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.
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 aminopolycarboxylatediethylenetriaminepentaacetic 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 humancolon 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.
Authors: G Vaidyanathan; B J White; D J Affleck; X G Zhao; P C Welsh; D McDougald; J Choi; M R Zalutsky Journal: Bioorg Med Chem Date: 2012-10-29 Impact factor: 3.641
Authors: Serengulam V Govindan; Thomas M Cardillo; Sung-Ju Moon; Hans J Hansen; David M Goldenberg Journal: Clin Cancer Res Date: 2009-09-29 Impact factor: 12.531
Authors: Ganesan Vaidyanathan; Emmanuelle Jestin; Tove Olafsen; Anna M Wu; Michael R Zalutsky Journal: Nucl Med Biol Date: 2009-08 Impact factor: 2.408