Novel drugs block the CD40 ligand molecule expressed transiently on recently activated T cells, thereby limiting a spectrum of both adaptive and innate immune mechanisms. In a Perspective published in Science on the 23th of August, UMCG immunologist Jon Laman and his colleagues Randy Noelle (Geisel School of Medicine at Dartmouth) and Mike Molloy (ImmuNext Corporation, Lebanon, NH, USA ) discuss this potential breakthrough in the treatment of these autoimmune diseases.
This Perspective was invited based on a recent successful phase 2 clinical trial of one such new biological drug, the monoclonal antibody frexalimab. In this trial, an international group of MS-neurologists led by Prof. Gavin Giovannoni (Queen Mary University London, UK) found that frexalimab strongly reduced brain lesions at week 12 as compared with placebo.
The Perspective in Science anticipates applications for anti-CD40L drugs of different molecular designs in a wide variety of immune mediated inflammatory disorders. Currently, multiple phase 3 trial with frexalimab are ongoing in MS, and anti-CD40L therapeutics are also investigated in lupus, diabetes, Sjögren’s disease and kidney transplantation.
Already in 1996, a Dutch-American team of investigators including Noelle and Laman had demonstrated that blocking CD40 ligand with an antibody could effectively block EAE in mice, an autoimmune inflammatory model with similarities to MS. Moreover, this team demonstrated that both CD40 ligand and its counterpart receptor CD40 are expressed in postmortem human MS brain.
However, the original antibody against CD40L showed unexpected thromboembolic complications, which caused the long delay between the basic science observations and the recent successful clinical trial. Since then, the biological was improved by amino acid substitutions abolishing interactions with platelets, and also its affinity was eliminated.
Publication: Switching off autoimmunity
