Abstract P076: Humanized anti-αvβ3 antibody engineered to selectively promote macrophage-mediated cancer cell death

Integrin αvβ3, an epithelial-to-mesenchymal transition marker, promotes drug resistance and metastasis in a range of epithelial cancers. Hence, a humanized anti-αvβ3 antibody (Etaracizumab), developed in the 1990s, was designed to eliminate αvβ3+ cells via NK-mediated antibody-dependent cellular-cytotoxicity (ADCC). Etaracizumab has been tested in clinical trials and proven to be safe with some activity in a subset of patients. However, in a recent examination of the immune microenvironment of αvβ3+ human epithelial tumors, we observed a large number of tumor-associated macrophages (TAMs) but minimal accumulation of NK or T cells. This suggests the efficacy of Etaracizumab may have been limited based on the relative lack of NK cells in αvβ3+ tumors. Therefore, we re-engineered Etaracizumab by changing its Fc receptor binding properties to favor TAM engagement over NK cells. This newly designed anti-αvβ3 antibody (ABT-101) while binding to αvβ3 with the same affinity as Etaracizumab, not only eliminates tumor cells via TAM-mediated ADCC but promotes a two-fold increased anti-tumor activity in mice and accumulates to a higher degree in tumors compared to Etaracizumab. Based on these preclinical findings, ABT101 is currently being evaluated in IND enabling studies with the hope to initiate phase I clinical trials in mid-2022. Citation Format: Hiromi I. Wettersten, Ryan M. Shepard, Sara M. Weis, David A. Cheresh. Humanized anti-αvβ3 antibody engineered to selectively promote macrophage-mediated cancer cell death [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P076.