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  • Review Article
  • Published:

CD3-specific antibodies: a portal to the treatment of autoimmunity

Nature Reviews Immunology volume 7, pages 622–632 (2007)Cite this article

Key Points

  • This Review summarizes the results from preclinical and clinical studies that use CD3-specific monoclonal antibody therapy and highlights future combination opportunities to enhance the efficacy of this promising immunotherapeutic.

  • CD3-specific monoclonal antibodies inactivate pathogenic cells by inducing rapid internalization of the T-cell receptor (TCR)–CD3 complex from the cell surface. Upon TCR re-expression and exposure to the autoantigen, an 'altered' TCR signal causes the T cells to die, become anergic or even change from a pathogenic to a regulatory T-cell phenotype.

  • Preclinical studies strongly suggested that the long-term therapeutic effect of CD3-specific monoclonal antibodies in non-obese diabetic (NOD) mice could not be explained solely by their capacity to eliminate and/or inactivate pathogenic T cells. Evidence suggests that this long-term effect results as a consequence of a significant increase in the number of transforming growth factor-β (TGFβ)-dependent adaptive regulatory T cells, as well as an increased sensitivity of pathogenic T cells to the effects of regulatory T cells.

  • At variance with presently available therapies for autoimmunity and transplantation, CD3-specific monoclonal antibodies afford long-term effects following a short administration — a capacity that is directly linked to their tolerogenic properties. The present challenge is to build on this experience; first to attain the use of CD3-specific monoclonal antibodies as an established therapy in well-selected subsets of patients with autoimmune diabetes; second, to adapt CD3-specific monoclonal antibody treatment to other autoimmune disorders in which it could also prove beneficial; and third, to use CD3-specific monoclonal antibody therapies in combination with other treatments for increased efficiency.

Abstract

Targeted immunotherapies hold great promise for the treatment and cure of autoimmune diseases. The efficacy of CD3-specific monoclonal antibody therapy in mice and humans stems from its ability to re-establish immune homeostasis in treated individuals. This occurs through modulation of the T-cell receptor (TCR)–CD3 complex (also termed antigenic modulation) and/or induction of apoptosis of activated autoreactive T cells, which leaves behind 'space' for homeostatic reconstitution that favours selective induction, survival and expansion of adaptive regulatory T cells, which establishes long-term tolerance. This Review summarizes the pre-clinical and clinical studies of CD3-specific monoclonal antibody therapy and highlights future opportunities to enhance the efficacy of this potent immunotherapeutic.

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Figure 1: Postulated mode of action of FcR-non-binding CD3-specific monoclonal antibodies in type 1 diabetes.
Figure 2: Potential therapeutic window for CD3-specific monoclonal antibody in type 1 diabetes.

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Acknowledgements

The authors wish to acknowledge the many students, postdoctoral researchers and colleagues who have participated in the development, mechanistic understanding and clinical application of CD3-specific monoclonal anitbodies. In particular, we wish to acknowledge the contributions of J.-F. Bach, K. Herold and H. Waldmann without whose support and insights none of these studies would have been possible.

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Authors and Affiliations

  1. Université René Descartes, Paris 5, Institut National de la Santé et de la Recherche Médicale, Unité 580, Hôpital Necker — Enfants Malades, 161 rue de Sèvres, Paris, 75743, CEDEX 15, France

    Lucienne Chatenoud

  2. University of California San Francisco (UCSF) Diabetes Center, UCSF, 513 Parnassus Ave., BOX 0540, San Francisco, 94143, California

    Jeffrey A. Bluestone

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Competing interests

J.A.B. has a financial interest in one of the CD3-specific monoclonal antibodies, teplizumab, and is a consultant for the company developing the drug, MacroGenics Inc.

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FURTHER INFORMATION

Jeffrey Bluestone's homepage

Immune Tolerance Network

Juvenile Diabetes Research Foundation

Glossary

Multiple sclerosis

A chronic inflammatory and demyelinating disease of the central nervous system. It is an autoimmune response against components of myelin, which is thought to contribute to disease pathogenesis. Self glycolipids are autoantigens that are recognized by T cells in this disease.

Epitope spreading

This term was used to describe how a self-directed immune response induced by a single peptide (or epitope) could spread to include other peptides (or epitopes) not only on the same autoantigen (intramolecular spreading) but also on other self-molecules clustered in close vicinity within the target cell (intermolecular spreading). A good example for epitope spreading is the de novo activation of autoreactive T cells by self-antigens that have been released after β-cell damage.

Bystander suppression

The extension of tolerogen-induced suppression to immune responses that are directed against antigens not structurally related to the tolerogen but expressed by the same target tissue.

Anergy

A state of unresponsiveness that is sometimes observed in T and B cells that are chronically stimulated or that are stimulated through the antigen receptor in the absence of co-stimulatory signals.

Immunological synapse

A region that can form between two cells of the immune system in close contact. The immunological synapse originally referred to the interaction between a T cell and an antigen-presenting cell. It involves adhesion molecules, as well as antigen receptors and cytokine receptors.

Activation-induced cell death

A pathway of T-cell apoptosis that often involves the upregulation of CD95 ligand that binds to the cell-death receptor CD95.

Connecting peptide

(C-peptide). Insulin is synthesized by β-cells as a hormone precursor pro-insulin. When released from the pancreas into the blood pro-insulin is cleaved into insulin and a small peptide known as C-peptide. C-peptide can be used as a measure of endogenous insulin secretion (one C-peptide is released for each insulin molecule secreted).

Lymphocytosis

An increase in the number of lymphocytes in the blood, which is usually associated with chronic infections or inflammation.

Anti-idiotypic antibody

An antibody that is directed against the antigen-specific binding site of an immunoglobulin or a T-cell receptor and therefore may compete with antigen for binding.

Secretagogues

Molecules, often peptides, that stimulate the secretion of a variety of substances including hormones and enzymes.

Rheumatoid arthritis

An immunological disorder that is characterized by symmetrical polyarthritis, often progressing to crippling deformation after years of synovitis. It is associated with systemic immune activation, with acute-phase reactants being present in the peripheral blood, as well as rheumatoid factor (immunoglobulins specific for IgG), which forms immune complexes that are deposited in many tissues.

Crohn's disease

A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract, but is most common in the colon and terminal ileum. It is characterized by transmural inflammation, strictures and granuloma formation, and is believed to result from an abnormal T-cell-mediated immune response to commensal bacteria.

Adjuvant

An agent that is mixed with an antigen for the purpose of increasing the immune response to that antigen following immunization.

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Chatenoud, L., Bluestone, J. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol 7, 622–632 (2007). https://doi.org/10.1038/nri2134

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