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Preclinical therapy of breast cancer with a radioiodinated humanized anti-EGP-1 monoclonal antibody: advantage of a residualizing iodine radiolabel.

AbstractBACKGROUND:
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.
CONCLUSION:
131I-IMP-R4-hRS7 is a promising new agent for RAIT, providing significant therapeutic advantage in comparison to the conventionally 131I-labeled antibody.
AuthorsSerengulam V Govindan, Rhona Stein, Zhengxing Qu, Susan Chen, Philip Andrews, Hong Ma, Hans J Hansen, Gary L Griffiths, Ivan D Horak, David M Goldenberg
JournalBreast cancer research and treatment (Breast Cancer Res Treat) Vol. 84 Issue 2 Pg. 173-82 (Mar 2004) ISSN: 0167-6806 [Print] Netherlands
PMID14999147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antibodies, Monoclonal
  • Iodine Radioisotopes
Topics
  • Animals
  • Antibodies, Monoclonal (pharmacokinetics, therapeutic use)
  • Breast Neoplasms (metabolism, radiotherapy)
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Iodine Radioisotopes (pharmacokinetics, therapeutic use)
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Radioimmunotherapy (methods)
  • Tissue Distribution
  • Treatment Outcome

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