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Multispecific drugs herald a new era of biopharmaceutical innovation

Abstract

The modern biopharmaceutical industry traces its roots to the dawn of the twentieth century, coincident with marketing of aspirin—a signature event in the history of modern drug development. Although the archetypal discovery process did not change markedly in the first seven decades of the industry, the past fifty years have seen two successive waves of transformative innovation in the development of drug molecules: the rise of ‘rational drug discovery’ methodology in the 1970s, followed by the invention of recombinant protein-based therapeutic agents in the 1980s. An incipient fourth wave is the advent of multispecific drugs. The successful development of prospectively designed multispecific drugs has the potential to reconfigure our ideas of how target-based therapeutic molecules can work, and what it is possible to achieve with them. Here I review the two major classes of multispecific drugs: those that enrich a therapeutic agent at a particular site of action and those that link a therapeutic target to a biological effector. The latter class—being freed from the constraint of having to directly modulate the target upon binding—may enable access to components of the proteome that currently cannot be targeted by drugs.

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Fig. 1: Four transformative waves have shaped development of the biopharmaceutical industry.
Fig. 2: Tetherbodies are multispecific drugs that enrich an active agent at a particular location.
Fig. 3: Small-molecule-based concurrent obligate matchmaker multispecific drugs that induce the proximity of a target and biological effector.
Fig. 4: Biologic matchmaker drugs that induce proximity of a target with a biological effector.
Fig. 5: Potential next-generation bispecific and trispecific CD3 engagers.

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Acknowledgements

I thank C. Kiefer and L. Jia for artwork, J. Bailis, R. Desphande, H. Hsu, G. Moffat, J. Murry, N. Ogbechie, and D. Rock for supplying content and comments, and D. Baker, M. Chu-Moyer, A. Gouliaev, S. Haldar, E. Levy, F. Martin, D. Reese, E. Sigal, K. Stefánsson, P. Tagari, and S. Wang for comments on the manuscript.

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Correspondence to Raymond J. Deshaies.

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R.J.D. is an employee, officer and shareholder of Amgen.

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Peer review information Nature thanks Alessio Ciulli, Ira Mellman and Nurulain Zaveri for their contribution to the peer review of this work.

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Deshaies, R.J. Multispecific drugs herald a new era of biopharmaceutical innovation. Nature 580, 329–338 (2020). https://doi.org/10.1038/s41586-020-2168-1

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