Autoimmune Disease Drug Discovery

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INDUSTRY TRENDS Autoimmune disease drug discovery

Aris Persidis

Autoimmune disorders occur when the detail. For example, diagnostic correlations mals against the disease, showing that with body’s immune system turns against the were made between molecular markers, appropriate molecular intervention, it was body itself, attacking it as if it were a foreign such as β2 microglobulin concentration in possible to divert the immune response from pathogen. They comprise more than 50 dis- saliva, and local inflammation in Sjogren’s a destructive to a nondestructive response11. tinct diseases and syndromes, and affect syndrome, suggesting how it was possible to These efforts and others have resulted in a about 5% of the population in Europe and identify specific molecules that were variety of therapeutic approaches against North America, with two thirds of the involved in the development of an autoim- autoimmune disorders that continues to be patients being female1. Examples of autoimmune disease, and could therefore serve as refined. mune disorders include rheumatoid arthri- diagnostics8. By the early 1980s, there were tis, multiple sclerosis, juvenile diabetes, car- significant concerns about the links between Current state diomyopathy, antiphospholipid syndrome, bone marrow transplantation—a leading- Since autoimmune disorders cover such a Guillain-Barré syndrome, Crohn’s disease, edge procedure at the time—and autoim- wide variety of molecular and clinical phe- Graves’ disease, Sjogren’s syndrome, alope- mune disease side effects9. By the early nomena, it should come as no surprise that cia, myasthenia gravis, lupus erythematosus, 1990s there was an interesting application of research efforts span the gamut of and psoriasis. In addition, such disorders autoimmune disease principles in a novel approaches and therapeutic targets. The complicate other diseases that are not direction, namely that of birth control by increasing understanding of the molecular autoimmune in origin, such as Duchenne’s immunization against sperm10. basis of these diseases is helping to focus muscular dystrophy and artherosclerosis. The last decade has also benefited from research directions in specific areas. Table 1 The total societal disease burden for the advances of molecular biology and other shows a selection of companies active in the autoimmune disorders is difficult to esti- techniques that enabled the identification of development of autoimmune disorder ther- mate because while some of these are chron- specific autoantigens involved in a variety of apeutics. The approaches range from gene ic and debilitating diseases, others are less autoimmune disorders. This was critical for therapy to antisense to administration of

http://biotech.nature.com • serious. Arthritis alone is estimated to cause strategies to combat these disorders effective- antibodies, vaccines, and a variety of a $65 billion disease burden2, so autoim- ly, by focusing on the triggers and actual cytokines. mune disorders as a group are among the molecules that were involved. Significant At present, the advent of large amounts most expensive diseases faced by society progress has been made in these molecular of genomic information is enabling the sys- today. As a result, they are the subject of sig- approaches by using appropriate animal tematic attempt at correlating homologies nificant research in both academic and models. One example is autoimmune between pathogens, such as viruses and bac- industrial laboratories. encephalomyelitis, a debilitating brain dis- teria, and specific self proteins. The hypoth- ease. Here, treatment of animal models of the esis is that these pathogens might trigger an Historical perspective disease with a neuroantigen and an antibody autoimmune response by virtue of these Although the clinical manifestations of against CD11a (LFA-1) protected the ani- homologies. For example, the novel thyroid 1999 Nature America Inc.

© autoimmune diseases have long been known, the concept that the body’s own immune system was responsible did not become estab- Table 1. Selected companies with autoimmune drug discovery programs. lished until reproducible experimental evi- dence began to be obtained from the mid- Company Program 1960s onward. For example, auto-antibodies Alexion (New Haven, CT) Monoclonal antibody for lupus against diseased organs in Sjogren’s sydrome Anergen (Redwood City, CA) Peptide vaccine for rheumatoid arthritis 3 were first described in 1965 . Animal models Biogen (Cambridge, MA) Anti-CD40 antibody for lupus at the time also showed how antibodies could Centocor (Malvern, PA) Chimeric anti-TNF antibody for rheumatoid arthitis be formed against red blood cells, suggesting Chiron (Emeryville, CA) Anti-TNF antiobody for multiple sclerosis 4 correlations with some anemias . The mid- Connetics (Palo Alto, CA) Recombinant relaxin for scleroderma 1960s also saw initial connections being IDEC Pharmaceuticals (San Diego, CA) Monoclonal antibodies for rheumatoid arthritis made between viral infections and autoim- and lupus mune diseases, specifically hemolytic ane- Immune Response Corp. (Carlsbad, CA) Vaccine for rheumatoid arthritis mia, based on clinical observations5. Immunex (Seattle, WA) Recombinant TNF receptor for rheumatoid arthritis In the early 1970s, autoimmune heart Isis Pharmaceuticals (Carlsbad, CA) Antisense for rheumatoid arthritis disease was first linked to α-hemolytic Medarex (Annandale, NJ) Monoclonal antibody for idiopathic thrombocy- streptococcus6, and the first theories were topenic purpura developed linking aging and autoimmuni- Neurocrine Biosciences (San Diego, CA) Cytokines for autoimmune diseases ty7. Some autoimmune diseases also began Ortho Biotech (Raritan, NJ) Monoclonal antibody for CD4-mediated to be described in increasing molecular autoimmune diseases Protein Design Labs (Mountain View, CA) Monoclonal antibody for autoimmune diseases Schering-Plough (Madison, NJ) IL-10 for rheumatoid arthritis Aris Persidis is managing director of Seragen (Hopkinton, MA) IL-2 fusion protein for severe rheumatoid arthritis RheoGene, 706 Forest Street, Charlottsville, Source: Biovista (www.biovista.com). VA 22903 ([email protected]).

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autoantigen that is the sodium/iodide sym- munity is a major challenge to researchers. It al genomics techniques. For example, a new porter (NIS) has local amino acid sequence is being addressed by systematic analysis and MHC-restricted autoantigen from the homologies with three other known thyroid sequence comparison derived from insulin B chain was recently identified in an autoantigens, namely thyroglobulin, thy- genomics coupled with relevant clinical animal model of type I diabetes by screening roid peroxidase, and thyrotropin receptor. A information. a disease and pancreatic-specific cDNA recent report describes the application of a Another challenge is identifying not only library16. This epitope was found to be the computer-aided search that showed how the those autoantigens that are shared with same one recognized by pathogenic CD4+ T- NIS was found to have significant local pathogens, but also those that are part of the cells, and may thus be formulated into an homologies with no fewer than other 11 native body itself, and that trigger disease as a insulin-derived preventive therapy. proteins from bacteria or viruses, such as result of as yet poorly understood events. A We are also likely to see major efforts Streptococcus or herpes. It was also found to good example of new classes of such being undertaken to explain the gender dif- have extensive—but not local—homologies autoantigens is DNA itself. A recent report ference that is observed in susceptibility to with several unknown proteins from inver- highlights the identification and characteri- autoimmune disease. There are hypotheses tebrates such as Drosophila melanogaster zation of antibodies against DNA itself, that involve hormonal and other differences, and Caenorhabditis elegans, and with bacte- which might lead to numerous complica- but at this point many questions have yet to ria such as Bacillus subtilis and tions associated with cell division and gene be answered17. Xanthobacter12. expression14. Finally, the future will also see the appli- Animal models are being used extensive- cation of gene therapy approaches to the ly to discover and confirm antigens involved treatment of autoimmune disorders, based in autoimmune disorders, and also to help New approaches tend to on the administration of genes or mini-genes develop effective therapies based on that employ therapies based encoding for immunomodulatory cytokines, knowledge. A recent study describes how or antigens that would cause tolerization. rats were induced to have a particular ver- on immunomodulation, Efforts are already underway with adminis- sion of myasthenia by injecting them with tration of antiinflammatory cytokines such peptides derived from the voltage-gated cal- rather than immunosup- as transforming growth factor-β1 and inter- cium channel found in neuromuscular junc- pression, and in the case leukin 4, which had protective effects in ani- tions13. This protein is believed to be the tar- mal models of experimental allergic get of autoantibodies found in patients with of multiple sclerosis, these encephalomyelitis18. this disease, and the rat model is helping to approaches are proving

http://biotech.nature.com • characterize the specific epitopes of the pro- Conclusions tein that are recognized by these antibodies. to be more effective. Autoimmune disorders are a family of dis- Such knowledge can then be used to tailor a eases that represent a major societal burden. vaccine or other therapeutic modality to While the pace of our understanding of the interfere with and perhaps abrogate this Future directions molecular and cellular processes of these autoimmune response. As our understanding of the molecular and complex disorders have thus far been behind cellular aspects of autoimmunity increases, that of other, simpler diseases, the advent of Industry challenges we will continue to see more effective treat- large-scale genomic and functional analysis A key challenge to developing therapies for ments for these diseases. For example, multi- tools are now helping redress the balance, autoimmune disorders is the cross-reactivi- ple sclerosis (MS) is an autoimmune neuro- and the enormous pressure to understand 1999 Nature America Inc.

© ty between normal body proteins and those logical disorder thought to be mediated by these diseases and cure them is the best guar- of a variety of pathogenic agents. For exam- antigen-specific CD4+ T helper (Th1) T-cells antee of progress in this area. ple, hepatitis B virus has an amino acid which cause demyelination of the central sequence in one of its proteins that is highly nervous system (CNS). Many current thera- 1. American Autoimmune Related Diseases homologous to that of myelin basic protein peutic strategies attempt to downregulate the Association (www.aarda.org). (MBP), which is the target of autoimmune entire immune system by causing generalized 2. Persidis, A. Nat. Biotechnol. 17, 726–728 (1999). attack in multiple sclerosis. Brain inflam- immunosuppression, in the hope that this 3. Bertram, U. & Halberg, P. Acta Allergol. 20, 472–483 (1965). mation is caused in animal models injected will reduce the specific action of the T-cells 4. Sundermann, A. & Mey, U. Folia Haematol. Int. Mag. with the MBP-homologous component of involved. This approach, incidentally, is Klin. Morphol. Blutforsch. 84, 387–401 (1965). 5. Puxeddu, A. et al. Haematologica 50, 1073–1092 the hepatitis B virus. Adenovirus type 2 is widespread in autoimmune treatments in the (1965). another virus with a protein that has signifi- absence of better options. Unfortunately, 6. Wachsmuth, E.D. & Born, U. Br. Med. J. 3, 623 cant sequence homology to MBP. Another generalized immunosuppression has not met (1972). 7. Bastenie, P.A Bull. Mem. Acad. R. Med. Belg. 130, example is rheumatoid arthritis. In animal with the success expected. Now, new 517–526 (1975). models, inflammation of the joints can be approaches tend to employ therapies based 8. Michalski, J.P. et al. N. Engl. J. Med. 293, 1228–1231 (1975). caused by infection with Mycobacterium on immunomodulation, rather than 9. Minchinton, R.M. et al. Lancet 2, 391 (1982). tuberculosis, which has protein components immunosuppression, by administration of 10. De Almeida, M. et al. Hum. Reprod. 6, 405–410 similar to normal cartilage. Finally, cytokines such as interferon (IFN)-β and (1991). 11. Willenborg, D.O. et al. J. Immunol. 157, 1973–1980 rheumatic fever is sometimes accompanied glatiramer acetate, and in the case of MS, (1996). by damage to heart valves. Animal models these approaches are proving to be more 12. Benvenga, S. et al. J. Endocrinol. Invest. 22, 15 535–540 (1999). have shown the connection between such effective . Refinements in our understanding 13. Komai, K. et al. J. Neurol. Sci. 166, 126–130 (1999). damage and hemolytic streptococcus, which of the effects of immunomodulation versus 14. Eilat, D. & Naparstek, Y. Immunol. Today 20, has a cell wall protein similar to heart mus- more drastic measures will no doubt help us 339–342 (1999). 15. Giovannoni, G. & Miller, D.H. J. R. Coll. Physicians cle myosin. Determining all of these devise even more effective therapies. Lond. 33, 315–322 (1999). sequence similarities that are not by-prod- The future will also see the identification 16. Wong, F.S. et al. Nat. Med. 5, 1026–1031 (1999). 17. Nikezic-Ardolic, M. et al. Lupus 8, 375–379 (1999). ucts of evolutionary conservation but that of putative autoantigens occur at an increas- 18. Piccirillo, C.A. & Prud’homme, G.J. Hum. Gene actually have a causative effect in autoim- ing rate, based on the application of funtion- Ther. 10, 1915–1922 (1999).

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