Structural and functional characterization of IgG- and non-IgG-based T-cell-engaging bispecific antibodies

Mohan, Nishant; Ayinde, Safiat; Peng, Hanjing; Dutta, Shraboni; Shen, Yi; Falkowski, Vincent M.; Biel, Thomas G.; Ju, Tongzhong; Wu, Wen Jin

doi:10.3389/fimmu.2024.1376096

Structural and functional characterization of IgG- and non-IgG-based T-cell-engaging bispecific antibodies

Journal Article · Tue May 28 00:00:00 EDT 2024 · Frontiers in Immunology

DOI:https://doi.org/10.3389/fimmu.2024.1376096· OSTI ID:2471353

Mohan, Nishant ^[1]; Ayinde, Safiat ^[1]; Peng, Hanjing ^[1]; Dutta, Shraboni ^[1]; Shen, Yi ^[1]; Falkowski, Vincent M. ^[1]; Biel, Thomas G. ^[1]; Ju, Tongzhong ^[1]; Wu, Wen Jin ^[1]

US Food and Drug Administration (USFDA), Silver Spring, MD (United States)

Bispecific T-cell-engaging antibodies are a growing class of therapeutics with numerous molecules being tested in clinical trials and, currently, seven of them have received market approval. They are structurally complex and function as adaptors to redirect the cytotoxicity of T cells to kill tumor cells. T-cell-engaging bispecific antibodies can be generally divided into two categories: IgG/IgG-like and non-IgG-like formats. Different formats may have different intrinsic potencies and physiochemical properties, and comprehensive studies are needed to gain a better understanding of how the differences in formats impact on structural and functional characteristics. In this study, we designed and generated bispecific T-cell-engaging antibodies with IgG-like (DVD-Ig) and non-IgG (BiTE) formats. Both target the same pair of antigens (EGFR and CD3) to minimize the possible influence of targets on functional characterization. We performed a side-by-side comparison to assess differences in the physiochemical and biological properties of these two bispecific T-cell-engaging antibodies using a variety of breast and ovarian cancer cell-based functional assays to delineate the structural–functional relationships and anti-tumor activities/potency. We found that the Fc portion of T-cell-engaging bispecific antibodies can significantly impact antigen binding activity, potency, and stability in addition to eliciting different mechanisms of action that contribute the killing of cancer cells.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0014664

OSTI ID:: 2471353

Journal Information:: Frontiers in Immunology, Journal Name: Frontiers in Immunology Vol. 15; ISSN 1664-3224

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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