Suppressive myeloid cells in the tumor microenvironment (TME) are associated with poor survival of cancer patients and resistance to T cell checkpoint inhibitors. These myeloid cells shield cancer cells from the sentinel immune response and create a niche for tumor growth. Repolarizing immuno-suppressive myeloid populations in the TME attracted considerable interest from scientific community and several companies, and has produced early positive clinical data. One of the targets that potently sustains macrophage suppressive phenotypes and is highly expressed on tumor associated macrophages is PSGL-1. Blocking a previously unknown epitope on PSGL-1 triggers macrophage repolarization to a pro inflammatory state. We have determined that our therapeutic candidate VTX-0811, anti-PSGL-1 monoclonal antibody (mAb), repolarizes M2-like macrophages to a more M1-like state both phenotypically and functionally as assessed by primary in vitro macrophage assays. Transcriptomics profiling of M2c macrophages showed that VTX-0811 upregulated TNF-α/NF-κB and chemokine-mediated signaling, while downregulating oxidative phosphorylation, fatty acid metabolism, and Myc signaling pathways, consistent with a broad M2-to-M1 shift. Furthermore, repolarized macrophages enhanced inflammatory responses in complex primary multi-cellular assays.VTX-0811 also showed efficacy in a humanized mouse PDX model of melanoma. VTX-0811 suppressed tumor growth to a significantly greater degree compared with an anti-PD-1 mAb. At the cellular and molecular levels, the treatment led to an inflammatory microenvironment, including a reduced MDSC population, and increased systemic pro-inflammatory mediators. Compared with anti-PD-1 monotherapy, VTX-0811 alone and in combination with anti-PD-1 increased the fraction of CD8+ T cells among the infiltrating T cells. Significant combination effects of VTX-0811 plus anti-PD-1 were seen within the tumor tissue, spleen, and peripheral blood.Additionally, pre-clinical efficacy of VTX-0811 was demonstrated using ex vivo cultures of fresh patient-derived tumors that preserve cellular and molecular composition of the TME. VTX-0811 increased secretion of inflammatory cytokines and chemokines known to be involved in immune activation of the TME and fresh leukocyte recruitment, as well as linked to clinical response to T cell checkpoint inhibitors.VTX-0811 is a humanized high affinity IgG4/κ mAb that demonstrated safety in NHP primates up to 200mg/kg dosed weekly for 5 total doses. VTX-0811 does not induce activation of unstimulated PBMC or unstimulated blood-derived neutrophil or T cell cultures. These data provide biological and mechanistic support for advancing this program into the clinic with a first in human trial planned for early 2022.
Citation Format: Igor Feldman, Tatiana Novobrantseva, Ani Nguyen, Jessica Ritter, Mohammad Zafari, Denise Manfra, Susan Low, Steve Sazinsky, Michael Brehm, Boris Klebanov. VTX-0811, a first-in-class PSGL-1 blocking monoclonal antibody, repolarizes tumor associated macrophages and induces inflammation in the tumor microenvironment, leading to suppression of tumor growth in pre-clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5602.