Zw38, A Bispecific Cd3 X Cd19 Azymetric Antibody To Deplete Human Leukemic B Cells By The "Controlled" Activation Of T Cells.

e14019 Background: Redirected T cell cytotoxicity (RTCC) has emerged as a promising mechanism for cancer treatments and relies on the co-engagement of tumor antigens and T cells, which can be achieved by the use of bi-specific antibodies. While efficacious, drug classes (like bi-specific T-cell engagers) that redirect the immune system are associated with severe cytokine release syndrome and neurological toxicities. ZW38 is an efficacious bi-specific CD3 x CD19 antibody engineered to confer T cell cytotoxicity with controlled T cell activation for maximal B cell depletion while retaining favorable antibody-like PK and CMC properties. Methods: A bi-specific CD3 x CD19 T cell engager, ZW38, was engineered based on our proprietary Azymetric IgG1-based antibody scaffold. ZW38 was evaluated for its ability to deplete B cells, stimulate T cell proliferation, and promote cytokine release. Results: ZW38 binds to CD3+ and CD19+ cells with nM affinity, and efficiently forms cytolytic immune synapses between human T and B cells. ZW38 effectively depletes human CD19+ lymphoma cells and autologous B cells from ex vivo PBMC and human whole blood cultures and robustly depletes autologous B cells in CLL, MCL, and NHL patient-derived whole blood. In vivo activity of ZW38 was assessed in NSG mice engrafted with IL-2 activated human PBMC and human B-ALL cells. ZW38 induced near complete depletion of leukemic ALL B cells in peripheral blood and secondary lymphoid organs. ZW38’s activity is strictly target dependent as it has been demonstrated to spare CD19- erythroleukemia cells even in the presence of IL-2 stimulated T cells. Furthermore, low levels of T cell proliferation and cytokine release accompanied ZW38-mediated killing, which may translate into an improved therapeutic index. ZW38’s Fc domain has been engineered to knockout Fc-mediated effector functions while retaining binding to FcRn to maintain antibody-like serum half-life and a favorable dosing schedule. Conclusions: ZW38’s efficacy, toxicity profile, PK characteristics, and manufacturability position it as a promising potential therapeutic to treat CD19+ B cell malignancies.