A novel monospecific tetravalent IgG1-(scFv)2 version shown enhanced neutralizing and Fc-mediated effector functions against SARS-CoV-2

Zhang-Zhao Gao; Jing-Yu Jiao; Ya-Qiong Zhou; Jian Qi; Shan-Shan Zhu; Jing-Ya Xu; Lei Nie; Hai-Bin Wang

doi:10.1007/s13205-023-03702-z

A novel monospecific tetravalent IgG1-(scFv)₂ version shown enhanced neutralizing and Fc-mediated effector functions against SARS-CoV-2

3 Biotech. 2023 Aug;13(8):283. doi: 10.1007/s13205-023-03702-z. Epub 2023 Jul 25.

Authors

Zhang-Zhao Gao^{1

2}, Jing-Yu Jiao^{1

2}, Ya-Qiong Zhou^{1

2}, Jian Qi^{1

2}, Shan-Shan Zhu^{1

2}, Jing-Ya Xu^{1

2}, Lei Nie^{1

2}, Hai-Bin Wang^{1

2}

Affiliations

¹ BioRay Biopharmaceutical Co., Ltd., Taizhou, 318000 Zhejiang China.
² Hisun Biopharmaceutical Co., Ltd., Hangzhou, 311404 Zhejiang China.

PMID: 37501919
PMCID: PMC10368608 (available on 2024-08-01)
DOI: 10.1007/s13205-023-03702-z

Abstract

Neutralizing monoclonal antibodies (nMABs) have been proved to be effective therapeutics in treating coronavirus disease (COVID-19). To enhance the potency of nMAB 553-15, we generated a novel monospecific tetravalent IgG1-(scFv)₂ version. This was achieved by covalently fusing two forms of 553-15-derived single chain variable fragments (scFv) to the C-terminus of the hIgG1 (human Immunoglobulin G1) Fc fragment. We found that the Fc-fused VL-linker-VH format achieved similar binding affinity and neutralizing behavior as 553-15. The tetravalent versions were constructed by fusing the scFv domains to the C-terminus of nMAB 553-15. As a result, the tetravalent version 55,315-VLVH exhibited significantly higher binding activity to target spike protein variants and enhanced neutralization against VOCs (variants of concern) pseudovirus compared to 553-15. We also measured the Fc effector responses of candidates using wild-type Spike-expressing CHOK1 cells. The 55,315-VLVH enhanced the function of ADCP (antibody-dependent cellular phagocytosis) but had similar IL-6 release levels compared to the bivalent 553-15. It seemed that the novel tetravalent version avoids the pro-inflammatory effect induced by macrophage activation. However, the 55,315-VLVH displayed slightly increased potency in ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity), which might contribute to higher systemic inflammation. Further investigation is necessary to determine whether the tetravalent version is beneficial to balance efficiency and safety against COVID-19.

Keywords: COVID-19; Fc-mediated effector functions; Neutralizing; Tetravalent antibody.

© King Abdulaziz City for Science and Technology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.