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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 ofthe 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 ofrecombinant 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.
Since the 1970s, discovery and development of therapeutic agents has been dominated by rational drug discovery1, which supplanted classical empiric pharmacology (Fig. 1a). The basis of rational drug discoveryreferred to here as 'one target:one drug' (1T1D)-is to start with a target and identify a molecule that binds the target, such that it increases or decreases its function. These 1T1D strategies were a break from the past, which emphasized searches for substances-often in culture broths or biological extracts-that had desired effects on cells or organisms. The chemical composition of the active substance was identified and manufactured to yield a drug (Fig. 1b). This marriage of pharmacology and chemistry (referred to here as wave 1) launched the modern pharmaceutical industry2 and yielded hundreds of drugs. A limitation of this approach is that the molecular target is often unknown, which makes it difficult to optimize compounds to enhance efficacy or tolerability, or to predict synergistic combinations. By contrast, in the 1T1D paradigm, the drug hunter starts with a defined target and seeks a specific molecule to modulate it. An early example was Squibb's development of captopril as an angiotensin-converting enzyme...