Extracorporeal Adsorption Following Infusion of Radiolabeled Anti-CD20 Antibody Clears Unbound Radioimmunoconjugate from the Circulation and Reduces Radiation Exposure of Normal Organs in the Nonhuman Primate.

Abstract

The efficacy of anti-CD20 radioimmunotherapy (RIT) has been validated by high rates of response in patients with non-Hodgkin's lymphoma; however individuals treated with conventional RIT usually relapse. While dose escalation of RIT should theoretically improve patient outcomes, the maximum deliverable dose of isotope has been limited by non-specific irradiation of normal tissues. To establish the efficacy of extracorporeal adsorption therapy (ECAT) in removing unbound radioimmunoconjugate, thereby enhancing the therapeutic index of RIT; and, to investigate the lanthanide radiometal 177Lu as a potential therapeutic isotope for use in future human trials - three groups containing two Macaca fascicularis males each were injected with rituximab trace labeled with 111In-DOTA-biotin (n=4) or 177Lu-DOTA-biotin (n=2). One animal in each group underwent ECAT by circulating three blood volumes over an avidin-agarose column 24 hours following the infusion. The second Macaque served as a control in each group. Animals underwent serial serum, marrow and excisional lymph node sampling. Following euthanasia, target tissues (lymph node and spleen) and non-target tissues (lung, liver and kidney) were sampled in triplicate. The radiation activity for each organ was estimated by serial quantitative gamma camera imaging and the amount of radiation per gram of tissue was directly quantified with a multi-channel gamma counter. Corrected tissue uptake values were calculated and absorbed doses to organs determined using standard MIRD methods adjusted for organ sizes. ECAT was well tolerated by all animals and no significant side effects were observed. Serial blood counts, serum creatinine, hepatic transaminase and coagulation profiles were unaffected. When compared with controls, ECAT reduced the amount of radioimmunoconjugate in the blood by greater than 95% immediately following the procedure; this effect was sustained throughout each study. Radiation doses delivered to both target and non-target tissues were decreased in the ECAT animals. Localization of antibody in lymph nodes and spleen relative to blood was superior in animals undergoing ECAT (p=0.039 by Spearman correlation). Following ECAT, the radiation doses to critical non-target tissues (lung, liver and kidney) were reduced by 52%, 30% and 40% in the 111In-DOTA-biotin-Rituximab group and 64%, 66% and 68% in the 177Lu-DOTA-biotin-Rituximab group compared to controls. In target tissues (lymph node and spleen), ECAT resulted in dose reductions of 12% and 27% for 111In-DOTA-biotin-Rituximab, respectively, and 35% and 48%, respectively, for 177Lu-DOTA-biotin-Rituximab treated animals. These findings indicate 177Lu to be an imageable radiometal capable of conjugation to anti-CD20 antibody. Further, ECAT is identified as a safe and feasible procedure capable of achieving a significant reduction in circulating levels of unbound radioimmunoconjugate. As a result, radiation absorbed doses to normal tissues are significantly reduced.