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Antibody-enabled small-molecule drug discovery

Nature Reviews Drug Discovery volume 11, pages 519–525 (2012)Cite this article

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Abstract

Although antibody-based therapeutics have become firmly established as medicines for serious diseases, the value of antibodies as tools in the early stages of small-molecule drug discovery is only beginning to be realized. In particular, antibodies may provide information to reduce risk in small-molecule drug discovery by enabling the validation of targets and by providing insights into the design of small-molecule screening assays. Moreover, antibodies can act as guides in the quest for small molecules that have the ability to modulate protein–protein interactions, which have traditionally only been considered to be tractable targets for biological drugs. The development of small molecules that have similar therapeutic effects to current biologics has the potential to benefit a broader range of patients at earlier stages of disease.

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Figure 1: Structures of antibody-stabilized G protein-coupled receptors.
Figure 2: Antibody-enabled small-molecule fragment screening and elaboration.

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Acknowledgements

I am grateful to my colleagues at UCB for stimulating discussion and refinement of ideas.

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Authors and Affiliations

  1. Alastair D. G. Lawson is at UCB, 216 Bath Road, Slough, SL1 4EN, UK. alastair.lawson@ucb.com,

    Alastair D. G. Lawson

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Alastair D. G. Lawson is an employee of UCB, and holds shares and share options in the company.

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FURTHER INFORMATION

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Glossary

Allosteric modulation

An allosteric effect (such as inhibition, which is also referred to as non-competitive inhibition) that can result from a change in the shape of an active site when an inhibitor binds at an alternative site.

Apo structure

The ligand-free structure of a protein.

Biological risk

In the context of this article, biological risk is the risk associated with modulating the biology of a specific target: for example, the consequences of inhibiting a particular signalling pathway.

Complementarity determining region 3

(CDR3). A region found within an antibody variable region; the CDR has a highly variable amino acid sequence and confers binding specificity.

Chemical risk

In the context of this article, chemical risk is the risk inherent in the therapeutic molecule itself: for example, its off-target activity as well as its pharmacokinetic and pharmacodynamic profiles.

Chaperone

An auxiliary protein that binds to a target of interest, enhances crystallization, optimizes crystal packing and provides high-quality phasing information.

Fragment-based drug discovery

A method that is used for finding lead compounds in drug discovery. It is based on identifying small chemical fragments, which bind relatively weakly to the biological target, and then either increasing the size of the fragments or combining them to produce a lead compound with a higher affinity and increased potency.

Intrabodies

Antibodies, usually antibody fragments, that bind to targets inside a cell (such as intracellular proteins) and are typically expressed intracellularly.

Protofibrils

Transient structures that are implicated as the toxic species responsible for cell dysfunction and neuronal loss in diseases associated with protein aggregation, such as Alzheimer's disease.

Tethering

A technique in which a disulphide bond is used to stabilize the binding of thiol-containing fragments at a specific site on proteins where a cysteine residue has been engineered.

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Lawson, A. Antibody-enabled small-molecule drug discovery. Nat Rev Drug Discov 11, 519–525 (2012). https://doi.org/10.1038/nrd3756

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