Radiocurability by Targeting Tumor Necrosis Factor-α Using a Bispecific Antibody in Carcinoembryonic Antigen Transgenic Mice

• Published in: International journal of radiation oncology, biology, physics Vol. 69; no. 4; pp. 1231 - 1237
• Main Authors: Larbouret, Christel, Ph.D, Robert, Bruno, Ph.D, Linard, Christine, Ph.D, Teulon, Isabelle, Ph.D, Gourgou, Sophie, M.Sc, Bibeau, Frederic, M.D, Martineau, Pierre, Ph.D, Santoro, Lore, M.Sc, Pouget, Jean-Pierre, Ph.D, Pelegrin, Andre, Ph.D, Azria, David, M.D., Ph.D
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-11-2007; Elsevier
• Subjects: Animals; Antibodies, Bispecific; Antibodies, Bispecific - therapeutic use; Bispecific antibody; Cancer; Carcinoembryonic Antigen; Carcinoembryonic Antigen - immunology; CEA-transgenic mice; Cell Survival; Colonic Neoplasms; Colonic Neoplasms - immunology; Colonic Neoplasms - radiotherapy; Combined Modality Therapy; Combined Modality Therapy - methods; Drug Evaluation, Preclinical; Drug Evaluation, Preclinical - methods; Hematology, Oncology and Palliative Medicine; Humans; Immunocompromised Host; Life Sciences; Mice; Mice, Transgenic; Radiology; Radiotherapy enhancement; Random Allocation; RNA, Messenger; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Synergism; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - therapeutic use; Tumor necrosis factor-α; Tumor Stem Cell Assay; Tumor Stem Cell Assay - methods; CEA-transgenic mice; Tumor necrosis factor-α; Bispecific antibody; Radiotherapy enhancement; Synergism; synergism; Tumor Necrosis FactorΑ; radiotherapy enhancement
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2007.07.2372

Purpose Tumor necrosis factor-α (TNF-α) enhances radiotherapy (RT) killing of tumor cells in vitro and in vivo . To overcome systemic side effects, we used a bispecific antibody (BsAb) directed against carcinoembryonic antigen (CEA) and TNF-α to target this cytokine in a CEA-expressing colon carcinoma. We report the evaluation of this strategy in immunocompetent CEA-transgenic mice. Methods and Materials The murine CEA-transfected colon carcinoma MC-38 was used for all experiments. In vitro , clonogenic assays were performed after RT alone, TNF-α alone, and RT plus TNF-α. In vivo , the mice were randomly assigned to treatment groups: control, TNF-α, BsAb, BsAb plus TNF-α, RT, RT plus TNF-α, and RT plus BsAb plus TNF-α. Measurements of endogenous TNF-α mRNA levels and evaluation of necrosis (histologic evaluation) were assessed per treatment group. Results In vitro , combined RT plus TNF-α resulted in a significant decrease in the survival fraction at 2 Gy compared with RT alone ( p < 0.00001). In vivo , we observed a complete response in 5 (50%) of 10, 2 (20%) of 10, 2 (18.2%) of 11, and 0 (0%) of 12 treated mice in the RT plus BsAb plus TNF-α, RT plus TNF-α, RT alone, and control groups, respectively. This difference was statistically significant when TNF-α was targeted with the BsAb ( p = 0.03). The addition of exogenous TNF-α to RT significantly increased the endogenous TNF-α mRNA level, particularly when TNF-α was targeted with BsAb ( p < 0.01). The percentages of necrotic area were significantly augmented in the RT plus BsAb plus TNF-α group. Conclusion These results suggest that targeting TNF-α with the BsAb provokes RT curability in a CEA-expressing digestive tumor syngenic model and could be considered as a solid rationale for clinical trials.