Cascade Biotechnology INC | Complement Therapeutics; novel approach to CNS/PNS disease management using the innate complement system.
Myasthenia gravis (MG) is primarily caused by antibodies directed towards the skeletal muscle acetylcholine receptor, leading to muscle weakness.
Although these antibodies may induce compromise of neuromuscular transmission by blocking acetylcholine receptor function, the predominant mechanism of injury to the neuromuscular junction is complement-mediated lysis of the postsynaptic membrane.
Complement plays a central role in EAMG and MG pathogenesis, as well as an important role in T- and B-cell function. Complement inhibitor-based therapy has great potential to treat human MG.
Complement is important in both innate and adaptive immunity (Kemper C, Atkinson JP. T-cell regulation: with complements from innate immunity. Nat Rev Immunol. 2007;7(1):9–18) (Morgan BP and Kavanaugh D. Introduction to complement in health and disease. Semin Immunopathol. 2018 Jan;40(1):1-2).
Activation of the complement system protects the host against invading pathogens by distinct mechanisms, which include cell lysis of pathogens, opsonization with complement fragments, chemotaxis of inflammatory cells and formation of the membrane attack complex (MAC) ( Kohl J. Self, non-self, and danger: a complementary view. Adv Exp Med Biol. 2006;586:71–94).
In the adaptive immune response, complement is the effector system for the primary and secondary antibody responses of B cells (Boackle SA, Holers VM. Role of complement in the development of autoimmunity. Curr Dir Autoimmun. 2003;6:154–168.) (Blank M, Schoenfeld Y. B cell targeted therapy in autoimmunity. J Autoimmun. 2007;28(2–3):62–68).
Complement activation is regulated by a series of approximately 30 plasma and membrane proteins participating in classical, alternative and lectin pathways. The classical pathway is activated by immune complexes containing antigen and IgM or complement fixing IgG (Austen KF, Feeron DT. A molecular basis of activation of the alternative pathway of human complement. Adv Exp Med Biol. 1979;120B:3–17).
The alternative pathway is activated by foreign pathogens and polymeric IgA. (Austen KF, Feeron DT. A molecular basis of activation of the alternative pathway of human complement. Adv Exp Med Biol. 1979;120B:3–17.) (Bogers WM et al. Complement enhances the clearance of large- sized soluble IgA aggregates in rats. Eur J Immunol. 1991;21(5):1093–1099).
The lectin pathway is initiated by binding of mannose-binding lectin to microbial pathogens and may involve IgA-containing immune complexes (Roos A et al. IgA (2001) and activates the complement system via the mannan-binding lectin pathway. J Immunol. 167(5):2861–2868.) (Thiel S, et al. A second serine protease associated with mannan-binding lectin that activates complement. Nature. 1997;386(6624):506–510).
Although initiated differently, all three pathways converge at the cleavage of C3 by specific convertase enzymes followed by the generation of the MAC.
The existence of a new activation pathway by which generation of C5a through a coagulation pathway involving thrombin in the absence of C3 has been proposed (Huber-Lang Met al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med. 2006;12(6):682–687).
Complement activity is modulated by regulatory proteins that prevent the cascade from progressing toward tissue damage as a result of inadvertent binding of activated complement components. (Kusner et al. 2008 Effect of complement and its regulation on myasthenia gravis pathogenesis Expert Rev Clin Immunol. January ; 4(1): 43–520).