# Preclinical Efficacy of VTX-0811: A Humanized First-in-Class PSGL-1 mAb Targeting TAMs to Suppress Tumor Growth

## TL;DR

VTX-0811 is a new drug that reprograms immune cells in tumors to fight cancer, showing strong preclinical results and safety in animals.

## Contribution

VTX-0811 is a first-in-class humanized monoclonal antibody targeting PSGL-1 to repolarize tumor-associated macrophages.

## Key findings

- VTX-0811 repolarizes human macrophages from M2-suppressive to M1 inflammatory phenotype.
- VTX-0811 induces pro-inflammatory mediators in tumor cultures and modulates similar pathways as PSGL-1 knockdown.
- A chimeric version of VTX-0811 inhibits tumor growth in humanized mouse models.

## Abstract

Cancer can create a shield of suppressive innate immune cells that stop our body’s natural defenses from tumors. VTX-0811 is a new drug that targets these cells and turns them from allies of cancer to fighters against it. Preclinical tests show that it works in the lab on human cells and tumors and is safe and efficacious in animals. The results are promising and pave the way for human trials to see if VTX-0811 can become a new powerful weapon against cancer.

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.