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IsAb: a general in silico protocol for antibody design

Liang, Tianjian (2021) IsAb: a general in silico protocol for antibody design. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

The design of therapeutic antibodies has attracted a large amount of attention over the past ten years. Antibodies are widely used to treat many diseases due to their high efficiency and low risk of adverse events. However, the experimental methods of antibody design are time-consuming and expensive. Although computational antibody design techniques have had significant advances in the past years, there are still some challenges that need to be solved, such as the flexibility of antigen structure, the lack of antibody structure data, and the absence of standard antibody design protocol. In the present work, we elaborated on an in-silico antibody design protocol for users to easily perform computer-aided antibody design. First, the Rosetta web server will be applied to generate the 3D structure of query antibodies if there is no structural information available. Then, two-step docking will be used to identify the binding pose of an antibody-antigen complex when the binding information is unknown. ClusPro is the first method to be used to conduct the global docking, and SnugDock is applied for the local docking. Sequentially, based on the predicted binding poses, in-silico alanine scanning will be used to predict the potential hotspots (or key residues). Finally, computational affinity maturation protocol will be used to modify the structure of antibodies to increase their affinity and stability. We also redesigned antibody D44.1 which is an anti-hen egg white lysozyme antibody and compared it with previously reported data to strengthen the persuasion of IsAb protocol. To further illustrate our proposed protocol, we used an FDA-approved PD-1 checkpoint inhibitors antibody, cemiplimab as an example to showcase a step-by-step tutorial.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Liang, Tianjiantil60@pitt.edutil60
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFeng, Zhiweizhf11@pitt.edu
Committee MemberWang, Junmeijunmei.wang@pitt.edu
Committee MemberKirisci, Leventlevent@pitt.edu
Committee MemberXie, Xiangqunsean.xie@pitt.edu
Date: 15 April 2021
Date Type: Publication
Defense Date: 24 March 2021
Approval Date: 15 April 2021
Submission Date: 2 April 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 77
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: antibody design, protein engineering, protein-protein docking, computer-aided antibody protocol
Date Deposited: 15 Apr 2021 12:55
Last Modified: 15 Apr 2021 12:55
URI: http://d-scholarship.pitt.edu/id/eprint/40489

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