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Advantage of a Residualizing Iodine Radiolabel in the Therapy of a Colon Cancer Xenograft Targeted with an Anticarcinoembryonic Antigen Monoclonal Antibody

Authors' Affiliations: ¹ Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey and ² Immunomedics Inc., Morris Plains, New Jersey

Requests for reprints: Rhona Stein, Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ. Phone: 973-844-7012; Fax: 973-844-7020; E-mail: rstein{at}gscancer.org.

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.

Key Words: Gastrointestinal cancers: colorectal • Animal models of cancer • Chemistry of Imaging Agents and Radiotherapeutics • Biological Therapeutic Agents • Antibodies/immunoconjugates

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