Application of a MABEL Approach for a T-Cell-Bispecific Monoclonal Antibody: CEA TCB. Issue 7 (September 2016)

• Record Type: Journal Article
• Authors: Dudal, Sherri; Hinton, Heather; Giusti, Anna M.; Bacac, Marina; Muller, Magali; Fauti, Tanja; Colombetti, Sara; Heckel, Tobias; Giroud, Nicolas; Klein, Christian; Umaña, Pablo; Benincosa, Lisa; Bachl, Juergen; Singer, Thomas; Bray-French, Katharine
• Is Part Of: Journal of immunotherapy. Volume 39:Issue 7(2016:Sep.)
• Publication Date: 2016-09
• Subjects: carcinoembryonic antigen -- T-cell-bispecific antibody -- minimum anticipated biological effect level -- cancer immunotherapy -- FIH dose selection -- preclinical development; Immunotherapy -- Periodicals; Immunotherapy -- Periodicals; Neoplasms -- therapy -- Periodicals; Electronic journals; Electronic journals; 615.37
• DOI: 10.1097/CJI.0000000000000132
• Languages: English
• ISSNs: 1524-9557

Abstract

Abstract : CEA TCB is a novel T-cell-bispecific (TCB) antibody targeting the carcinoembryonic antigen (CEA) expressed on tumor cells and the CD3 epsilon chain (CD3e) present on T cells, which is currently in Phase 1 clinical trials (NCT02324257) for the treatment of CEA-positive solid tumors. Because the human CEA (hCEA) binder of CEA TCB does not cross-react with cynomolgus monkey and CEA is absent in rodents, alternative nonclinical safety evaluation approaches were considered. These included the development of a cynomolgus monkey cross-reactive homologous (surrogate) antibody (cyCEA TCB) for its evaluation in cynomolgus monkey and the development of double-transgenic mice, expressing hCEA and human CD3e (hCEA/hCD3e Tg), as a potential alternative species for nonclinical safety studies. However, a battery of nonclinical in vitro/ex vivo experiments demonstrated that neither of the previous approaches provided a suitable and pharmacologically relevant model to assess the safety of CEA TCB. Therefore, an alternative approach, a minimum anticipated biological effect level (MABEL), based on an in vitro tumor lysis assay was used to determine the starting dose for the first-in-human study. Using the most conservative approach to the MABEL assessment, a dose of 52 μg was selected as a safe starting dose for clinical study. Abstract : Supplemental Digital Content is available in the text.