Preclinical evaluation of 90Y-labeled anti-CD20 monoclonal antibody for treatment of non-Hodgkin's lymphoma

• Published in: International journal of oncology Vol. 15; no. 5; p. 1017
• Main Authors: Chinn, P C, Leonard, J E, Rosenberg, J, Hanna, N, Anderson, D R
• Format: Journal Article
• Language: English
• Published: Greece 01.11.1999
• Subjects: Animals; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Antigens, CD20 - immunology; Humans; Immunoglobulin G; Immunoglobulin kappa-Chains; Lymphoma, B-Cell - radiotherapy; Lymphoma, Non-Hodgkin - radiotherapy; Mice; Mice, Inbred BALB C; Radioimmunotherapy; Tissue Distribution; Tumor Cells, Cultured; Yttrium Radioisotopes - pharmacokinetics; Yttrium Radioisotopes - therapeutic use
• ISSN: 1019-6439
• DOI: 10.3892/ijo.15.5.1017

A high-affinity IgG1 kappa murine monoclonal anti-CD20 antibody (IDEC-2B8) was developed for radioimmunotherapy of non-Hodgkin's B-cell lymphoma. A stable immunoconjugate (Zevalintrade mark) was prepared by reacting IDEC-2B8 with a derivative of diethylenetriaminepentaacetic acid, designated MX-DTPA, a chelator exhibiting high affinity and retention for 90Y. Zevalin exhibited antigen specificity, human tissue reactivity, and preclinical safety profile comparable to the native antibody. The conjugate radiolabeled with 90Y (90Y-Zevalin) or 111In (111In-Zevalin) exhibited excellent retention of immunoreactivity with radioincorporations >95%. The radiolabeled conjugates formulated in PBS containing human serum albumin were stable in vitro at 4 degrees C for 48 h as indicated by negligible loss of radioisotope and retention of binding to CD20+ cells. In vitro human serum stability studies at 37 degrees C with 90Y-Zevalin indicated that loss of 90Y from the conjugate was minimal, averaging 1% per day. Biodistribution studies in BALB/c mice confirmed the in vitro stability of 90Y-Zevalin and 111In-Zevalin. In particular, excellent in vivo retention of 90Y by the conjugate was demonstrated by minimal bone accumulation (</=3% of the injected dose over three days). Radiation dose estimates to normal organs calculated from mouse biodistribution studies with 90Y-Zevalin were comparable to those determined in a phase I/II clinical trial and below generally accepted safe radiation levels. Studies in athymic mice bearing CD20+ tumors demonstrated that 111In-Zevalin accumulated in the tumors preferentially compared with normal organs. 90Y-Zevalin is currently being evaluated in phase III clinical trials for treatment of relapsed or refractory low-grade, follicular or transformed B-cell non-Hodgkin's lymphoma.