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Review
. 2021 Mar 30;10(2):13.
doi: 10.3390/antib10020013.

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

Xiaotian Zhong  1 , Aaron M D'Antona  1
Affiliations
Review

Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics

Xiaotian Zhong et al. Antibodies (Basel). .

Abstract

Recombinant protein-based biotherapeutics drugs have transformed clinical pipelines of the biopharmaceutical industry since the launch of recombinant insulin nearly four decades ago. These biologic drugs are structurally more complex than small molecules, and yet share a similar principle for rational drug discovery and development: That is to start with a pre-defined target and follow with the functional modulation with a therapeutic agent. Despite these tremendous successes, this "one target one drug" paradigm has been challenged by complex disease mechanisms that involve multiple pathways and demand new therapeutic routes. A rapidly evolving wave of multispecific biotherapeutics is coming into focus. These new therapeutic drugs are able to engage two or more protein targets via distinct binding interfaces with or without the chemical conjugation to large or small molecules. They possess the potential to not only address disease intricacy but also exploit new therapeutic mechanisms and assess undruggable targets for conventional monospecific biologics. This review focuses on the recent advances in molecular design and applications of major classes of multispecific biotherapeutics drugs, which include immune cells engagers, antibody-drug conjugates, multispecific tetherbodies, biologic matchmakers, and small-scaffold multispecific modalities. Challenges posed by the multispecific biotherapeutics drugs and their future outlooks are also discussed.

Keywords: antibody-drug conjugates; biologic matchmakers; immune cells engagers; multispecific biotherapeutics; multispecific tetherbodies; small-scaffold multispecific modalities.

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Conflict of interest statement

X.Z. and A.M.D. currently are employees of Pfizer Worldwide Research, Cambridge, MA.

Figures

Figure 1
Figure 1
Examples of multispecific biotherapeutics drugs. (A). T-cell and NK-cell engagers (TCE/KCE) [4,5,11]. (B). Antibody-drug conjugates (ADC) [3,6,15,17,18,31]. (C). Tetherbody cytokine [95]. (D). Piggybacking tetherbody [96,97,98]. (E). Emicizumab matchmaker [99,100]. (F). Sweeping antibody matchmaker [3,101]. (G). Agonist matchmaker [102,103]. (H). Linker matchmaker [104]. (I). Receptor attenuating matchmaker [105].
Figure 2
Figure 2
New technologies for multispecific biotherapeutics. (A). TCE and KCE-armed oncolytic viruses (OV) [227]. (B). In vitro transcribed (IVT) mRNA-encoded multispecific biotherapeutics [228].
See this image and copyright information in PMC

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