Marian Gutowski1, Bérénice Framery2, Martin C Boonstra3, Véronique Garambois4, François Quenet1, Karen Dumas2, François Scherninski5, Françoise Cailler2, Alexander L Vahrmeijer3, André Pèlegrin6. 1. Institut régional du Cancer de Montpellier, ICM, Montpellier, F-34298, France. 2. SurgiMAb, 10 Parc Club du Millénaire, 1025 Avenue Henri Becquerel, 34000, Montpellier, France. 3. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. 4. Institut régional du Cancer de Montpellier, ICM, Montpellier, F-34298, France; IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34298, France. 5. Laboratoires Synth-Innove, 2bis rue Dupont de l'Eure, 75020, Paris, France. 6. Institut régional du Cancer de Montpellier, ICM, Montpellier, F-34298, France; IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U1194, Montpellier, F-34298, France; Université de Montpellier, Montpellier, F-34298, France. Electronic address: andre.pelegrin@inserm.fr.
Abstract
PURPOSE: Fluorescence-guided surgery (FGS) provides surgeons with new opportunities to improve real-time cancer nodule detection and tumor margin visualization. Currently, the most important challenge in this field is the development of fluorescent dyes that specifically target tumors. We developed, characterized and evaluated SGM-101, an innovative antibody-dye conjugate in which the fluorochrome BM104, which has an absorbance band centered at 700 nm, is coupled to a chimeric monoclonal antibody (mAb) against carcinoembryonic antigen (CEA). METHODS: The dye to mAb ratio, binding to CEA and photobleaching of SGM-101 were determined. FGS was performed and results analyzed using different mouse models of human digestive tumors. RESULTS: SGM-101 allowed the detection of tumor nodules in three different colon cancer models: LS174T human colorectal adenocarcinoma cell-induced peritoneal carcinomatosis (PC) and liver metastases, and orthotopic grafts of HT29 human colorectal adenocarcinoma cells. In the PC model, submillimeter-sized nodules were detected during SGM-101-based FGS and SGM-101 predictive positive values ranged from 99.04% to 90.24% for tumor nodules >10 mg and nodules <1 mg, respectively. Similarly, in the orthotopic model of pancreatic cancer using BxPC3 (pancreas adenocarcinoma) cells, SGM-101 could clearly delineate tumors in vivo with a tumor-to-background ratio of 3.5, and penetrated in tumor nodules, as demonstrated by histological analysis. Free BM105 dye (BM104 with an activated ester for conjugation to the antibody) and an irrelevant conjugate did not induce any NIR fluorescence. CONCLUSION: These preclinical data indicate that SGM-101 is an attractive candidate for FGS of CEA-expressing tumors and is currently assessed in clinical trials.
PURPOSE: Fluorescence-guided surgery (FGS) provides surgeons with new opportunities to improve real-time cancer nodule detection and tumor margin visualization. Currently, the most important challenge in this field is the development of fluorescent dyes that specifically target tumors. We developed, characterized and evaluated SGM-101, an innovative antibody-dye conjugate in which the fluorochrome BM104, which has an absorbance band centered at 700 nm, is coupled to a chimeric monoclonal antibody (mAb) against carcinoembryonic antigen (CEA). METHODS: The dye to mAb ratio, binding to CEA and photobleaching of SGM-101 were determined. FGS was performed and results analyzed using different mouse models of human digestive tumors. RESULTS:SGM-101 allowed the detection of tumor nodules in three different colon cancer models: LS174T humancolorectal adenocarcinoma cell-induced peritoneal carcinomatosis (PC) and liver metastases, and orthotopic grafts of HT29 humancolorectal adenocarcinoma cells. In the PC model, submillimeter-sized nodules were detected during SGM-101-based FGS and SGM-101 predictive positive values ranged from 99.04% to 90.24% for tumor nodules >10 mg and nodules <1 mg, respectively. Similarly, in the orthotopic model of pancreatic cancer using BxPC3 (pancreas adenocarcinoma) cells, SGM-101 could clearly delineate tumors in vivo with a tumor-to-background ratio of 3.5, and penetrated in tumor nodules, as demonstrated by histological analysis. Free BM105 dye (BM104 with an activated ester for conjugation to the antibody) and an irrelevant conjugate did not induce any NIR fluorescence. CONCLUSION: These preclinical data indicate that SGM-101 is an attractive candidate for FGS of CEA-expressing tumors and is currently assessed in clinical trials.
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