Pretargeted radioimmunotherapy (PRIT (TM)) 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 mu lti-step delivery system in which an antibody is used to target streptavidi n to a tumor associated antigen receptor and subsequently biotin is then us ed to target Y-90 radioisotope to the tumor localized streptavidin. A chime ric IgG1, anti-CD20 antibody, designated C2B8 or Rituximab, was conjugated to streptavidin (SA) and administered to patients with NHL. Thirty-four hou rs later, a clearing agent, synthetic biotin-N-acetyl-galactosamine, was ad ministered to remove non-localized conjugate from the circulation. Finally, a DOTA-biotin ligand, labeled with In-111 for imaging and/or Y-90 for ther apy was administered Ten patients with relapsed or refractory NHL were stud ied. In three patients, the C2B8/SA conjugate was radiolabeled with a trace amount of Re-186 in order to assess pharmacokinetics and biodistribution u sing gamma camera imaging. Seven patients received 30 or 50 mCi/m(2) Y-90 D OTA-biotin. Re-186 C2B8/SA images confirmed that the conjugate localized to known tumor sites and that the clearing agent removed >95% of the conjugat e from the circulation. Radiolabeled biotin localized well to tumor. Unboun d radiobiotin was rapidly excreted from the whole body and normal organs. T he mean tumor dose calculated was 29 +/- 23 cGy/mCi Y-90 and the average wh ole body dose was 0.76 +/- 0.3 cGy/mCi Y-90, resulting in a mean tumor to w hole 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 on ly transient grade III (but no grade ly) hematologic toxicity. Although six of ten patients developed humoral immune responses to the streptavidin, th ese 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 tum or regression, including three complete and one partial response. The estim ate of tumor to whole body dose ratio (38:1) achieved with PRIT in these NH L patients is higher than has been achieved in other studies using conventi onal RIT. Toxicity was mild and tumor response encouraging. PRIT clearly de serves additional study in patients with NHL.