Preclinical evaluation of 90Y-labeled anti-CD20 monoclonal antibody for treatment of non-Hodgkin's lymphoma.
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.
Chinn
P C
PC
IDEC Pharmaceuticals Inc., San Diego, CA 92121, USA.
Leonard
J E
JE
Rosenberg
J
J
Hanna
N
N
Anderson
D R
DR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use; D018951:Antigens, CD20 / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D016393:Lymphoma, B-Cell / Q000532:radiotherapy; D008228:Lymphoma, Non-Hodgkin / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016499:Radioimmunotherapy; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D015021:Yttrium Radioisotopes