Preclinical Efficacy of VTX-0811: A Humanized First-in-Class PSGL-1 mAb Targeting TAMs to Suppress Tumor Growth
Tatiana Novobrantseva1, Denise Manfra1, Jessica Ritter1
1Verseau Therapeutics, 2000 Commonwealth Ave, Newton, MA 02466, USA.
Abstract:
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.
Insights
A new antibody, VTX-0811, effectively repolarizes suppressive myeloid cells in the tumor microenvironment. This approach enhances anti-cancer immunity and shows promise for improving immunotherapy outcomes in patients.
Area of Science:
- Immunology
- Oncology
- Drug Development
Background:
- Suppressive myeloid cells in the tumor microenvironment limit immunotherapy efficacy and correlate with poor patient survival.
- Tumor-associated macrophages (TAMs) often exhibit an M2-suppressive phenotype, partly due to P-selectin glycoprotein ligand-1 (PSGL-1) expression.
- Repolarizing these myeloid populations presents a therapeutic strategy to enhance anti-cancer immunity.
Purpose of the Study:
- To characterize VTX-0811, a novel monoclonal antibody targeting PSGL-1, for its ability to repolarize suppressive myeloid cells.
- To evaluate the mechanism of action and therapeutic potential of VTX-0811 in preclinical cancer models.
Main Methods:
- Developed a humanized monoclonal antibody (VTX-0811) targeting PSGL-1.
- Assessed VTX-0811's effect on macrophage phenotype (M2 to M1 repolarization) using in vitro assays and patient-derived tumor cultures.
- Utilized RNA sequencing to analyze pathway modulation in treated cells and tumors.
- Tested a chimeric version of VTX-0811 in a humanized mouse model of cancer.
- Conducted non-human primate (NHP) toxicology studies.
Main Results:
- VTX-0811 successfully repolarizes human macrophages from an M2-suppressive to an M1-inflammatory phenotype, mimicking PSGL-1 knockdown effects.
- The antibody induces pro-inflammatory mediators in multi-cellular and patient-derived tumor assays.
- RNAseq data reveals conserved pathway modulation in both isolated macrophages and ex vivo tumor cultures.
- A chimeric VTX-0811 demonstrated inhibition of tumor growth in a humanized mouse model.
- VTX-0811 exhibited excellent tolerability in NHP toxicology assessments.
Conclusions:
- VTX-0811 is a first-in-class antibody that repolarizes suppressive myeloid cells by targeting PSGL-1.
- The antibody's mechanism of action is consistent across different models, from isolated cells to patient tumors.
- VTX-0811 shows significant therapeutic potential for enhancing cancer immunotherapies and is advancing to clinical trials.
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