Clinical Development Challenges
Peter Lipsky, M.D. from the National Institutes of Arthritis, Musculoskeletal and Skin Diseases discussed
CD40/CTLA4/CD40 Ligand Coactivation Signaling.
Defects in CD40L (CD154) were first discovered in the Hyper IgM Syndrome in which children are unable to make IgG, IgE and IgA and lack germinal centers in their lymph nodes. CD40 is a member of the TNF receptor superfamily that includes Fas and RANK and was originally described on B cells. CD40L (CD 154) is a member of the TNF ligand family and was originally described on T cells. CD40/CD40L interaction between T and B cells is critical for the development of germinal centers. A disturbance in this interaction is felt to be responsible for the Hyper IgM Syndrome.
However, CD40 and CD40L are expressed on a variety of other cells as well. CD40L is upregulated in some autoimmune diseases such as systemic lupus erythematosus (SLE). CD40 is also expressed on monocyte precursors and its interaction with CD40L can drive monocyte transformation to antigen presenting cells. CD40 can be upregulated on synovial fibroblasts by gamma-interferon which, in turn, allows interaction with T and B cells. CD40 on endothelial cells interacts with CD40L on platelets which could theoretically promote thrombogenesis. All of these actions/interacations of CD40/CD40L could play a role in the pathogenesis of inflammatory, autoimmune diseases.
Dr. Lipsky discussed strategies for inhibiting CD40L. Three antibodies directed against different epitopes in the CD40 binding site of CD40L have been developed and were discussed briefly. Dr. Lipsky presented preliminary data from a multicenter trial of antibody 5C8 (Biogen) in human SLE. This was an open label safety study in patients with active SLE with nephritis. 20 mg/kg of 5C8 were administered at wks 0, 2, 4, 8 and 12 weeks. The study was prematurely discontinued because of a higher than expected number of thrombotic events (see summary by Vaishnaw below ). However, laboratory studies performed on patients treated with 5C8 showed a decrease in the number of CD40L positive cells; a decrease in anti-DNA antibody titers, in proteinuria, in anti-cardiolipin antibody titers, and in disease activity indices. These preliminary data suggest that the CD40-CD40L interaction is a good target for interruption/inhibition in inflammatory and autoimmune diseases. However, potential toxicities need to be addressed.
Iain McInnis, MRCP, PhD from the University of Glasgow spoke on
Targeting Novel Pathways that Regulate TNF-aProduction.
Dr. McInnis began by querying the hypothesis that TNF-aplays the central role in the rheumatoid inflammatory process, since about 40% of RA patients who receive TNF inhibitors do not respond dramatically. He discussed several other potential targets for inhibition in RA:
1) Interleukin-18 (IL-18). This cytokine is a member of the IL-1 family and is present on CD3+ cells. IL-18 is generated from its pro-IL-18 precursor by caspase. It stimulates synovial macrophages to release TNF-a. Neutralization of IL-18 in the acute carageenin model reduces paw pad inflammation, causes decreases myeloperoxidase, IL-8 and TNF-aexpression from synovial fluid PMNs. Administration of IL-18 makes some animal models of arthritis worse. IL-18 -/- knockout mice have decreased TNF-aand IL-1 levels and are more resistant to the induction of arthritis.
2) Interleukin-15 (IL-15). This cytokine is a member of the IL2 family but is primarily macrophage derived. IL-15 and IL-18 have a synergistic effect on inducing TNF-aproduction. IL-15 has an intracellular distribution; there is only scant extracellular release. Therefore, inhibition of IL-15 could be problematic. However, soluble IL-15 receptor alpha chain suppressed the development and severity of collagen induced arthritis in mice.
3) Another approach is to shift the Th1 T cell response to Th2. Are there molecules on Th2 cells that can be exploited for their anti-inflammatory effect? Dr. McInnis discussed two potential candidates -- toll receptor homologs -- which have exhibited anti-inflammatory potential in vitro. (more info on toll receptors)
4) Thymosin beta 4 sulphoxide (TB4so). This agent inhibits FMLP-induced chemotaxis of neutrophils, promotes apoptosis of PMNs and monocytes, enhances phagocytosis of apoptotic bodies by macrophages, inhibits TNF-aproduction by PBMC and inhibits carrageenan-induced paw edema at an equivalent potency to dexamethasone. Its potential as an anti-inflammatory agent in human disease may be explored.
Gerd R. Burmester, M.D. from Charite-Humboldt University in Berlin, Germany spoke on
Bone Morphogenic Proteins (BMPs).
BMPs were originally identified by their ability to induce ectopic bone formation and were called osteogenin. They are members of the transforming growth factor-Bfamily (TGF-B). BMPs are key regulators of developmental processes. Their function are very diverse and include cell proliferation and differentiation, apoptosis, morphogenesis, and others. BMPs dimerize and bind to their receptors and induce the transcription factors SMADs. BMPs are stored in the extracellular matrix and the effects of BMPs are counteracted by noggin, chordin and other molecules.
BMPs could have potential applications for fracture repair. Osteoporosis could be another target although systemic delivery would be difficult.
