Toward Drug-Like Multispecific Antibodies by Design

Abstract

The success of antibody therapeutics is strongly influenced by their multifunctional nature that couples antigen recognition mediated by their variable regions with effector functions and half-life extension mediated by a subset of their constant regions. Nevertheless, the monospecific IgG format is not optimal for many therapeutic applications, and this has led to the design of a vast number of unique multispecific antibody formats that enable targeting of multiple antigens or multiple epitopes on the same antigen. Despite the diversity of these formats, a common challenge in generating multispecific antibodies is that they display suboptimal physical and chemical properties relative to conventional IgGs and are more difficult to develop into therapeutics. Here we review advances in the design and engineering of multispecific antibodies with drug-like properties, including favorable stability, solubility, viscosity, specificity and pharmacokinetic properties. We also highlight emerging experimental and computational methods for improving the next generation of multispecific antibodies, as well as their constituent antibody fragments, with natural IgG-like properties. Finally, we identify several outstanding challenges that need to be addressed to increase the success of multispecific antibodies in the clinic.

An end-to-end automated platform process for high-throughput engineering of next-generation multi-specific antibody therapeutics

“…Multi-specific antibody therapeutics are at high risk for chemical or physical stability issues, 6 , 8 which are difficult to predict from the primary amino acid sequence alone. 7 Usually, such issues become apparent at late discovery stages during comprehensive developability assessments of the drug pre-candidates. To mitigate the risk of late-stage failure, it is therefore desirable to select variants for developability assessments from large variant panels that comprise significant diversity on the sequence or structural level.…”

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

“…The complex structures of multispecific molecules also present significant challenges in achieving their drug-like properties [32], including favorable physical and chemical stability, solubility, viscosity, polyspecificity, immunogenicity, and pharmacokinetic properties. Compared to conventional monospecific antibody, much less is known about the developability properties of multispecific biotherapeutics.…”

“…The topic of multispecific biotherapeutics represents a fast-growing field regarding formats, design strategies, and applications. A number of outstanding review articles have been written on this topic or related themes for the past few years [2][3][4][5][6][9][10][11][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. This review summarizes comprehensively the recent advances in molecular design and applications of the multispecific biotherapeutics from the early stages of research discovery to the late stages of clinical and regulatory development.…”

Targeting Human Papillomavirus-Associated Cancer by Oncoprotein-Specific Recombinant Antibodies

“…Both diabodies and tandem scFvs can have two different binding specificities, and in this case, they are called bispecific (bs). Interestingly, even the VH and VL arrangement in the scFv fusion protein can influence the binding activity, and it is currently possible to predict the best functional structure so as to design scFvs that meet all requirements by molecular modelling using a computer-aided homology method [6,7]. A few decades ago, it was observed that the N-terminal IgG fragment including the VH and VL retains the same antigen-binding capacity as the whole IgG molecule.…”