Pretargeted radioimmunotherapy (PRIT™) for treatment of non-Hodgkin's lymphoma (NHL):: Initial phase I/II study results

Pretargeted radioimmunotherapy (PRIT(TM)) was investigated in patients with non-Hodgkin's lymphoma (NHL). The PRIT approach used in this study is a multi-step delivery system in which an antibody is used to target streptavidin to a tumor associated antigen receptor and subsequently biotin is then used to target Y-90 radioisotope to the tumor localized streptavidin. A chimeric IgG1, anti-CD20 antibody, designated C2B8 or Rituximab, was conjugated to streptavidin (SA) and administered to patients with NHL. Thirty-four hours later, a clearing agent, synthetic biotin-N-acetyl-galactosamine, was administered to remove non-localized conjugate from the circulation. Finally, a DOTA-biotin ligand, labeled with In-111 for imaging and/or Y-90 for therapy was administered Ten patients with relapsed or refractory NHL were studied. In three patients, the C2B8/SA conjugate was radiolabeled with a trace amount of Re-186 in order to assess pharmacokinetics and biodistribution using gamma camera imaging. Seven patients received 30 or 50 mCi/m(2) Y-90 DOTA-biotin. Re-186 C2B8/SA images confirmed that the conjugate localized to known tumor sites and that the clearing agent removed >95% of the conjugate from the circulation. Radiolabeled biotin localized well to tumor. Unbound radiobiotin was rapidly excreted from the whole body and normal organs. The mean tumor dose calculated was 29 +/- 23 cGy/mCi Y-90 and the average whole body dose was 0.76 +/- 0.3 cGy/mCi Y-90, resulting in a mean tumor to whole body dose ratio of 38:1. Only grade I/II non-hematologic toxicity was observed Hematologic toxicity was also not severe; i.e., five of the seven patients who received -30 or 50 mCi/m(2) of Y-90-DOTA-biotin experienced only transient grade III (but no grade ly) hematologic toxicity. Although six of ten patients developed humoral immune responses to the streptavidin, these were delayed and transient and hence may not preclude retreatment. Six of seven patients who received 30 or 50mCi/m(2) Y-90 achieved objective tumor regression, including three complete and one partial response. The estimate of tumor to whole body dose ratio (38:1) achieved with PRIT in these NHL patients is higher than has been achieved in other studies using conventional RIT. Toxicity was mild and tumor response encouraging. PRIT clearly deserves additional study in patients with NHL.