Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria
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Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 2007 |
| Tidsskrift | Nature Communications |
| Vol/bind | 15 |
| Udgave nummer | 1 |
| Antal sider | 16 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
This work was partially supported by the Research Council of Norway through its Centers of Excellence scheme, project number 332727, the Global Health and vaccination research (GLOBVAC) program, project 285136 (J.T.A., S.F., D.S., J.B., S.A.S.), the grants 274993, 287927 (J.T.A. and F.R.J.) and 335688 (S.F.), the South-Eastern Norway Regional Health Authority project 2018052 (J.T.A.), the Norwegian Cancer Society, Grant no. 223315 (J.T.A. and S.F.) as well as the Novo Nordisk Distinguished Innovator Grant NNF22OC0076567. The project also received funding from European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 101001937, ERC-ACCENT to S.H.M.R.). M.L. and T.V. were supported by the German Research Organization (DFG; CRU 5010, P6). J.B. was supported by DBT Wellcome Trust India Alliance Team Science Grant (IA/TSG/19/1/600019).
Publisher Copyright:
© The Author(s) 2024.
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