Preclinical therapy of breast cancer with a radioiodinated humanized anti-EGP-1 monoclonal antibody: advantage of a residualizing iodine radiolabel.
BACKGROUND
A humanized monoclonal antibody (MAb), hRS7, labeled with 131I-IMP-R4, was evaluated for the preclinical radioimmunotherapy (RAIT) of breast cancer. 131I-IMP-R4 is an improved residualizing form of 131I that overcomes the short tumor residence time associated with conventionally radioiodinated MAbs. RS7, an internalizing MAb, recognizes epithelial glycoprotein-1, which is highly expressed in the carcinomas of breast, lung, ovary, and prostate.


METHODS
A humanized version of RS7 was generated by CDR-grafting and transfection. In vivo experiments were carried out in nude mice bearing subcutaneous MDA-MB-468 human breast cancer xenografts. Therapy experiments were performed using established tumors with mean tumor volume (MTV) of 0.3 cm3, and single administrations, at approximately 70% of the estimated maximum tolerated doses (MTD), of the residualizing 131I-IMP-R4-hRS7 and 131I-hRS7 prepared by the conventional chloramine-T method [131I-hRS7 (CT)]. Therapeutic specificity was determined by comparison with untreated and non-specific MAb controls.


RESULTS
hRS7 was functionally very similar to murine and chimeric RS7. A biodistribution study using 125I-IMP-R4-hRS7 and 131I-hRS7 (CT) indicated a dosimetric advantage for the former. The MTVs 8 weeks post-treatment were 20, 163, and 280% of the starting MTVs of 131I-IMP-R4-hRS7-treated, 131I-hRS7 (CT)-treated, and untreated groups, respectively. Complete remissions were seen in 5 of 11 [and 6 of 8] mice treated with 131I-IMP-R4-hRS7, and in 1 of 11 mice treated with 131I-hRS7(CT). 131I-IMP-R4-hRS7 was significantly more efficacious than 131I-hRS7 (CT) [ P = 0.01 for AUC] and the control 131I-IMP-R4-MAb.


CONCLUSIONS
131I-IMP-R4-hRS7 is a promising new agent for RAIT, providing significant therapeutic advantage in comparison to the conventionally 131I-labeled antibody.
Govindan
Serengulam V
SV
R & D Department, Immunomedics, Inc., Morris Plains, NJ 07950, USA. sgovindan@immunomedics.com
Stein
Rhona
R
Qu
Zhengxing
Z
Chen
Susan
S
Andrews
Philip
P
Ma
Hong
H
Hansen
Hans J
HJ
Griffiths
Gary L
GL
Horak
Ivan D
ID
Goldenberg
David M
DM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy / Q000379:methods; D014018:Tissue Distribution; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D007457:Iodine Radioisotopes