Advantage of a Residualizing Iodine Radiolabel in the Therapy of a Colon Cancer Xenograft Targeted with an Anticarcinoembryonic Antigen Monoclonal Antibody
- 1 April 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 11 (7), 2727-2734
- https://doi.org/10.1158/1078-0432.ccr-04-2100
Abstract
Purpose: A disadvantage of conventionally radioiodinated monoclonal antibodies (mAb) for cancer therapy is the short retention time of the radionuclide within target cells. To address this issue, we recently developed a method in which radioiodine is introduced onto antibodies using an adduct consisting of a nonmetabolizable peptide attached to the aminopolycarboxylate diethylenetriaminepentaacetic acid, designated IMP-R4. 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. Experimental Design: The properties of 131I-IMP-R4-labeled anticarcinoembryonic antigen (CEA) humanized mAb hMN-14 were compared with the directly radioiodinated hMN-14 (131I-hMN-14) in CEA-expressing human colon cancer cell lines, LoVo and LS174T, and in nude mice bearing established LoVo tumor xenografts. Results: 125I-IMP-R4-hMN-14 retention in the cell lines was significantly increased (61.5% after 3 days) compared with 125I-hMN-14. In vivo, a significant improvement in tumor accretion of radiolabel was obtained using 131I-IMP-R4-hMN-14, which led to a marked improvement in therapeutic efficacy. Eight weeks post-treatment, mean tumor volumes were 0.16 ± 0.19 and 1.99 ± 1.35 cm3 in mice treated with 131I-IMP-R4-hMN-14 and 131I-hMN-14, respectively, with complete remissions observed in 27% of mice treated with 131I-IMP-R4-hMN-14 and none using 131I-hMN-14. Conclusion: 131I-IMP-R4-hMN-14 provides a significant therapeutic advantage in comparison to the conventionally 131I-labeled antibody. The ability of this labeling method to lend itself to clinical-scale labeling, the broad applicability of a humanized anti-CEA mAb for CEA-expressing cancers, and the clinical benefits of radioimmunotherapy with anti-CEA mAb shown recently for small-volume and minimal residual disease combine to make 131I-IMP-R4-hMN-14 a promising new agent for radioimmunotherapy.Keywords
This publication has 34 references indexed in Scilit:
- N-Succinimidyl 3-[131I]Iodo-4-phosphonomethylbenzoate ([131I]SIPMB), a Negatively Charged Substituent-Bearing Acylation Agent for the Radioiodination of Peptides and mAbsBioconjugate Chemistry, 2003
- Radioimmunotherapy of small-volume disease of metastatic colorectal cancerCancer, 2002
- Combining radioimmunotherapy and chemotherapy for treatment of medullary thyroid carcinomaCancer, 2001
- Radioiodinated antibody targeting of the HER-2/neu oncoprotein: effects of labeling method on cellular processing and tissue distributionNuclear Medicine and Biology, 1999
- The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissuesSeminars in Cancer Biology, 1999
- Labeling of Monoclonal Antibodies with Diethylenetriaminepentaacetic Acid-Appended Radioiodinated Peptides Containingd-Amino AcidsBioconjugate Chemistry, 1999
- Metabolism of receptor targeted 111In-DTPA-glycoproteins: Identification of 111In-DTPA-ϵ-lysine as the primary metabolic and excretory productNuclear Medicine and Biology, 1994
- Characterization of second-generation monoclonal antibodies against carcinoembryonic antigenCancer, 1993
- Use of Radiolabeled Antibodies to Carcinoembryonic Antigen for the Detection and Localization of Diverse Cancers by External PhotoscanningNew England Journal of Medicine, 1978
- A Method of Trace Iodination of Proteins for Immunologic StudiesInternational Archives of Allergy and Immunology, 1966