Abstract 3823: Bat4306f, an anti-CD20 antibody devoid of fucose modification, demonstrates enhanced ADCC effect and potent in vivo efficacy

Abstract

Abstract Depletion of malignant B cells using anti-CD20 antibodies is one of the most effective approaches for CD20-positive non-Hodgkin lymphoma therapy. Anti-CD20 antibodies can activate several pathways including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or programmed cell death to kill tumor cells. ADCC is mediated via Fc region of antibody binding to FcγRIIIa receptor on effector cells, such as NK cells. Previous studies have shown that non-fucosylated antibody binds to FcγRIIIa with increased affinity and can thus trigger FcγRIIIa-mediated effector functions more efficiently than native, fucosylated antibody. Obinutuzumab, an FDA-approved anti-CD20 antibody with approximate 30% fucose level of a normal antibody, has demonstrated better efficacy than fucosylated rituximab. We generated BAT4306F, which has the same sequence as obinutuzumab yet is completely devoid of fucose modification. BAT4306F induced higher level of ADCC effect compared with rituximab and obinutuzumab in vitro. BAT4306F also showed significantly superior activity on depleting B cells in whole blood compared to rituximab, and superior activity compared to obinutuzumab. In monkeys dosed once with these antibodies, BAT4306F demonstrated much stronger B-cell depletion activity than that of obinutuzumab and rituximab, whether detected in serum, spleen, or lymph node. The residual B cells detected in spleen of monkey treated with BAT4306F were 8-fold less than that of obinutuzumab, and 10-fold less than that of rituximab. Furthermore, BAT4306F demonstrated stronger tumor-inhibition activity than rituximab in a DLBCL tumor cell xenograft mouse model. Preclinical acute and long-term toxicity studies in monkey reveal that BAT4306F is well tolerated. Together these data demonstrate that BAT4306F is more potent than obinutuzumab and rituximab due to a complete defucosylation. The result warrants further clinical development of BAT4306F. Citation Format: Jin-Chen Yu, Chao Qin, Shengfeng Li. Bat4306f, an anti-CD20 antibody devoid of fucose modification, demonstrates enhanced ADCC effect and potent in vivo efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3823.