Pharmacodynamics, Pharmacokinetics, and Tolerability of a B-Cell Specific Antibody-Targeted Chemotherapeutic Agent, Anti-CD79b-MCC-DM1, in Cynomolgus Monkeys (41.12)

Abstract

Abstract Antibody-based therapeutic approaches have revolutionized the treatment of non-Hodgkin's lymphomas (NHL) as well as other hematological malignancies. However, a large variability in clinical response has been observed and patients with refractory or relapsed lymphomas have limited therapeutic options. Antibody drug conjugates (ADC) may prove valuable in this respect. The B cell surface antigen, CD79b, is an attractive target for this approach as it is rapidly internalized upon antibody engagement and has an appropriate expression pattern, being expressed only on normal and malignant B-cells. Anti-CD79b-MCC-DM1 is an ADC consisting of a chimeric monoclonal anti-CD79b antibody, 10D10, conjugated via a thioether linker to a cytotoxic drug, DM1 (a potent tubulin polymerization inhibitor). To investigate the pharmacodynamics (PD), pharmacokinetics (PK), and tolerability of 10D10-MCC-DM1 in nonhuman primates, we administered 10D10-MCC-DM1 or unconjugated antibody 10D10 to cynomolgus monkeys. 10D10-MCC-DM1 and 10D10 resulted in sustained depletion of B-cells and B cell subsets in blood, with more substantial depletion in the group given 10D10-MCC-DM1. These findings correlated well with the depletion of B-cells observed in lymphoid tissues (bone marrow, lymph nodes, and spleen). Both 10D10-MCC-DM1 and 10D10 were well tolerated. Taken together, these preclinical data suggest that targeting CD79b with ADCs may provide a safe and effective therapy for B-cell malignancies in humans.