Pc. Chinn et al., Preclinical evaluation of Y-90-labeled anti-CD20 monoclonal antibody for treatment of non-Hodgkin's lymphoma, INT J ONCOL, 15(5), 1999, pp. 1017-1025
A high-affinity IgG1 kappa murine monoclonal anti-CD20 antibody (IDEC-2B8)
was developed for radioimmunotherapy of non-Hodgkin's B-cell lymphoma. A st
able immunoconjugate (Zevalin(TM)) was prepared by reacting IDEC-2B8 with a
derivative of diethylenetriaminepentaacetic acid, designated MX-DTPA, a ch
elator exhibiting high affinity and retention for Y-90. Zevalin exhibited a
ntigen specificity, human tissue reactivity, and preclinical safety profile
comparable to the native antibody. The conjugate radiolabeled with 90Y (Y-
90-Zevalin) or In-111 (In-111-Zevalin) exhibited excellent retention of imm
unoreactivity with radioincorporations >95%. The radiolabeled conjugates fo
rmulated in PBS containing human serum albumin were stable in vitro at 4 de
grees C for 48 h as indicated by negligible loss of radioisotope and retent
ion of binding to CD20(+) cells. In vitro, human serum stability studies at
37 degrees C with Y-90-Zevalin indicated that loss of 90Y from the conjuga
te was minimal, averaging 1% per day. Biodistribution studies in BALB/c mic
e confirmed the in vitro stability of Y-90-Zevalin and In-111-Zevalin. In p
articular, excellent in vivo retention of 90Y by the conjugate was demonstr
ated by minimal bone accumulation (less than or equal to 3% of the injected
dose over three days). Radiation dose estimates to normal organs calculate
d from mouse biodistribution studies with Y-90-Zevalin were comparable to t
hose determined in a phase I/II clinical trial and below generally accepted
safe radiation levels. Studies in athymic mice bearing CD20(+) tumors demo
nstrated that In-111-Zevalin accumulated in the tumors preferentially compa
red with normal organs. Y-90-Zevalin is currently being evaluated in phase
III clinical trials for treatment of relapsed or refractory low-grade, foll
icular or transformed B-cell non-Hodgkin's lymphoma.