Abstract 2725: Preclinical development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent anti-tumor activity

Abstract

Abstract Antigens that are tumor-specific or over-expressed on cancer cells represent opportunities for developing target-specific antibody-based therapeutics. Utilizing a non-target-biased intact cell-based immunization approach, we have generated greater than 1600 mAbs to cell-surface proteins that are expressed on cancer cells. A subset of the mAbs exhibit differential reactivity to tumor cells compared to normal cells. One of the differentially expressed proteins identified was B7-H3 (also referred to as CD276). B7-H3 is a member of the B7 family of immune regulatory proteins. Over-expression of B7-H3 has been correlated with disease severity and outcome in a growing number of cancer types, and several lines of evidence support a functional role for B7-H3 in cancer. In this report we describe the development of a humanized anti-B7-H3 mAb, designated MGA271, which bears an engineered Fc domain that imparts enhanced antibody-dependent cellular cytotoxicity (ADCC) through increased affinity for the human activating Fc-gamma receptor IIIA (CD16A) and decreased affinity for the human inhibitory Fc-gamma receptor IIB (CD32B). MGA271 displays strong reactivity to multiple tumors including kidney, prostate, pancreatic, breast, colon, gastric and ovarian cancer as well as melanoma, but limited reactivity toward normal human tissues. Independently of the donor's CD16A genotype, MGA271 mediates ADCC in vitro against human tumor cell lines representing these tumor types, as well as to human lung and gastrointestinal cell lines that exhibit properties of cancer stem cells. MGA271 exhibits potent anti-tumor activity toward B7-H3-expressing tumor xenografts in mice knocked-out for the murine CD16 gene and transgenic for the low affinity allele of human CD16A. Single- and repeat-dose toxicology studies were carried out in cynomolgus monkeys and no significant test article-related safety findings were observed. Taken together, these data support the clinical development of MGA271 for the treatment of patients who have B7-H3-expressing cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2725. doi:1538-7445.AM2012-2725