Abstract 4246: ABL103, A novel T-cell engaging bispecific antibody, exhibits potent in vitro and vivo antitumor activity and low toxicity via B7-H4 dependent 4-1BB activation in tumor microenvironment

Abstract

Abstract B7-H4 (B7x, VTCN1), a member of the B7-family, is overexpressed in majority of cancer patients with ovarian, endometrial and breast cancers. B7-H4 expression was also observed in tumor associated macrophages and implicated as an immune checkpoint regulating T cell responses. Although B7-H4 expression in normal tissues is quite limited, tumor-specific immune response by ABL103 would minimize potential adverse effects. ABL103, B7-H4 Grabody-T, is a First-in Class bispecific antibody targeting B7-H4 and 4-1BB and augments T cell function by a dual mechanism, i.e., 1) blocks the B7-H4 mediated T cell inhibition, and 2) elicits superior T cell activation through B7-H4-dependent 4-1BB clustering. Our data showed that simultaneous binding of B7-H4 and 4-1BB by ABL103 led to potent in vitro T cell activation only in the presence of B7-H4 expressing tumor cells. In the established tumor model, ABL103 potently inhibited tumor progression in a dose-dependent manner and showed higher rate of complete remission (CR) at 2 and 10 mg/kg dose groups. Moreover, mice were protected from the tumor re-challenge 3 months after cessation of ABL103 treatment, suggesting long-term memory has been established. In 4-week pilot tox study using cynomolgus monkeys, ABL103 was tolerable up to 100 mg/kg dosed weekly with no ABL103-related toxicity observations. To understand the relationship of target expression, expression of B7-H4, CD4, CD8, PD-L1, and 4-1BB was examined in 142 ovarian cancer patient biopsies. About 83% of ovarian cancer patient tissues showed B7-H4 positive staining and 62% of them showed strong positive. In addition, the staining of 4-1BB as well as CD4 and CD8 T cells were observed in both tumor nest and stroma, suggesting that cross-linking of B7-H4 and 4-1BB is feasible in tumor microenvironment. Overall, ABL103 has a strong in vitro and vivo anti-tumor activity and good safety profile via B7-H4-dependent 4-1BB activation. This strongly suggests ABL103 is a promising therapeutic agent potentially benefitting patients with B7-H4 overexpression. Citation Format: Kyungjin Park, Yangsoon Lee, Saeyi Lim, Kyeongsu Park, Eunjung Kim, Hanbyul Lee, Jiseon Yoo, Youngdon Pak, Yeunju Kim, Minji Ko, Jonghwa Won. ABL103, A novel T-cell engaging bispecific antibody, exhibits potent in vitro and vivo antitumor activity and low toxicity via B7-H4 dependent 4-1BB activation in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4246.