A novel carcinoembryonic antigen t cell bispecific antibody (cea tcb) for the treatment of solid tumors

Journal article

CEA TCB is a novel IgG-based T Cell Bispecific antibody for the treatment of CEA-expressing solid tumors currently in Phase 1 clinical trials (NCT02324257). Its format incorporates bivalent binding to CEA, a head-to-tail fusion of CEA and CD3e binding Fab domains and an engineered Fc region with completely abolished binding to FcγRs and C1q. The study provides novel mechanistic insights into the activity and mode of action of CEA TCB.CEA TCB activity was characterized on 110 cell lines in vitro and in xenograft tumor models in vivo using NOG mice engrafted with human PBMCs.Simultaneous binding of CEA TCB to tumor and T cells leads to formation of immunological synapses, T cell activation, secretion of cytotoxic granules and tumor cell lysis. CEA TCB activity strongly correlates with CEA expression, with higher potency observed in highly CEA-expressing tumor cells and a threshold of approximately 10,000 CEA binding sites/cell, which allows distinguishing between high- and low-CEA expressing tumor and primary epithelial cells, respectively. Genetic factors do not affect CEA TCB activity confirming that CEA expression level is the strongest predictor of CEA TCB activity. In vivo, CEA TCB induces regression of CEA-expressing xenograft tumors with variable amounts of immune cell infiltrate, leads to increased frequency of activated T cells and converts PD-L1 negative into PD-L1 positive tumors.CEA TCB is a novel generation TCB displaying potent anti-tumor activity; it is efficacious in poorly-infiltrated tumors where it increases T cell infiltration and generates a highly-inflamed tumor microenvironment.

Authors: Bacac, M; Fauti, T; Sam, J; Colombetti, S; Weinzierl, T

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for Cancer Research
• Journal: Clinical Cancer Research
• Volume: 22
• Issue: 13
• Pages: 3286-3297
• Publication date: 2016-02-09
• Acceptance date: 2016-01-15
• DOI: 10.1158/1078-0432.CCR-15-1696
• EISSN: 1078-0432
• ISSN: 1078-0432
• Language: English
• Keywords: Bispecific antibody; Cancer Immunotherapy; cytotoxicity; CEA; T cell