Anergen Inc. (Redwood City, CA, USA) has had an Investigational New Drug (IND) application accepted by the US Food and Drug Administration to start clinical evaluation of AnergiX for RA, a new immunosuppressant treatment for rheumatoid arthritis (RA) that is based on selective inhibition of T cells. A Phase I trial will be conducted in patients with longstanding RA who are concomitantly taking methotrexate.AnergiX for RA is a soluble complex that combines a peptide derived from a 39 kDa human cartilage-derived glycoprotein (HCgp39), produced by Organon (Oss, The Netherlands), with full length major histocompatibility complex (MHC) class II antigen DR4, one of two HLA-DRB1 subtypes (the other being DR1) that are commonly associated with RA. The complex is designed to selectively inactivate T cells that cause the inflammatory autoimmune response without inducing generalized suppression of the immune system. It will be administered by slow intravenous infusion.`Conventional immunosuppressants can improve signs and symptoms of RA, but they can be associated with potentially serious toxicity', says Anergen's vice-president of clinical development, Michael Shulman. `We hope to overcome this problem by specifically targeting the disease-producing cells. Our approach is to engage the receptors of autoreactive T cells with an MHC class II molecule in association with a specific autoantigenic peptide, Hcgp39.'The AnergiX complex selectively inactivates disease-causing T cells because two stimulatory signals are necessary for activation of T cells by macrophages and other antigen-presenting cells (Fig. 1Fig. 1): the main signal is the binding of an MHC-associated antigen to its cognate T-cell receptor; the second (or co-stimulatory) signal involves a cell-surface antigen such as CD28 on the T-cell surface binding to its ligand, B7, on the antigen-presenting cell. If the co-stimulatory signal does not occur, the T cell either becomes unresponsive (anergic) or dies through apoptosis. `The idea behind AnergiX technology', explains Shulman, `is to deliver a drug that provides only one signal, so that the immune response is never completed, and T-cell anergy and/or apoptosis is induced instead of activation and proliferation.'Fig. 1Mechanism of action of AnergiX. (a) In autoimmune disease, autoantigens bound to MHC antigens on the surface of antigen-presenting cells (APCs) are presented to T cells in the presence of a co-stimulatory signal (e.g. B7–CD28). This causes T-cell activation, leading to a chronic inflammatory response against the autoantigen. (b) AnergiX specifically blocks autoreactive T cells by presenting an MHC-bound autoantigen to the autoreactive T cells in the absence of a co-stimulatory signal. This causes the T cells either to become anergic or to die by apoptosis.View Large Image | Download PowerPoint SlideHCgp39, the source of the peptide moiety of the AnergiX-RA MHC–peptide complex, is a putative RA autoantigen that is expressed in synovial cells and chrondrocytes of patients with RA, but not by unaffected individuals. The AnergiX-RA complex contains the amino acids 263–275 of the protein—the part that is specifically recognized by peripheral T cells from RA patients. Unaffected individuals do not appear to have T cells that react to HCgp39. Further support for the role of HCgp39 in causing RA comes from experiments in BALB/c mice, performed by scientists at Organon, in which injection of 10 μg of the peptide induces chronic/relapsing arthritis similar to RA.Anergen's entire research programme focuses on developing treatments for autoimmune diseases, using a targeted approach to shut down the errant immune responses that underlie these diseases. One AnergiX product, AnergiX for multiple sclerosis (MS), is already in Phase I trial in patients with secondary progressive MS. It comprises a complex of HLA-DR2 and an MS-specific autoantigenic amino acid sequence, residues 84–102 of myelin binding protein, which is thought to be an important autoantigen in the disease. Other disease targets for AnergiX products are likely to include diabetes mellitus and myasthenia gravis. AnergiX complexes containing appropriate autoantigens have already been shown to ameliorate disease in experimental models of allergic encephalomyelitis (in SJL mice), type I diabetes (in non-obese diabetic mice) and autoimmune myasthenia gravis (in Lewis rats).`It is estimated that 5–10% of the US population is afflicted with at least one autoimmune disorder', notes Anergen's president and chief executive officer, Barry Sherman. `About US $5 billion are spent each year on treatments that are directed towards controlling symptoms, rather than curing the disease, which is our objective.'
