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

Ariel Tennenhouse; Lev Khmelnitsky; Razi Khalaila; Noa Yeshaya; Ashish Noronha; Moshit Lindzen; Emily K. Makowski; Ira Zaretsky; Yael Fridmann Sirkis; Yael Galon-Wolfenson; Peter M. Tessier; Jakub Abramson; Yosef Yarden; Deborah Fass; Sarel J. Fleishman

doi:10.1038/s41551-023-01079-1

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

Ariel Tennenhouse, Lev Khmelnitsky, Razi Khalaila, Noa Yeshaya, Ashish Noronha, Moshit Lindzen, Emily K. Makowski, Ira Zaretsky, Yael Fridmann Sirkis, Yael Galon-Wolfenson, Peter M. Tessier, Jakub Abramson, Yosef Yarden, Deborah Fass, Sarel J. Fleishman^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	30-44
Number of pages	15
Journal	Nature Biomedical Engineering
Volume	8
Issue number	1
Early online date	7 Aug 2023
DOIs	https://doi.org/10.1038/s41551-023-01079-1
Publication status	Published - Jan 2024

Bibliographical note

Funding Information:
We thank A. Mechaly (Israel Institute for Biological Research, Department of Infectious Diseases) for a critical reading of the paper, and R. Diskin (Weizmann Institute of Science, Department of Chemical and Structural Biology) and O. Khersonsky (Weizmann Institute of Science, Department of Biomolecular Sciences) for advice. Research in the Fleishman lab was supported by the European Research Council through a Consolidator Award (815379), the Dr Barry Sherman Institute for Medicinal Chemistry, and a donation in memory of Sam Switzer. Research in the Fass lab was supported by the European Research Council through a Proof-of-Concept grant (825076). Research in the Tessier lab was supported by the National Institutes of Health (RF1AG059723 and R35GM136300) and the National Science Foundation (1804313). We acknowledge the European Synchrotron Radiation Facility for the provision of beam time on ID30B, and A. McCarthy for assistance. The collaboration between the Yarden and Fleishman labs was supported by the Weizmann Institute’s BINA framework. Funding for this research was provided by Teva Pharmaceutical Industries Ltd as part of the Israeli National Forum for BioInnovators (NFBI). This work was supported in part by a grant from the Manya Igel Centre for Biomedical Engineering and Signal Processing and the Moross Integrated Cancer Center.

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.

All Science Journal Classification (ASJC) codes

Biotechnology
Bioengineering
Medicine (miscellaneous)
Biomedical Engineering
Computer Science Applications

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10.1038/s41551-023-01079-1

sjf_NatBiomedEngineering_ReliableEnergyBasedAntibody_AM2022Accepted author manuscript, 5.61 MBLicence: CC BY-NC-ND

https://doi.org/10.1101/2022.08.14.503891Licence: CC BY-NC-ND

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Tennenhouse, A., Khmelnitsky, L., Khalaila, R., Yeshaya, N., Noronha, A., Lindzen, M., Makowski, E. K., Zaretsky, I., Sirkis, Y. F., Galon-Wolfenson, Y., Tessier, P. M., Abramson, J., Yarden, Y., Fass, D., & Fleishman, S. J. (2024). Computational optimization of antibody humanness and stability by systematic energy-based ranking. Nature Biomedical Engineering, 8(1), 30-44. https://doi.org/10.1038/s41551-023-01079-1

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title = "Computational optimization of antibody humanness and stability by systematic energy-based ranking",

abstract = "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.",

author = "Ariel Tennenhouse and Lev Khmelnitsky and Razi Khalaila and Noa Yeshaya and Ashish Noronha and Moshit Lindzen and Makowski, {Emily K.} and Ira Zaretsky and Sirkis, {Yael Fridmann} and Yael Galon-Wolfenson and Tessier, {Peter M.} and Jakub Abramson and Yosef Yarden and Deborah Fass and Fleishman, {Sarel J.}",

note = "Funding Information: We thank A. Mechaly (Israel Institute for Biological Research, Department of Infectious Diseases) for a critical reading of the paper, and R. Diskin (Weizmann Institute of Science, Department of Chemical and Structural Biology) and O. Khersonsky (Weizmann Institute of Science, Department of Biomolecular Sciences) for advice. Research in the Fleishman lab was supported by the European Research Council through a Consolidator Award (815379), the Dr Barry Sherman Institute for Medicinal Chemistry, and a donation in memory of Sam Switzer. Research in the Fass lab was supported by the European Research Council through a Proof-of-Concept grant (825076). Research in the Tessier lab was supported by the National Institutes of Health (RF1AG059723 and R35GM136300) and the National Science Foundation (1804313). We acknowledge the European Synchrotron Radiation Facility for the provision of beam time on ID30B, and A. McCarthy for assistance. The collaboration between the Yarden and Fleishman labs was supported by the Weizmann Institute{\textquoteright}s BINA framework. Funding for this research was provided by Teva Pharmaceutical Industries Ltd as part of the Israeli National Forum for BioInnovators (NFBI). This work was supported in part by a grant from the Manya Igel Centre for Biomedical Engineering and Signal Processing and the Moross Integrated Cancer Center. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

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doi = "10.1038/s41551-023-01079-1",

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Tennenhouse, A, Khmelnitsky, L, Khalaila, R, Yeshaya, N, Noronha, A, Lindzen, M, Makowski, EK, Zaretsky, I , Sirkis, YF, Galon-Wolfenson, Y, Tessier, PM, Abramson, J , Yarden, Y , Fass, D & Fleishman, SJ 2024, 'Computational optimization of antibody humanness and stability by systematic energy-based ranking', Nature Biomedical Engineering, vol. 8, no. 1, pp. 30-44. https://doi.org/10.1038/s41551-023-01079-1

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AU - Noronha, Ashish

AU - Lindzen, Moshit

AU - Makowski, Emily K.

AU - Zaretsky, Ira

AU - Sirkis, Yael Fridmann

AU - Galon-Wolfenson, Yael

AU - Tessier, Peter M.

AU - Abramson, Jakub

AU - Yarden, Yosef

AU - Fass, Deborah

AU - Fleishman, Sarel J.

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

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