Application of a MABEL Approach for a T-Cell-Bispecific Monoclonal Antibody: CEA TCB.

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.

• Authors: Sherri Dudal, Heather Hinton, Anna M Giusti, Marina Bacac, Magali Muller, Tanja Fauti, Sara Colombetti, Tobias Heckel, Nicolas Giroud, Christian Klein, Pablo Umaña, Lisa Benincosa, Juergen Bachl, Thomas Singer, Katharine Bray-French
• Journal: Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) Vol. 39 Issue 7 Pg. 279-89 (09 2016) ISSN: 1537-4513 [Electronic] United States
• PMID: 27404941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific
• CD3 Complex
• Carcinoembryonic Antigen

Topics

• Animals
• Antibodies, Bispecific (metabolism)
• Apoptosis
• CD3 Complex (immunology)
• Carcinoembryonic Antigen (immunology)
• Cells, Cultured
• Clinical Trials, Phase I as Topic
• Cross Reactions
• Drug Dosage Calculations
• Drug Evaluation, Preclinical
• Humans
• Immunotherapy (methods)
• Macaca fascicularis
• Mice
• Mice, Transgenic
• Neoplasms (immunology, therapy)
• Rats
• Structural Homology, Protein