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CDRxAb: Antibody Small-Molecule Conjugates with Computationally Designed Target-Binding Synergy

Citation

Wang, Jingzhou (2021) CDRxAb: Antibody Small-Molecule Conjugates with Computationally Designed Target-Binding Synergy. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/p0kj-9d56. https://resolver.caltech.edu/CaltechTHESIS:05282021-080632319

Abstract

Antibody-drug conjugates (ADCs), or chimeric modalities in general, combine the advantages and offset the flaws of their constituent parts to achieve a broader target space than traditional approaches of pharmaceutical development. My project combines the concept of ADCs with the full atomic simulation capability of computational protein design to define a new class of molecular recognition agents: CDR-extended antibodies, abbreviated as CDRxAbs. A CDRxAb incorporates a small-molecule binding event into de novo designed antibody/target interactions, creating antibody small-molecule conjugates that bind tighter against the target of the small molecule than the small molecule itself. In a proof-of-concept study using monomeric streptavidin/biotin pairs at either a nanomolar or micromolar-level affinity, nanobody-biotin conjugates were efficiently designed to exhibit >20-fold affinity improvement against the model protein targets, with stepwise optimization of binding kinetics and the overall stability. A yeast display-based workflow was subsequently developed to further improve the off rate of the best designed conjugate by another 6 folds. By fully incorporating the chemical space of immunoglobulins into the optimization of small molecule binding events, the workflow explored in this work could be potentially used as a generalizable new method to optimize small molecule-based therapeutics, by exploring a previously uncharted chemical space and the related target space. Chapter 1 reviews background information to justify the proposed CDRxAb molecular construct. Chapter 2 documents the detailed computational design process that generated the 10 conjugates, of which the characterization and discussion are elaborated in Chapter 3. Appendix I documents a slightly related ongoing work that uses computational design to improve existing antibody therapeutics.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Protein design, Protein engineering, Antibody-drug conjugates, Protein-protein interactions
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Biochemistry and Molecular Biophysics
Thesis Availability:Not set
Research Advisor(s):
  • Mayo, Stephen L.
Thesis Committee:
  • Bjorkman, Pamela J. (chair)
  • Arnold, Frances Hamilton
  • Shan, Shu-ou
  • Mayo, Stephen L.
Defense Date:13 May 2021
Record Number:CaltechTHESIS:05282021-080632319
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:05282021-080632319
DOI:10.7907/p0kj-9d56
ORCID:
AuthorORCID
Wang, Jingzhou0000-0002-2850-330X
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14189
Collection:CaltechTHESIS
Deposited By: Jingzhou Wang
Deposited On:03 Jun 2021 00:18
Last Modified:03 Jun 2021 00:18

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