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Optimizing Antibody Affinity and Developability Using a Framework-CDR Shuffling Approach-Application to an Anti-SARS-CoV-2 Antibody.
Gopal, Ranjani; Fitzpatrick, Emmett; Pentakota, Niharika; Jayaraman, Akila; Tharakaraman, Kannan; Capila, Ishan.
  • Gopal R; Discovery and Diagnostics Division, Peritia Inc., 12 Gill Street, Woburn, MA 01801, USA.
  • Fitzpatrick E; Discovery and Diagnostics Division, Peritia Inc., 12 Gill Street, Woburn, MA 01801, USA.
  • Pentakota N; Discovery and Diagnostics Division, Peritia Inc., 12 Gill Street, Woburn, MA 01801, USA.
  • Jayaraman A; Discovery and Diagnostics Division, Peritia Inc., 12 Gill Street, Woburn, MA 01801, USA.
  • Tharakaraman K; Discovery and Diagnostics Division, Peritia Inc., 12 Gill Street, Woburn, MA 01801, USA.
  • Capila I; Celltas Biosciences, 900 Middlesex Turnpike, Billerica, MA 01821, USA.
Viruses ; 14(12)2022 11 30.
Article in English | MEDLINE | ID: covidwho-2143729
ABSTRACT
The computational methods used for engineering antibodies for clinical development have undergone a transformation from three-dimensional structure-guided approaches to artificial-intelligence- and machine-learning-based approaches that leverage the large sequence data space of hundreds of millions of antibodies generated by next-generation sequencing (NGS) studies. Building on the wealth of available sequence data, we implemented a computational shuffling approach to antibody components, using the complementarity-determining region (CDR) and the framework region (FWR) to optimize an antibody for improved affinity and developability. This approach uses a set of rules to suitably combine the CDRs and FWRs derived from naturally occurring antibody sequences to engineer an antibody with high affinity and specificity. To illustrate this approach, we selected a representative SARS-CoV-2-neutralizing antibody, H4, which was identified and isolated previously based on the predominant germlines that were employed in a human host to target the SARS-CoV-2-human ACE2 receptor interaction. Compared to screening vast CDR libraries for affinity enhancements, our approach identified fewer than 100 antibody framework-CDR combinations, from which we screened and selected an antibody (CB79) that showed a reduced dissociation rate and improved affinity against the SARS-CoV-2 spike protein (7-fold) when compared to H4. The improved affinity also translated into improved neutralization (>75-fold improvement) of SARS-CoV-2. Our rapid and robust approach for optimizing antibodies from parts without the need for tedious structure-guided CDR optimization will have broad utility for biotechnological applications.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Complementarity Determining Regions / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: V14122694

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Complementarity Determining Regions / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: V14122694