Pharmacokinetics of Anti-CD22 Antibody Conjugates with Uncleavable and Cleavable Linkers in Rats.

CD22 is a B cell specific antigen and is expressed in Non-Hodgkin lymphoma (NHL) with limited expression on normal tissues. Currently, we are evaluating anti-CD22 antibody drug conjugates (anti-CD22 ADC) consisting of a humanized monoclonal IgG antibody conjugated to mitotic inhibitors such as DM1 (a maytansinoid), Monomethylauristatin F (MMAF), or Monomethylauristatin E (MMAE). The antibody binds to human and cynomolgus monkey CD22, but does not bind to rodent CD22. The cytotoxic drugs were conjugated to the antibody via uncleavable linkers (MCC-DM1, MC-MMAF) or cleavable linkers (SPP-DM1, vc-MMAE). These conjugates have demonstrated anti-tumor activity in mouse xenograft models of human B-cell tumors. This study was to assess and to compare the antigen-independent pharmacokinetics of anti-CD22 ADCs with uncleavable linkers (anti-CD22-MCC-DM1 and anti-CD22-MC-MMAF) and cleavable linkers (anti-CD22-SPP-DM1 and anti-CD22-vc-MMAE) in rats, and to support a pilot rat safety study. Following a single IV dose, the anti-CD22 ADCs exhibited a biphasic disposition profile. The conjugates with cleavable linkers had faster clearance compared to those with uncleavable linkers (59.4 mL/day/kg for anti-CD22-SPP-DM1 vs. 18.0 mL/day/kg for anti-CD22-MCC-DM1). The faster clearance for anti-CD22 ADCs with cleavable linker has also been observed with other ADCs (different target). In addition, it was found that free DM1 in plasma that was deconjugated from anti-CD22-SPP-DM1 had ∼70 fold higher exposure compared with that from anti-CD22-MCC-DM1 (area under curve (AUC) for free DM1 in plasma: 562 day*ng/mL for anti-CD22-SPP-DM1 vs. 8.18 day*ng/mL for anti-CD22-MCC-DM1). Furthermore, anti-CD22-SPP-DM1 had a different DM1 release profile compared with anti-CD22-MCC-DM1 when incubated with human plasma in vitro. Maximum concentrations of free DM1 were reached at ∼6 hr and ∼24 hr for anti-CD22-SPP-DM1 and anti-CD22-MCC-DM1, respectively. These observations were consistent with the safety findings in rats: anti-CD22-SPP-DM1 had greater toxicity (body weight loss, renal toxicity) compared with anti-CD22-MCC-DM1. The data described here indicate that the anti-CD22 ADCs with uncleavable linkers are cleared slower than, and have a better safety profile than the conjugates with cleavable linkers.