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mmCSM-AB: guiding rational antibody engineering through multiple point mutations.
Nucleic Acids Res. 2020 07 02; 48(W1):W125-W131.NA

Abstract

While antibodies are becoming an increasingly important therapeutic class, especially in personalized medicine, their development and optimization has been largely through experimental exploration. While there have been many efforts to develop computational tools to guide rational antibody engineering, most approaches are of limited accuracy when applied to antibody design, and have largely been limited to analysing a single point mutation at a time. To overcome this gap, we have curated a dataset of 242 experimentally determined changes in binding affinity upon multiple point mutations in antibody-target complexes (89 increasing and 153 decreasing binding affinity). Here, we have shown that by using our graph-based signatures and atomic interaction information, we can accurately analyse the consequence of multi-point mutations on antigen binding affinity. Our approach outperformed other available tools across cross-validation and two independent blind tests, achieving Pearson's correlations of up to 0.95. We have implemented our new approach, mmCSM-AB, as a web-server that can help guide the process of affinity maturation in antibody design. mmCSM-AB is freely available at http://biosig.unimelb.edu.au/mmcsm_ab/.

Authors+Show Affiliations

Computational Biology and Clinical Informatics, Baker Institute, Melbourne, VIC 3004, Australia. Structural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, VIC 3052, Australia.Computational Biology and Clinical Informatics, Baker Institute, Melbourne, VIC 3004, Australia. Structural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, VIC 3052, Australia. School of Computing and Information Systems, University of Melbourne, Parkville, VIC 3052, Australia.Computational Biology and Clinical Informatics, Baker Institute, Melbourne, VIC 3004, Australia. Structural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, VIC 3052, Australia. Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32432715

Citation

Myung, Yoochan, et al. "MmCSM-AB: Guiding Rational Antibody Engineering Through Multiple Point Mutations." Nucleic Acids Research, vol. 48, no. W1, 2020, pp. W125-W131.
Myung Y, Pires DEV, Ascher DB. MmCSM-AB: guiding rational antibody engineering through multiple point mutations. Nucleic Acids Res. 2020;48(W1):W125-W131.
Myung, Y., Pires, D. E. V., & Ascher, D. B. (2020). MmCSM-AB: guiding rational antibody engineering through multiple point mutations. Nucleic Acids Research, 48(W1), W125-W131. https://doi.org/10.1093/nar/gkaa389
Myung Y, Pires DEV, Ascher DB. MmCSM-AB: Guiding Rational Antibody Engineering Through Multiple Point Mutations. Nucleic Acids Res. 2020 07 2;48(W1):W125-W131. PubMed PMID: 32432715.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - mmCSM-AB: guiding rational antibody engineering through multiple point mutations. AU - Myung,Yoochan, AU - Pires,Douglas E V, AU - Ascher,David B, PY - 2020/05/16/accepted PY - 2020/04/18/revised PY - 2020/03/10/received PY - 2020/5/21/pubmed PY - 2020/5/21/medline PY - 2020/5/21/entrez SP - W125 EP - W131 JF - Nucleic acids research JO - Nucleic Acids Res. VL - 48 IS - W1 N2 - While antibodies are becoming an increasingly important therapeutic class, especially in personalized medicine, their development and optimization has been largely through experimental exploration. While there have been many efforts to develop computational tools to guide rational antibody engineering, most approaches are of limited accuracy when applied to antibody design, and have largely been limited to analysing a single point mutation at a time. To overcome this gap, we have curated a dataset of 242 experimentally determined changes in binding affinity upon multiple point mutations in antibody-target complexes (89 increasing and 153 decreasing binding affinity). Here, we have shown that by using our graph-based signatures and atomic interaction information, we can accurately analyse the consequence of multi-point mutations on antigen binding affinity. Our approach outperformed other available tools across cross-validation and two independent blind tests, achieving Pearson's correlations of up to 0.95. We have implemented our new approach, mmCSM-AB, as a web-server that can help guide the process of affinity maturation in antibody design. mmCSM-AB is freely available at http://biosig.unimelb.edu.au/mmcsm_ab/. SN - 1362-4962 UR - https://www.unboundmedicine.com/medline/citation/32432715/mmCSM_AB:_guiding_rational_antibody_engineering_through_multiple_point_mutations_ L2 - https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkaa389 DB - PRIME DP - Unbound Medicine ER -
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