title: 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.affiliation: *Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Basel †Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Glycart AG, Schlieren, Switzerland.
authors.forename: Sherri
authors.initials: S
authors.lastname: Dudal
authors.forename: Heather
authors.initials: H
authors.lastname: Hinton
authors.forename: Anna M
authors.initials: AM
authors.lastname: Giusti
authors.forename: Marina
authors.initials: M
authors.lastname: Bacac
authors.forename: Magali
authors.initials: M
authors.lastname: Muller
authors.forename: Tanja
authors.initials: T
authors.lastname: Fauti
authors.forename: Sara
authors.initials: S
authors.lastname: Colombetti
authors.forename: Tobias
authors.initials: T
authors.lastname: Heckel
authors.forename: Nicolas
authors.initials: N
authors.lastname: Giroud
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.forename: Pablo
authors.initials: P
authors.lastname: Umaña
authors.forename: Lisa
authors.initials: L
authors.lastname: Benincosa
authors.forename: Juergen
authors.initials: J
authors.lastname: Bachl
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.forename: Katharine
authors.initials: K
authors.lastname: Bray-French
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000378:metabolism*; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002478:Cells, Cultured; D017321:Clinical Trials, Phase I as Topic; D003429:Cross Reactions; D054796:Drug Dosage Calculations; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008252:Macaca fascicularis; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D051381:Rats; D040681:Structural Homology, Protein
chemical_list: D018033:Antibodies, Bispecific; D017252:CD3 Complex; D002272:Carcinoembryonic Antigen