Computer-aided antibody design

Abstract

Recent clinical trials using antibodies with low toxicity and high efficiency have raised expectations for the development of next-generation protein therapeutics. However, the process of obtaining therapeutic antibodies remains time consuming and empirical. This review summarizes recent progresses in the field of computer-aided antibody development mainly focusing on antibody modeling, which is divided essentially into two parts: (i) modeling the antigen-binding site, also called the complementarity determining regions (CDRs), and (ii) predicting the relative orientations of the variable heavy (VH) and light (VL) chains. Among the six CDR loops, the greatest challenge is predicting the conformation of CDR-H3, which is the most important in antigen recognition. Further computational methods could be used in drug development based on crystal structures or homology models, including antibody–antigen dockings and energy calculations with approximate potential functions. These methods should guide experimental studies to improve the affinities and physicochemical properties of antibodies. Finally, several successful examples of in silico structure-based antibody designs are reviewed. We also briefly review structure-based antigen or immunogen design, with application to rational vaccine development.

Specific Amyloid β Clearance by a Catalytic Antibody Construct

“…Second, antigen recognition developed by acquired immune processes occurs at the extensively mutated complementarity-determining regions (CDRs), whereas the IgV contains minimal CDR mutations (14). Third, V H domain CDR3 and proper V L -V H domain pairing are specificity-defining factors in acquired immunity (54), but IgV 2E6 does not contain a V H domain, and pairing of an A␤ hydrolytic V L domain with a V H domain suppressed the catalytic activity (14). Fourth, A␤ recognition without acquired immunity processes is not limited to catabodies; selective noncovalent binding of the C-terminal A␤ epitope by antibody fragments from "non-immune" humans was described by another group (55).…”

Redesign of a cross-reactive antibody to dengue virus with broad-spectrum activity and increased in vivo potency

“…For instance, the influenza FI6 antibody, which neutralizes clade 1 and 2 viruses, was identified by screening 104,000 B cells (33). An alternative strategy is to modify the properties of an existing antibody via rational engineering (34). In this study, computational methods for ab initio modeling and antibody redesign are presented.…”

MoFvAb: Modeling the Fv region of antibodies

“…[8][9][10][11] Many of those tasks are enabled, or at least greatly facilitated, by structure-based considerations on the atomic level. 12 The large number of publicly available antibody crystal structures that have been solved during the last 25 y is an indicator for the relevance of this class of proteins. As of April 2015, the structural antibody database SAbDab 13 counts 2025 entries, a number that is steadily increasing.…”

“…[12][13][14][15][16] Among these computational methods is a number of homology modeling applications that have been tailored to exclusively generate atomistic models of the antigen-binding (Fv) region of antibodies, [17][18][19] a functionality that is meant to complement and relieve experimental structure elucidation by crystallography.…”

“…The relative orientation of the 2 domains exhibits a notable variability over the known repertoire of antibody crystal structures, [30][31][32] and it has been suggested that VH-VL orientation, in addition to length and sequence of the CDRs, is a co-modulator of antigen specificity and affinity. 12 The parameters of VH-VL orientation determine how the CDRs are presented to the antigen, and thus contribute to the shape of the paratope (the antibody counterpart of the antigen's epitope). It seems likely that the variability in VH-VL orientation is a necessary means to accommodate the diverse antigenic shapes that antibodies are confronted with, 33 ranging from spacious conformational epitopes on globular proteins to linear peptides and even small molecule-like haptens.…”