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

Abstract

Antibody-based therapeutic approaches have revolutionized the treatment of non- Hodgkin's lymphomas (NHL) as well as other hematological malignancies. However, given the biological and clinical heterogeneity of the diseases, a large variability in clinical response has been observed. Currently, patients with refractory or relapsed lymphomas have limited therapeutic options, and therefore the need to develop effective new treatments remains urgent.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. DM1, a maytansinoid derivative, is a potent tubulin polymerization inhibitor. Anti-CD79b ADCs have demonstrated strong therapeutic activity against B-cell lymphoma xenografts (Polson, 2007). To investigate the pharmacodynamics (PD), pharmacokinetics (PK), and tolerability of 10D10-MCC-DM1 in nonhuman primates, we administered 2 intravenous ~30 mg/kg doses (q 3 weeks) of 10D10-MCC-DM1 or unconjugated antibody 10D10 to cynomolgus monkeys, along with vehicle controls. 10D10-MCC-DM1 and 10D10 resulted in sustained depletion of B-cells and B cell subsets in peripheral 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). We observed an initial rapid depletion of B-cells, likely attributed to probable antibody-mediated clearance by the reticuloendothelial system. This was followed by a greater sustained B-cell depletion by the ADC, attributed to the anti-mitotic pharmacology expected following B-cell receptorbound ADC internalization. In addition, unconjugated 10D10 showed substantially less depletion than 10D10-MCC-DM1 of the CD20+CD21− B cell subset, a subgroup of B cells which is phenotypically similar to human germinal center cells. There was no substantial difference in T cells or NK cells. The PD profiles are particularly encouraging from a therapeutic perspective, as the ADC may be expected to target proliferating NHL cells in a manner similar to dividing B-cells in germinal centers.The pharmacokinetics are described by the plasma measures of total antibody, conjugate, and DM1. 10D10-MCC-DM1 was cleared slowly from the plasma with a terminal half-life of 8.98 ± 1.7 days. The apparent central volume of distribution for 10D10-MCC-DM1 was 47.7 mL/kg, which approximated the physiological plasma volume in monkeys. Modest and expected accumulation was observed following the second dose. At the similar dose level of 10D10 and 10D10-MCC-DM1, the exposure of the total antibody was similar. These PK data, when compared alongside the PD results, point to the increased effectiveness of the drug conjugate in depleting B-cells. Free DM1 concentration in plasma following administration of 10D10-MCC-DM1 exhibited a profile similar to that of 10D10-MCC-DM1 but concentrations were much lower than the corresponding 10D10-MCC-DM1 with a Cmax of 189 ± 23 ng/mL. Based on the species-invariant method, it is projected that the half-life in humans for the conjugate is approximately 19.3 ± 3.4 days. Thus the pharmacokinetic profiles of the conjugate appear to support a dosing schedule of every three weeks in clinical studies.Both 10D10-MCC-DM1 and 10D10 were well tolerated. In monkeys administered 10D10-MCC-DM1, in addition to changes in the lymphoid and hematopoietic systems (B-cell depletion), minimal axonal degeneration of the sciatic nerve was observed. Trastuzumab (Herceptin)-MCC-DM1, an ADC which has shown promising safety and efficacy profiles in clinical trials, displayed similar non-B-cell related effects in cynomolgus monkeys with dose-limiting thrombocytopenia in humans. Thus it appears that targeting B-cells by an anti-CD79b ADC does not have any additional target-independent toxicity. Taken together, these preclinical data suggest that targeting CD79b with ADCs may provide a safe and effective therapy for B-cell malignancies in humans.