Targeted immunosuppressant on trial for rheumatoid arthritis
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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. 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.’ HCgp39, 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 mg 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.’ Dorothy Bonn 277 N e w s MOLECULAR MEDICINE TODAY, JULY 1998 Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1357 - 4310/98/$19.00 Figure 1. Mechanism of action of AnergiX. (a) In autoimmune disease, autoantigens bound to MHC anti- gens 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. APC Auto-antigenic peptide Autoimmune disease T cell TCR CD28 B7 MHC antigen a AnergiX therapeutic Anergy or apoptosis b Targeted immunosuppressant on trial for rheumatoid arthritis
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Transcript of Targeted immunosuppressant on trial for rheumatoid arthritis
Anergen Inc. (Redwood City, CA, USA) has hadan Investigational New Drug (IND) applicationaccepted by the US Food and Drug Administrationto start clinical evaluation of AnergiX for RA, anew immunosuppressant treatment for rheumatoidarthritis (RA) that is based on selective inhibitionof T cells. A Phase I trial will be conducted inpatients with longstanding RA who areconcomitantly taking methotrexate.
AnergiX for RA is a soluble complex thatcombines a peptide derived from a 39 kDa humancartilage-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 arecommonly associated with RA. The complex is designed to selectively inactivate Tcells that cause the inflammatory autoimmuneresponse without inducing generalizedsuppression of the immune system. It will beadministered by slow intravenous infusion.
‘Conventional immunosuppressants canimprove signs and symptoms of RA, but they canbe associated with potentially serious toxicity’,says Anergen’s vice-president of clinicaldevelopment, Michael Shulman. ‘We hope toovercome this problem by specifically targetingthe disease-producing cells. Our approach is toengage the receptors of autoreactive T cells withan MHC class II molecule in association with aspecific autoantigenic peptide, Hcgp39.’
The AnergiX complex selectively inactivatesdisease-causing T cells because two stimulatorysignals are necessary for activation of T cells bymacrophages and other antigen-presenting cells(Fig. 1): the main signal is the binding of anMHC-associated antigen to its cognate T-cellreceptor; the second (or co-stimulatory) signalinvolves a cell-surface antigen such as CD28 onthe T-cell surface binding to its ligand, B7, on theantigen-presenting cell. If the co-stimulatorysignal does not occur, the T cell either becomesunresponsive (anergic) or dies through apoptosis.‘The idea behind AnergiX technology’, explainsShulman, ‘is to deliver a drug that provides onlyone signal, so that the immune response is nevercompleted, and T-cell anergy and/or apoptosis isinduced instead of activation and proliferation.’
HCgp39, the source of the peptide moiety ofthe AnergiX-RA MHC–peptide complex, is a
putative RA autoantigen that is expressed insynovial cells and chrondrocytes of patients withRA, but not by unaffected individuals. TheAnergiX-RA complex contains the amino acids263–275 of the protein – the part that isspecifically recognized by peripheral T cells fromRA patients. Unaffected individuals do not appearto have T cells that react to HCgp39. Furthersupport for the role of HCgp39 in causing RAcomes from experiments in BALB/c mice,performed by scientists at Organon, in whichinjection of 10 mg of the peptide induceschronic/relapsing arthritis similar to RA.
Anergen’s entire research programme focuseson developing treatments for autoimmunediseases, using a targeted approach to shut downthe errant immune responses that underlie thesediseases. One AnergiX product, AnergiX formultiple sclerosis (MS), is already in Phase I trialin patients with secondary progressive MS. Itcomprises a complex of HLA-DR2 and an
MS-specific autoantigenic amino acid sequence,residues 84–102 of myelin binding protein, whichis thought to be an important autoantigen in thedisease. Other disease targets for AnergiXproducts are likely to include diabetes mellitus andmyasthenia gravis. AnergiX complexes containingappropriate autoantigens have already been shownto ameliorate disease in experimental models ofallergic encephalomyelitis (in SJL mice), type Idiabetes (in non-obese diabetic mice) andautoimmune myasthenia gravis (in Lewis rats).
‘It is estimated that 5–10% of the USpopulation is afflicted with at least oneautoimmune disorder’, notes Anergen’s presidentand chief executive officer, Barry Sherman.‘About US $5 billion are spent each year ontreatments that are directed towards controllingsymptoms, rather than curing the disease, whichis our objective.’
Dorothy Bonn
277
N e w sMOLECULAR MEDICINE TODAY, JULY 1998
Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1357 - 4310/98/$19.00
Figure 1. Mechanism of action of AnergiX. (a) In autoimmune disease, autoantigens bound to MHC anti-gens 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 anMHC-bound autoantigen to the autoreactive T cells in the absence of a co-stimulatory signal. This causesthe T cells either to become anergic or to die by apoptosis.
APC
Auto-antigenic peptide
Autoimmunedisease
T cell
TCR
CD28B7
MHCantigen
a
AnergiXtherapeutic
Anergy or apoptosis
b
Targeted immunosuppressant ontrial for rheumatoid arthritis
