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An Overview of the Development of Specific Inhibitors of Complement: Opportunities for Therapy of Paroxysmal Nocturnal Hemoglobinuria

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Paroxysmal Nocturnal Hemoglobinuria and Related Disorders

Abstract

The erythrocytes of PNH are abnormally sensitive to complementmediated lysis because they lack the two proteins (CD55 and CD59) that normally control the activity of complement on the cell surface. The hemolytic anemia of PNH is complement-mediated, but the mechanism by which complement induces spontaneous lysis of PNH RBC in vivo is speculative. Further, the basis of the greater hemolysis that occurs during sleep remains enigmatic, and it is unclear if aberrant regulation of complement underlies other symptoms of PNH. Currently available therapy for the hemolysis of PNH is suboptimal. Over the last decade, inhibitors have been developed that target the most critical functional sites of the complement cascade. These reagents have therapeutic potential in PNH. Ideally, the efficacy and safety of these inhibitors would be tested in an animal model of PNH to determine the optimal conditions and disease specific sites for complement inactivation. Due to differences in the mechanisms by which complement is regulated on murine cells, however, currently available transgenic mouse models of PNH are unlikely to be uninformative for these purposes. In the absence of an appropriate animal model, participation in phase I and phase II human trials appears to be the best available mechanism for developing a therapeutic strategy for complement inhibition in PNH. Careful analysis of the effects of these inhibitors will provide important insights into role of complement in the protean clinical manifestations of PNH.

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Author information

Authors and Affiliations

  1. Hematology/Oncology Section VA Medical Center and The University of Utah School of Medicine Salt Lake City, Utah

    Charles J. Parker M. D.

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  1. Charles J. Parker M. D.
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Editors and Affiliations

  1. Division of Hematology, Internal Medicine Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, 227-8501, Japan

    Mitsuhiro Omine M.D. (Professor) (Professor)

  2. Department of Immunoregulation, Research Institute for Microbial Diseases Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Taroh Kinoshita Ph.D. (Professor) (Professor)

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© 2003 Springer Japan

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Parker, C.J. (2003). An Overview of the Development of Specific Inhibitors of Complement: Opportunities for Therapy of Paroxysmal Nocturnal Hemoglobinuria. In: Omine, M., Kinoshita, T. (eds) Paroxysmal Nocturnal Hemoglobinuria and Related Disorders. Springer, Tokyo. https://doi.org/10.1007/978-4-431-67867-0_2

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  • DOI: https://doi.org/10.1007/978-4-431-67867-0_2

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-68004-8

  • Online ISBN: 978-4-431-67867-0

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