THE CHRONIC LYMPHOCYTIC-LEUKEMIA ANTIGEN (CCLLA) AS IMMUNOTHERAPY TARGET - PHARMACOKINETICS AND BIODISTRIBUTION OF 2 DIVALENT, RICIN-BASED IMMUNOTOXINS IN XENOGRAFTED ATHYMIC MICE

The chronic lymphocytic leukemia (CLL) antigen (cCLLa) is potentially suitable for targeted immunotherapy given its restriction to clonal CL L cells and lack of expression by normal lymphocytes. In order to asse ss the pharmacokinetics and biodistribution of two potent anti-cCLLa i mmunotoxins (ITs) were examined in the mouse model. The IgG fraction o f anti-cCLLa monoclonal antibody CLL2m was conjugated with I-125-label ed intact (RTA) or deglycosylated (dgA) ricin chain A, injected intrav enously into athymic mice engrafted with cCLLa-expressing human tumors , and monitored over 120 hours. Blood concentrations of CLL2m/I-125-RT A and CLL2m/I-125-dgA were best fit to biexponential equations but the latter exhibited a lower alpha T1/2 and beta T1/2 (4.1 and 102 min vs 5.9 and 126 min), a smaller volume of distribution (5.1 g vs 9.7 g), and a lower blood clearance (2.2 g/hr vs 4.6 g/hr). Both ITs exhibited preferential tumor uptake that followed distinct kinetics: rising tum or uptake for 2 hrs post-injection (while tissue uptake decreased), re aching tumor/non-tumoral tissue uptake ratios up to 16.9; and slower d issociation rates of tumor- vs tissue-bound ITs (>45% vs <20% remainin g tissue-bound 6 hrs post-injection, respectively). Non-specific liver uptake was not prominent for either IT. In vivo IT deconjugation reac hed 50% approximately 12 hours postinjection. The pharmacokinetics and biodistribution data in the mouse model suggest that ricin-based anti -cCLLa ITs are suitable for use in human trials.