Natural and man-made V-gene repertoires for antibody discovery

Abstract

Antibodies are the fastest-growing segment of the biologics market. The success of antibody-based drugs resides in their exquisite specificity, high potency, stability, solubility, safety, and relatively inexpensive manufacturing process in comparison with other biologics. We outline here the structural studies and fundamental principles that define how antibodies interact with diverse targets. We also describe the antibody repertoires and affinity maturation mechanisms of humans, mice, and chickens, plus the use of novel single-domain antibodies in camelids and sharks. These species all utilize diverse evolutionary solutions to generate specific and high affinity antibodies and illustrate the plasticity of natural antibody repertoires. In addition, we discuss the multiple variations of man-made antibody repertoires designed and validated in the last two decades, which have served as tools to explore how the size, diversity, and composition of a repertoire impact the antibody discovery process.

Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform

“…By merit of high specificity, potency, stability, solubility, clinical tolerability and relatively inexpensive manufacturing, monoclonal antibodies (mAb) made a leap in the field of targeted therapeutics. 1 A growing body of genetic, molecular and structural data has explained the success of antibody specificity and potency. 1 The potential for immunogenicity, i.e., the ability of a biological agent to induce a humoral or cell-mediated immune response, has long been the "Achilles' heel" of therapeutic antibodies.…”

“…1 A growing body of genetic, molecular and structural data has explained the success of antibody specificity and potency. 1 The potential for immunogenicity, i.e., the ability of a biological agent to induce a humoral or cell-mediated immune response, has long been the "Achilles' heel" of therapeutic antibodies. 2,3 When administered, non-human antibodies were commonly recognized as foreign by the immune systems of treated patients, leading to neutralization and rapid clearance of the injected therapeutic antibodies or derivatives thereof, thereby limiting their efficacy.…”

Reconciling the Structural Attributes of Avian Antibodies

“…6 Antibodies have come of age due to our increased understanding of their function, specificity, and origins. This collectively assembled knowledge-base draws observations from a number of disciplines including: structural biology, immunogenetics, cellular immunology, molecular biology, and bioinformatics (4). The three-dimensional structure of antibodies, both free and antigen-complexed, has played a central role in elucidating humoral immune response mechanisms, evolution of the antibody repertoire, and optimization of in vitro-generated antibodies (5).…”

“…This has resulted in a number of powerful technological advances that have allowed protein engineers to actively harness and augment the potential of the immune system, including in vitro display technologies (6), humanization (7), and engineering of biophysical properties (e.g. affinity, functional activity, specificity) (4).…”

“…The CDRs are described by canonical conformations, which are defined by the length of the hypervariable loop and both hypervariable loop/frame work region (FWR)-conserved residues (15). The FWR provides a structural scaffold for the antigen binding site and are important for structural diversity, the V L /V H orientation (4,17) and in some instances may make direct antigen contacts. The IgY (Fig.…”