Agonist antibody discovery: Experimental, computational, and rational engineering approaches. Issue 1 (January 2022)

• Record Type: Journal Article
• Authors: Schardt, John S.; Jhajj, Harkamal S.; O'Meara, Ryen L.; Lwo, Timon S.; Smith, Matthew D.; Tessier, Peter M.
• Is Part Of: Drug discovery today. Volume 27:Issue 1(2022)
• Page Start: 31
• Page End: 48
• Publication Date: 2022-01
• Subjects: Agonist -- Discovery -- Engineering -- High throughput -- mAb -- Antibody -- Biologic -- Function-based screening -- Activation -- signaling; Drugs -- Design -- Periodicals; Drugs -- Research -- Periodicals; 615.1
• DOI: 10.1016/j.drudis.2021.09.008
• Languages: English
• ISSNs: 1359-6446

Abstract

Highlights: Agonist antibodies have emerged as promising therapeutics for receptor agonism. Discovery methods have been adapted based on the endogenous signaling mechanisms. High-throughput screening for agonist function enables improved discovery efficiency. Computational methods are being used to design and optimize agonist antibodies. Molecular engineering has remedied the limited activity and safety of some IgGs. Abstract: Agonist antibodies that activate cellular signaling have emerged as promising therapeutics for treating myriad pathologies. Unfortunately, the discovery of rare antibodies with the desired agonist functions is a major bottleneck during drug development. Nevertheless, there has been important recent progress in discovering and optimizing agonist antibodies against a variety of therapeutic targets that are activated by diverse signaling mechanisms. Herein, we review emerging high-throughput experimental and computational methods for agonist antibody discovery as well as rational molecular engineering methods for optimizing their agonist activity.