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Tools to therapeutically harness the human antibody response

Nature Reviews Immunology volume 12, pages 709–719 (2012)Cite this article

Subjects

Key Points

  • There have been recent advances in the methodologies used for isolating and producing antigen-specific monoclonal antibodies that are naturally generated in humans in response to vaccines or infections. This has allowed a rapid and productive rise in the isolation and characterization of fully human monoclonal antibodies.

  • These human monoclonal antibodies are greatly improving our knowledge of the natural human response to pathogens and are instrumental in epitope discovery. They are also being developed as therapeutic agents against many infectious and autoimmune diseases.

  • Three different strategies have been used to identify and isolate B cells expressing immunoglobulins with the desired specificity and functional characteristics at the monoclonal level. The first involves panning phage display libraries that have been constructed from the immunoglobulin variable genes of immunized or infected individuals. In the second approach, memory B cells are immortalized, and then in vitro cultures are screened for antibody specificity. The third method involves single-cell sorting, followed by cloning of the transcribed immunoglobulin genes and their expression as monoclonal antibodies; this strategy may or may not include flow cytometry-based pre-selection.

  • If the intent is to isolate the most effective neutralizing human monoclonal antibodies, then highly targeted high-throughput screening is the most appropriate strategy. This can be achieved through phage display, memory B cell immortalization or flow cytometry-based antigen-specific selection from an immune individual. To fully characterize the spectrum of the B cell repertoire responding to an immune challenge, broader, less selective criteria can be used for cloning human monoclonal antibodies.

  • The most recent and exciting advances in the isolation of human monoclonal antibodies have been in response to HIV and influenza virus infection or vaccination. Clever antibody-screening methods and the careful selection of human donors have allowed for the isolation of rare, broadly neutralizing antibodies to both of these viruses.

  • It is hoped that these recent advances in isolating naturally generated broadly neutralizing antibodies specific for evolving viruses will speed up the development of effective vaccines.

Abstract

The natural human antibody response is a rich source of highly specific, neutralizing and self-tolerant therapeutic reagents. Recent advances have been made in isolating and characterizing monoclonal antibodies that are generated in response to natural infection or vaccination. Studies of the human antibody response have led to the discovery of crucial epitopes that could serve as new targets in vaccine design and in the creation of potentially powerful immunotherapies. With a focus on influenza virus and HIV, herein we summarize the technological tools used to identify and characterize human monoclonal antibodies and describe how these tools might be used to fight infectious diseases.

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Figure 1: Methodologies commonly used to isolate human monoclonal antibodies.
Figure 2: Summary of the processes typical of human monoclonal antibody isolation and analysis.
Figure 3: Structures of influenza haemagglutinin and HIV gp120.

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Acknowledgements

K. Kaur and C. Dunand provided helpful suggestions. This work was funded in part by grants from the US National Institute of Allergy and Infectious Diseases, National Institutes of Health: 5U54AI057158-08 (to P.C.W.), 5U19AI057266-08 (to P.C.W.), 5U19AI082724-03 (to P.C.W.), 1U19AI090023-01 (to P.C.W.) and F32AI930872 (to S.F.A.).

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  1. Department of Medicine/Rheumatology, University of Chicago, Chicago, 60637, Illinois, USA

    Patrick C. Wilson & Sarah F. Andrews

  2. Knapp Center for Lupus and Immunology Research, Committee on Immunology, University of Chicago, Chicago, 60637, Illinois, USA

    Patrick C. Wilson

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Glossary

Hybridoma technology

Fusion of activated, antibody-secreting primary B cells with an immortalized myeloma cell line to produce long-living cell lines expressing antibodies of a single specificity.

Phage display libraries

Pools of bacteriophage virions, each expressing a unique protein variant (such as immunoglobulin fragments) on the virion exterior.

AID

(Activation-induced cytidine deaminase). A cytosine deaminase that catalyses a pivotal step in antibody gene-diversification reactions.

Reverse transcription PCR

(RT-PCR). A type of PCR in which RNA is first converted into double-stranded DNA, which is then amplified.

Next-generation sequencing

A massively parallel high-throughput non-Sanger method of sequencing.

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Wilson, P., Andrews, S. Tools to therapeutically harness the human antibody response. Nat Rev Immunol 12, 709–719 (2012). https://doi.org/10.1038/nri3285

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