Fc Engineered Anti-CD19 Monoclonal Antibodies with Enhanced In Vitro Efficacy Against Multiple Lymphoma Cell Lines.

Abstract

CD19 is a pan-B cell surface receptor that is expressed from early stages of pre-B cell development through terminal differentiation into plasma cells. It is an attractive immunotherapy target for cancers of lymphoid origin since it is also expressed on the vast majority of Non-Hodgkin Lymphoma (NHL) cells. Although the anti-CD20 monoclonal antibody rituximab is efficacious for the treatment of lymphoid tumors, a growing population of rituximab-refractory patients has resulted in an unmet need for alternative B cell-specific immunotherapeutics. Engineered Fc variants that increase the affinity of IgG antibodies for Fc gamma receptors (FcγR) can dramatically enhance antibody-dependent cell-mediated cytotoxicity (ADCC). This technology has been applied to a humanized anti-CD19 antibody (XmAb™ CD19) and demonstrates ADCC against multiple cell lines representative of follicular lymphoma (FL/DOHH-2), chronic lymphocytic leukemia (CLL/MEC-1), B-cell acute lymphoblastic leukemia (B-ALL/VAL), mantle cell lymphoma (MCL/JeKo-1), hairy cell leukemia (HCL/BONNA-12), and Burkitt's lymphoma (Raji). The ADCC activity observed is in striking contrast with a wild type IgG1 version of the antibody, which mediates little or no ADCC. Moreover, the XmAb™ CD19 activity is comparable to that of rituximab for the majority of cell lines tested and occasionally superior. Fc variants of this antibody are being evaluated in vitro for their ability to conduct ADCC by various effector cell populations, and in relevant in vivo efficacy models. In summary, these data suggest that anti-CD19 Fc variant antibodies with increased effector function could be promising as NHL immunotherapeutics, particularly for rituximab-refractory NHL.