XmAb5574: In vitro and in vivo efficacy of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia and its effect on B cells in non-human primates

3078 Background: CD19 is a pan-B cell surface receptor expressed from early stages of pre-B cell development through terminal differentiation into plasma cells. It is an attractive target for cancers of lymphoid origin since it is expressed on the vast majority of Non- Hodgkin Lymphoma (NHL) and leukemia cells. The majority of NHL patients relapse after the current treatment regimen of chemotherapy combined with rituximab (CHOP-R), thus salvage regimens with non-cross resistant antibody therapies are warranted. We present the characterization of a novel humanized Fc-engineered anti-CD19 antibody (XmAb5574). Methods: We applied XmAb technology to a chimeric CD19 antibody to humanize it, increase its affinity for Fc gamma receptors, improve its effector function, and thus significantly increase its antitumor potency. This approach yielded a pre-clinical candidate (XmAb5574) that was tested in a series of in vitro cytotoxicity assays and in mouse xenograft models of NHL. We also tested the depletion of B cells in peripheral blood, lymph nodes, bone marrow and spleen of cynomolgus monkeys. Results: XmAb5574 is a novel anti-CD19 antibody that is highly cytotoxic against a panel of lymphoma and leukemia cell lines. This antibody does not appreciably internalize, and in vitro it mediates ADCC (EC50 ∼ 1 - 0.03 ng/ml) and phagocytosis (EC50 ∼ 3 - 0.1 ng/ml) superior to that of rituximab and alemtuzumab. XmAb5574-mediated ADCC is also significantly increased relative to rituximab in patient-derived ALL, CLL and MCL cells. XmAb5574 exhibits in vitro apoptotic activity that is significantly more potent than that of rituximab. Xenograft mouse models, Ramos and Raji sc and iv, show that XmAb5574 has robust protection in both protocols. Finally, we observed sustained depletion of peripheral and lymphoid B cells in cynomolgus monkeys dosed with XmAb5574. Conclusions: The main features of XmAb5574 are: i) improved in vitro cytotoxicity in tumor cells, ii) robust antitumor activity in mouse xenograft models, and iii) B cell depletion in cynomolgus monkeys. Thus XmAb5574, our anti-CD19 Fc variant antibody engineered for increased effector function, is a promising next-generation immunotherapeutic for leukemias and lymphomas. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Xencor Xencor