Breaking barriers in antibody discovery: harnessing divergent species for accessing difficult and conserved drug targets

• Published in: mAbs Vol. 15; no. 1; p. 2273018
• Main Authors: Banik, Soma S.R., Kushnir, Natasha, Doranz, Benjamin J., Chambers, Ross
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 31-12-2023; Taylor & Francis Group
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Camelid antibodies; chicken antibodies; Chickens; conserved epitopes; divergent species; Epitopes; membrane protein antibodies; Mice; pan-reactive antibody; paratope; rabbit antibodies; Rabbits; Review; therapeutic antibody discovery; divergent species; rabbit antibodies; paratope; conserved epitopes; therapeutic antibody discovery; Camelid antibodies; pan-reactive antibody; membrane protein antibodies; chicken antibodies
• ISSN: 1942-0862; 1942-0870
• DOI: 10.1080/19420862.2023.2273018

To exploit highly conserved and difficult drug targets, including multipass membrane proteins, monoclonal antibody discovery efforts increasingly rely on the advantages offered by divergent species such as rabbits, camelids, and chickens. Here, we provide an overview of antibody discovery technologies, analyze gaps in therapeutic antibodies that stem from the historic use of mice, and examine opportunities to exploit previously inaccessible targets through discovery now possible in alternate species. We summarize the clinical development of antibodies raised from divergent species, discussing how these animals enable robust immune responses against highly conserved binding sites and yield antibodies capable of penetrating functional pockets via long HCDR3 regions. We also discuss the value of pan-reactive molecules often produced by these hosts, and how these antibodies can be tested in accessible animal models, offering a faster path to clinical development.