Computational optimization of antibody humanness and stability by systematic energy-based ranking.

Autor: Tennenhouse A; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel., Khmelnitsky L; Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel., Khalaila R; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel., Yeshaya N; Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel., Noronha A; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.; Department of Urology, University of California, San Francisco, San Francisco, CA, USA., Lindzen M; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel., Makowski EK; Biointerfaces Institute and Departments of Chemical Engineering, Pharmaceutical Sciences and Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA., Zaretsky I; Antibody Engineering Unit, Weizmann Institute of Science, Rehovot, Israel., Sirkis YF; Protein Analysis Unit, Weizmann Institute of Science, Rehovot, Israel., Galon-Wolfenson Y; Protein Analysis Unit, Weizmann Institute of Science, Rehovot, Israel., Tessier PM; Biointerfaces Institute and Departments of Chemical Engineering, Pharmaceutical Sciences and Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA., Abramson J; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel., Yarden Y; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel., Fass D; Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel., Fleishman SJ; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel. sarel@weizmann.ac.il.
Jazyk: angličtina
Zdroj: Nature biomedical engineering [Nat Biomed Eng] 2024 Jan; Vol. 8 (1), pp. 30-44. Date of Electronic Publication: 2023 Aug 07.
DOI: 10.1038/s41551-023-01079-1
Abstrakt: Conventional methods for humanizing animal-derived antibodies involve grafting their complementarity-determining regions onto homologous human framework regions. However, this process can substantially lower antibody stability and antigen-binding affinity, and requires iterative mutational fine-tuning to recover the original antibody properties. Here we report a computational method for the systematic grafting of animal complementarity-determining regions onto thousands of human frameworks. The method, which we named CUMAb (for computational human antibody design; available at http://CUMAb.weizmann.ac.il ), starts from an experimental or model antibody structure and uses Rosetta atomistic simulations to select designs by energy and structural integrity. CUMAb-designed humanized versions of five antibodies exhibited similar affinities to those of the parental animal antibodies, with some designs showing marked improvement in stability. We also show that (1) non-homologous frameworks are often preferred to highest-homology frameworks, and (2) several CUMAb designs that differ by dozens of mutations and that use different human frameworks are functionally equivalent.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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