[Frontiers in Bioscience 14, 4173-4188, January 1, 2009]

CD137, implications in immunity and potential for therapy

Elaine Thum, Shao Zhe, Herbert Schwarz

Dept. of Physiology, and Immunology Programme, Yong Loo Lin School of Medicine, National University of Singapore, 117456 Singapore

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Biology of the CD137 receptor / ligand system
3.1. Expression of CD137
3.2. Expression of CD137 ligand
3.3. Costimulatory activities of CD137
3.4. CD137 as a coinhibitory molecule
3.5. Reverse signaling through CD137 ligand
3.6. Soluble CD137
4. Involvement of the CD137 receptor / ligand system in disease
4.1. Involvement of CD137 in cancer
4.2. Involvement of CD137 ligand in cancer
4.3. Disruption of CD137/CD137 ligand signaling prevents autoimmune diseases
4.4. Disruption of CD137/CD137 ligand signaling leads to increased disease severity
4.5. sCD137 and sCD137 ligand in autoimmune diseases
4.6. CD137 signaling in IgE-mediated allergic responses
4.7. CD137 signaling in allergic airway disease
5. Potential therapeutic applications of targeting the CD137 receptor / ligand system
5.1. Agonistic anti-CD137 antibodies for enhancing immune responses
5.2. Agonistic anti-CD137 antibodies for inhibiting immune responses
5.3. Cautionary notes
5.4. Antagonistic anti-CD137 or anti-CD137 ligand antibodies for inhibiting
5.5. Recombinant CD137 protein or agonistic anti-CD137 ligand antibodies for immune responses enhancing immune responses
5.6. Agonistic anti-CD137 ligand antibodies for inhibiting immune responses
5.7. Soluble CD137
6. Outlook / Conclusion
7. References

1. ABSTRACT

CD137 is a member of the TNF receptor family and a potent T cell costimulatory molecule. Crosslinking of CD137 on activated T cells has shown promise in enhancing anti-tumor immune responses in murine models, and agonistic anti-CD137 antibodies are currently being tested in phase I clinical trials. Surprisingly, these very same agonistic anti-CD137 antibodies have also been found to ameliorate autoimmune disease under certain circumstances. At the current state of knowledge these circumstances cannot be clearly defined. Therefore, anti-CD137 antibodies in man will need to be used with caution. CD137 ligand is expressed by antigen presenting cells. Antagonistic anti-CD137 ligand antibodies have shown efficacy in dampening disease in murine autoimmune models. A similar effect would be expected from antagonistic anti-CD137 antibodies, soluble CD137, or any other compound interfering with CD137 / CD137 ligand interaction. CD137 ligand is expressed as a transmembrane protein on the cell surface and it too can transmit signals into antigen presenting cells. Agonistic anti-CD137 ligand antibodies or a recombinant CD137 protein could stimulate the activity of antigen presenting cells.