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Creating molecules that modulate immune responses

Nature Reviews Chemistry volume 2, pages 184–193 (2018)Cite this article

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Abstract

During evolution, humans developed innate and adaptive immune systems to survive infection by pathogens. The immune system needs to be finely balanced, as an overactive immune system can result in autoimmunity, allergy and inflammatory disorders, whereas over-attenuation can result in infections and cancer. Here, we describe how the immune system can be modulated using chemical approaches, with a focus on the chemical modification and application of antibodies, one of the major components of the immune defence system. Progress includes the development of antibody–drug conjugates and imaging reagents based on antibody fragments and nanobodies, and their clinical and preclinical applications for the treatment of cancer and autoimmune disease are discussed.

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Fig. 1: Timeline showing key developments in immunology that have used chemistry3,11,28,35,41,45,129,130,131,132,133,134,135,136,137,138,139.
Fig. 2: Major systems that control the activity of T cells.
Fig. 3: Overview of the mode of action of antibody–drug conjugates.

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Acknowledgements

This work was supported by grants from the Gravity programme Institute of Chemical Immunology and the Oncode Initiative (to J.N. and H.O.) and a European Research Council (ERC) Starting Grant to 639005 (S.I.v.K.).

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Nature Reviews Chemistry thanks A. Esser-Kahn and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Division of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands

    Sander I. van Kasteren

  2. Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands

    Jacques Neefjes & Huib Ovaa

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  1. Sander I. van Kasteren
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S.I.v.K., J.N. and H.O. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Sander I. van Kasteren or Huib Ovaa.

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Glossary

Antibody–drug conjugates

(ADCs). Constructed of an antibody covalently linked to a small-molecule drug. The conjugation renders the drug inactive, and it is released only at the site targeted by the antibody. This should result in lower background toxicity.

Antigen

A molecule that is capable of inducing an immune response.

Co-stimulation

When an antigen-presenting cell (APC) presents a peptide to a T cell, it can initiate an immune response or an immunosuppressive response. For an immune response, a second set of T cell surface markers (for example, CD80 and CD86) is activated by receptors on the APC to inform the T cell that the peptide presented is dangerous. This second signal is called co-stimulation or signal 2.

Immune checkpoints

Signals — either from T cells or APCs — that initiate an immunosuppressive response. They are often exploited by tumours to stop an antitumour immune response.

Checkpoint inhibitors

Antibodies that block the immunosuppressive response triggered by immune checkpoints. This allows an immune response against a tumour to be re-activated.

‘Click-to-release’ chemistry

A chemical deprotection strategy based on the inverse-electron-demand Diels–Alder ligation. After the initial ligation of an allylic trans-cyclooctene to a tetrazine, the intermediate pyridazine can rearrange to warrant the elimination (release) of the allylic substituent. Carbamates, as well as ethers and esters, can be deprotected under biocompatible conditions in this manner126.

Immunophilins

Peptidyl–prolyl isomerase enzymes that ensure the proper folding of target proteins by interconverting between the cis and trans bonds of target prolines.

Ipilimumab

A first-generation checkpoint inhibitor. It targets the cytotoxic T lymphocyte antigen 4 (CTLA4) receptor on T cells, which usually binds the co-stimulatory signal on APCs without activating the T cell. The exact immunomodulatory action of this antibody is not yet fully understood.

Lipocalins

Small proteins that transport small hydrophobic molecules.

Nanobodies

Truncated antibodies consisting of a single immunoglobulin domain (12–15 kDa), usually derived from camelids. Their small size makes them easier to express and gives them a shorter half-life (~20 minutes) than full-sized antibodies (>180 kDa; half-life of 5 days or more).

Bispecific antibodies

Constructs that contain two different antigen-targeting domains in a single molecule. They are made by chemical or genetic fusion of different antibodies and can be used to bring two cells into proximity.

Cytokines

Small proteins that regulate the strength and shape of the immune response via intercellular signalling in the immune system. The immune response against a virus, bacteria or helminth is characterized by different cytokines, which can suppress or activate other immune cells and are thus categorized as pro-inflammatory or immunosuppressive.

Pictet–Spengler reaction

The ring-closing reaction between a β-arylethylamine and a ketone or aldehyde to yield a spirocyclic product127.

Single-chain variable fragments

Constructs created by linking genetic material encoding the variable fragment of one antibody heavy chain to the genetic code for the variable fragment of a light chain. They are the smallest fragments of a two-chain antibody that can be constructed.

T cells

Cells that play an essential role in the cellular immune response by recognizing peptides displayed on major histocompatibility proteins (MHCs) of other cells. T cells can be distinguished from other immune cells by the presence of a T cell receptor on their surface. Some T cells kill the cell they recognize, whereas others help the cell presenting the peptide to kill an intracellular pathogen128.

Therapeutic window

The concentration range in which a drug can be used. At the lower end, the drug is not effective, and at the top end, the drug is too toxic to use. A small therapeutic window reduces the usefulness of a drug.

Transcytosis

A form of vesicular transport that carries macromolecules across the interior of the cell.

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van Kasteren, S.I., Neefjes, J. & Ovaa, H. Creating molecules that modulate immune responses. Nat Rev Chem 2, 184–193 (2018). https://doi.org/10.1038/s41570-018-0023-9

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