体限制了T细胞导向免疫疗法的疗效，在给予T细胞检查点抑制剂后其抑制作用更强，并且总体上与癌症患者较差的生存率相关。在早期临床试验中，针对使肿瘤微环境中抑制性髓系细胞群体重新极化的疗法已显示出积极的结果。我们之前已经描述了P选择素糖蛋白配体-1（PSGL-1）在维持肿瘤相关巨噬细胞（TAM）抑制状态中的关键作用，其中大多数TAM表达高水平的PSGL-1。在此，我们描述了一种新型的、同类首创的人源化高亲和力单克隆抗体VTX-0811，它可使人类巨噬细胞从M2抑制表型重新极化至M1炎症表型，类似于PSGL-1的siRNA介导的敲低。VTX-0811与人及食蟹猴来源的PSGL-1结合，而不抑制PSGL-1与P选择素和L选择素或VISTA的相互作用。在多细胞试验和患者来源的人类肿瘤培养物中，VTX-0811可诱导促炎介质的产生。来自VTX-0811处理的体外肿瘤培养物和M2c巨噬细胞的RNAseq数据显示相似的途径受到调节，表明作用机制从分离的巨噬细胞转化至肿瘤。VTX-0811的嵌合版本，由人IgG4骨架中的亲本鼠抗体组成，在人源化癌症小鼠模型中可抑制肿瘤生长。VTX-0811在非人灵长类动物毒理学评估中耐受性极佳，在成功获得IND批准后即将进入临床评估。
