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

ABSTRACT

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.

KEYWORDS:

• Camelid antibodies
• chicken antibodies
• conserved epitopes
• divergent species
• membrane protein antibodies
• pan-reactive antibody
• paratope
• rabbit antibodies
• therapeutic antibody discovery

Acknowledgments

The authors are grateful for helpful discussions and manuscript assistance from Joseph Rucker, Ginny Feltzin, and Edgar Davidson. We also thank Dr. Janice Reichert for helpful advice regarding the derivation of clinical-stage antibodies.

Abbreviations

aa	=	amino acid
ADA	=	anti-drug antibody
CDR	=	complementarity determining region
FDA	=	Food and Drug Administration
GPCR	=	G protein-coupled receptor
HCAb	=	heavy chain-only antibodies
HCDR3	=	heavy-chain complementarity-determining region 3
IgNAR	=	immunoglobulin new antigen receptor
MAb	=	monoclonal antibody
NHP	=	non-human primate
scFv	=	single-chain variable fragment
VHH	=	variable domain of the heavy chain of HCAb

Disclosure statement

Integral Molecular is a biotech company that uses divergent species for antibody discovery. S.S.R.B., R.C., and B.J.D. are current employees and shareholders of Integral Molecular.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19420862.2023.2273018

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.