Broad reactivity and enhanced potency of recombinant anti-EGFR × anti-CD3 bispecific antibody-armed activated T cells against solid tumours. (31st December 2022)

• Record Type: Journal Article
• Authors: Huang, Manley T. F.; Sharma, Vikram; Mendelsohn, Andrew; Wei, Qisheng; Li, Jinjing; Yu, Bo; Larrick, James W.; Lum, Lawrence G.
• Is Part Of: Annals of medicine. Volume 54:Number 1(2022)
• Page Start: 1047
• Page End: 1057
• Publication Date: 2022-12-31
• Subjects: Bispecific antibody -- activated T cells -- OKT3 -- EGFR; cytotoxicity -- cytokines -- chemokines; Medicine -- Periodicals; 610
• DOI: 10.1080/07853890.2022.2059101
• Languages: English
• ISSNs: 0785-3890

Abstract

Abstract: Introduction: Bispecific antibody (BiAb)-armed activated T cells (BATs) comprise an adoptive T cell therapy platform for treating cancer. Arming activated T cells (ATC) with anti-CD3 x anti-tumour associated antigen (TAA) BiAbs converts ATC into non-major histocompatibility complex (MHC)-restricted anti-tumour cytotoxic T lymphocytes (CTLs). Binding of target antigens via the BiAb bridge enables specific anti-tumour cytotoxicity, Th1 cytokines release, and T cell proliferation. Clinical trials in breast, prostate, and pancreatic cancer using BATs armed with chemically heteroconjugated BiAbs demonstrated safety, feasibility, induction of anti-tumour immune responses and potential increases in overall survival (OS). Objectives: The primary objective of this study was to develop a recombinant BiAb that confers enhanced anti-tumour activity of BATs against a broad range of solid tumours. Methods: A recombinant anti-epidermal growth factor receptor (EGFR) x anti-CD3 (OKT3) BiAb (rEGFRBi) was designed and expressed in CHO cells, used to arm ATC (rEGFR-BATs), and tested for specific cytotoxicity against breast, pancreatic and prostate cancers and glioblastoma. Results: rEGFR-BATs exhibit remarkably enhanced specific cytotoxicity and T1 cytokine secretion against a wide range of solid tumour cell lines vs. their respective chemically-heteroconjugated BATs. Conclusion: rEGFR-BATs may provide a "universal" T cell therapy for treating a wide range of solid tumours. KEY MESSAGE: A (Gly4Ser)6 linker between the variable light and heavy chains of an scFv fused to the N-terminus of a heavy chain antibody confers unexpected stability to the heavy chain fusion protein and supports the efficient expression of the bispecific antibody. Arming of activated T cells with the rEGFRBi greatly enhances the relative cytotoxicity and Th1 cytokine secretion of theT cells relative to a chemically heteroconjugated BiAbs. rEGFR-BATs are promising candidates for the treatment of a broad range of solid tumours.