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Combinatorial antibody libraries: new advances, new immunological insights

Nature Reviews Immunology volume 16, pages 498–508 (2016)Cite this article

Subjects

Key Points

  • This Review discusses the theory and practices behind the generation of combinatorial antibody libraries.

  • Such libraries give scientists unprecedented control over the antibody repertoire.

  • They have led to many antibody drugs, including adalimumab (Humira; AbbVie), which is the best-selling drug in the world.

  • As combinatorial antibody libraries allow a detailed analysis of the output of the immune response, they have allowed us to understand how the adaptive immune system copes with infection when there is not sufficient time to develop a mature antibody response. This has been termed an 'SOS response'.

  • In their intracellular format, antibodies can be used as selectable proteins that perturb cell fates. Such antibodies are usually gain-of-function agonists.

  • We have moved from the engineering of antibodies to engineering with antibodies — this represents a whole new dimension in immunochemistry.

Abstract

Immunochemists have become quite proficient in engineering existing antibody molecules to control their pharmacological properties. However, in terms of generating new antibodies, the combinatorial antibody library has become a central feature of modern immunochemistry. These libraries are essentially an immune system in a test tube and enable the selection of antibodies without the constraints of whole animal or cell-based systems. This Review provides an overview of how antibody libraries are constructed and discusses what can be learnt from these synthetic systems. In particular, the Review focuses on new biological insights from antibody libraries — such as the concept of 'SOS antibodies' — and the growing use of intracellular antibodies to perturb cellular functions.

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Figure 1: Common fragments of antibodies generated by antibody engineering.
Figure 2: Construction and selection from combinatorial antibody libraries.
Figure 3: Germ-line 'SOS' antibodies against influenza virus.
Figure 4: Agonist antibodies reveal receptor pleiotropism.

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Acknowledgements

The author thanks I. Wilson, M. Pique, J. Joyce, D. Burton, R. Stanfield and W. Marisco for helpful discussions. M. Pique and I. Wilson helped with some of the figures. I thank the JPB Foundation and Zebra Biologics for their generous support.

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  1. Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Richard A. Lerner

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Correspondence to Richard A. Lerner.

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R.A.L. has a financial interest in Zebra Biologics.

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Lerner, R. Combinatorial antibody libraries: new advances, new immunological insights. Nat Rev Immunol 16, 498–508 (2016). https://doi.org/10.1038/nri.2016.67

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