CD40 Ligand

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder characterized by muscle fiber atrophy resulting from the degeneration of motor neurons in the spinal column and brain. Though ALS is characterized by loss of motor neurons in the spinal cord resulting in muscle atrophy, the disease also manifests itself with changes in axon transport, protein mis folding, excitotoxicity, neuroinflmamation, mitochondrial dysfunction, and synaptic remodeling. Neuroinflammation in the central and peripheral nervous system with infiltration of activated monocytes and T lymphocytes is an accepted pathophysiology associated with ALS animal models and patients. Although the role of infiltrating immune cells is poorly understood recent work would suggest that infiltrating T cell populations are neuroprotective and not cytotoxic however the role of infiltrating monocytes is less well understood.
It is generally accepted that two signals from antigen presenting cells (APCs) are required for maximal T cell activation and that this activation pathway is called the Costimulatory Pathway. These two signals are the engagement of the T Cell Receptor (TCR) on T cells with antigen bound Major Histocompatibility Complex (MHC) on antigen presenting cells (APCs) and the binding of activating ligand and their cognate B7 receptors on T cells and APCs respectively. The activation of APCs and up regulation of the B7 receptors and MHC molecules is sufficient to activate T cells and induce a humoral immune response.
In addition to the B7 receptors the Tumor Necrosis Factor (TNF) family member CD40 is up regulated on APCs after activation by foreign antigens. CD40 is expressed on mature B cells, macrophages, and dendritic cells. The receptor for CD40, CD40L (CD154, gp39) is a Type I membrane receptor and a member of the TNFR superfamily. CD40L expressed on activated T cells as a result of antigen presentation. CD40 ligation induces expression of adhesion molecules and costimulatory molecules on APCs such as CD44, ICAM1, ITGAX (CD11c ), CCL3 (Mip1); Fcgr2b (CD32); ITGAM (CD11b); ITGB2 (LFA1/CD18) and MHC class II molecules.n order to understand the dynamic interplay of molecular pathways underlying the onset and progression of ALS, ALS TD completed a longitudinal survey of the transcriptional changes in diseased tissues of the SOD1G93A transgenic mouse to identify the critical pathways associated with disease onset and progression. An unbiased gene set enrichment analysis of all known molecular pathways activated pre-symptomatically revealed a role for the T cell co-stimulatory pathway in spinal cord, skeletal muscle, and peripheral nerves.

In order to understand the dynamic interplay of molecular pathways underlying the onset and progression of ALS, ALS TD completed a longitudinal survey of the transcriptional changes in diseased tissues of the SOD1G93A transgenic mouse to identify the critical pathways associated with disease onset and progression. An unbiased gene set enrichment analysis of all known molecular pathways activated pre-symptomatically revealed a role for the T cell co-stimulatory pathway in spinal cord, skeletal muscle, and peripheral nerves.

The beneficial effects of blocking CD40L are well established in preclinical models of transplantation, multiple sclerosis, arthritis, systemic lupus erythrematosus, and Alzheimer’s disease. In an effort to determine whether anti-CD40L would impact disease progression in the SOD1G93A mouse model, ALS TDI administered an anti-CD40L monoclonal antibody, MR1, to SOD1G93A mice. Treatment with anti-CD40L delayed disease onset, improved body weight maintenance, and extended survival in this murine model of ALS. Pharmacokinetic studies demonstrated that anti-CD40L was detectable at stable levels in plasma throughout the disease course but was not detectable in spinal cord. This observation supports the hypothesis that the site of action of anti-CD40L therapy is outside of the central nervous system. Thus, early ALS pathology is amenable to immunomodulatory strategies that have shown clinical efficacy in other disease indications.

All intellectual property regarding the role of CD40L in ALS that has been issues to ALS TDI has been licensed to Anelixis Therapeutics.