Myeloid-targeting immune-stimulating antibody-TLR agonist conjugate (ISAC) for anti-tumor immunity 2713

Abstract Description Highly immunosuppressive tumor-associated macrophages (TAM) have been correlated with poor clinical outcome. Innate immune agonist binding to pattern recognition receptors can repolarize ‘M2’ TAM to immunostimulatory M1 macrophages to effect downstream effector functions to drive antitumor immunity. ISACs are large molecule therapeutic modalities that can be systemically administered to target specific cell subsets and induce local anti-tumor effects thereby reducing systemic toxicity. The myeloid cell-targeted ISAC approach is composed of an Fc-inactive antibody targeting immunosuppressive M2 TAM and is conjugated to a small molecule payload that agonizes several endosomal toll-like receptors (TLR) to reprogram M2 TAM to a pro-inflammatory M1 TAM phenotype. The ISAC demonstrated superior agonism over non-targeted controls in monocyte-derived macrophages in vitro as well as primary TAM ex vivo. Pro-inflammatory cytokines were induced in a dose-dependent manner. Target expression on TAM is correlated to functional response in human renal cell carcinoma ex vivo explants. The ISAC induced significant survival benefit in comparison to untreated animals in multiple murine models, including a PDx-resistant ID8 orthotopic model. M2 macrophage reprogramming and effector T cell recruitment was observed, while systemic toxicity was reduced when compared to a small molecule TLR agonist. The results presented here provide proof of concept for this novel modality. Funding Sources Pfizer, Inc. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)