Minimal-disease radioimmunotherapy of colorectal cancer
Principal Investigator: Serengulam V Govindan
Abstract: Colorectal cancer accounts for 15% of all cancers, and the 5-year survival rate for patients with metastatic tumors is close to zero. Targeted radiotherapy or radioimmunotherapy (RAIT) has the potential to bring about durable clinical responses in small-volume disease of colorectal cancer. The ultimate goal of the proposed work is to produce a clinically useful, commercially viable, radioimmunotherapeutic for treating minimal-disease of colorectal cancer using a humanized anti-CEA monoclonal antibody (MAb), hMN-14, and an intracellularly trapped form ('residualizing') of iodine-131 radionuclide, I-131-IMPR4. The latter is a specially designed radioiodinated peptide, with structural features to aid in residualization after catabolism of the carrier MAb, which solves the problem of in vivo 'deiodination' associated with directly radioiodinated MAbs. The immediate goal of the Phase I research is to obtain preclinical proof that hMN-14 labeled with I-131-IMPR4 (I-131-IMPR4-hMN-14) is significantly better than directly radioiodinated hMN-14 (I-131-hMN-14) in terms of tumor uptake and retention of radioactivity. This will be determined by (i) comparing in vitro bindings and processing of the two labels by four colorectal cell lines, and (ii) by targeting and maximum-tolerated-dose (MTD)/therapy experiments in a human tumor xenograft model of colon carcinoma in nude mice. A concurrent objective is to improve the achievable specific activity of I-131-IMPR4-hMN-14. Criteria of success will be the findings of (1) a 50-200% increase in tumor-cell retention of radioactivity of I-131-IMPR4 label versus direct I-131 label in in vitro experiments, (2) a preliminary evidence of therapeutic advantage for the residualizing I-131 versus direct I-131 label in the preclinical MTD/therapy study, and (3) specific activity enhancement to 10 mCi/mg in radioiodinations with I-131-IMPR4. Successful feasibility study will lead to extended preclinical therapy studies and the initiation of a clinical Phase I RAIT trial in a SBIR Phase II program.
Funding Period: 2003-07-01 - 2003-12-31
more information: NIH RePORT
- Clinical-scale radiolabeling of a humanized anticarcinoembryonic antigen monoclonal antibody, hMN-14, with residualizing 131I for use in radioimmunotherapySerengulam V Govindan
Immunomedics, Inc, 300 American Rd, Morris Plains, NJ 07950, USA
J Nucl Med 46:153-9. 2005..IMP-R4 is MCC-Lys(MCC)-Lys(X)-d-Tyr-d-Lys(X)-OH, where MCC is 4-(N-maleimidomethyl)-cyclohexane-1-carbonyl and X is 1-((4-thiocarbonylamino)benzyl)-diethylenetriaminepentaacetic acid...
- Advantage of a residualizing iodine radiolabel in the therapy of a colon cancer xenograft targeted with an anticarcinoembryonic antigen monoclonal antibodyRhona Stein
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey and Immunomedics Inc, Morris Plains, New Jersey, USA
Clin Cancer Res 11:2727-34. 2005..This adduct causes the radioiodine to become trapped in lysosomes following antibody catabolism. Clinical-scale production of 131I-IMP-R4-labeled antibodies is possible using a recently developed facile method...