Complement depletion with humanised cobra venom factor: Efficacy in preclinical models of vascular diseases

Summary

The complement system is an intrinsic part of the immune system and has important functions in both innate and adaptive immunity. On the other hand, inadvertent or misdirected complement activation is also involved in the pathogenesis of many diseases, contributing solely or significantly to tissue injury and disease development. Multiple approaches to develop pharmacological agents to inhibit complement are currently being pursued. We have developed a conceptually different approach of not inhibiting but depleting complement, based on the complement-depleting activities of cobra venom factor (CVF), a non-toxic cobra venom component with structural and functional homology to complement component C3. We developed a humanised version of CVF by creating human complement component C3 derivatives with complement-depleting activities of CVF (humanised CVF) as a promising therapeutic agent for diseases with complement pathogenesis. Here we review the beneficial therapeutic effect of humanised CVF in several murine models of vascular diseases such as reperfusion injury.

Keywords

Cobra venom factor - humanised cobra venom factor - CVF - complement depletion - reperfusion injury

• References

• 1 Vogel C-W, Fritzinger DC. Cobra venom factor: structure, function, and humani-zation for therapeutic complement depletion. Toxicon 2010; 56: 1198-1222.
• 2 Wang Y, Rollins SA, Madri JA. et al. Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease. Proc Natl Acad Sci USA 1995; 92: 8955-8959.
• 3 Buyon JP, Tamerius J, Ordorica S. et al. Activation of the alternative complement pathway accompanies disease flares in systemic lupus erythematosus during pregnancy. Arthritis Rheum 1992; 35: 55-61.
• 4 Lennon VA, Seybold ME, Lindstrom JM. et al. Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis. J Exp Med 1978; 147: 973-983.
• 5 Edwards AO, Ritter 3 R, Abel KJ. et al. Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308: 421-424.
• 6 Risitano AM. Paroxysmal nocturnal haemoglobinuria and other complement-mediated hematological disorders. Immunobiology 2012; 217: 1080-1087.
• 7 Arumugam TV, Shiels IA, Woodruff TM. et al. The role of the complement system in ischaemia-reperfusion injury. Shock 2004; 21: 401-409.
• 8 Gorsuch WB, Chrysanthou E, Schwaeble WJ. et al. The complement system in ischaemia-reperfusion injuries. Immunobiology 2012; 217: 1026-1033.
• 9 Riedemann NC, Ward PA. Complement in ischaemia reperfusion injury. Am J Pathol 2003; 162: 363-367.
• 10 Zhou W, Farrar CA, Abe K. et al. Predominant role for C5b-9 in renal ischae-mia/reperfusion injury. J Clin Invest 2000; 105: 1363-1371.
• 11 Vogel C-W. Cobra venom factor, the complement-activating protein of cobra venom. In: Tu AT. editor. Handbook of Natural Toxins: Reptile and Amphibian Venoms. New York:: Marcel Dekker; 1991. pp. 147-188.
• 12 Vogel C-W, Smith CA, Müller-Eberhard HJ. Cobra venom factor: structural homology with the third component of human complement. J Immunol 1984; 133: 3235-3241.
• 13 Fritzinger DC, Bredehorst R, Vogel C-W. Molecular cloning and derived primary structure of cobra venom factor. Proc Natl Acad Sci USA 1994; 91: 12775-12779.
• 14 Vogt W, Dieminger L, Lynen R. et al. Alternative pathway for the activation of complement in human serum. Formation and composition of the complex with cobra venom factor that cleaves the third component of complement. Hoppe Seyler’s Z Physiol Chem 1974; 355: 171-183.
• 15 Vogel C-W, Müller-Eberhard HJ. The cobra venom factor-dependent C3 convertase of human complement. A kinetic and thermodynamic analysis of a protease acting on its natural high molecular weight substrate. J Biol Chem 1982; 257: 8292-8299.
• 16 Janssen BJ, Gomes L, Koning RI. et al. Insights into complement convertase formation based on the structure of the factor B-cobra venom factor complex. Embo J 2009; 28: 2469-2478.
• 17 Götze O, Müller-Eberhard HJ. The C3-activator system: an alternate pathway of complement activation. J Exp Med 1971; 134: 90s-108s.
• 18 Forneris F, Ricklin D, Wu J. et al. Structures of C3b in complex with factors B and D give insight into complement convertase formation. Science 2010; 330: 1816-1820.
• 19 Lesavre PH, Hugli TE, Esser AF. et al. The alternative pathway C3/C5 conver-tase: chemical basis of factor B activation. J Immunol 1979; 123: 529-534.
• 20 Vogt W, Schmidt G, von Buttlar L. et al. A new function of the activated third component of complement: binding to C5, an essential step for C5 activation. Immunology 1978; 34: 29-41.
• 21 Lachmann PJ, Halbwachs L. The influence of C3b inactivator (KAF) concentration on the ability of serum to support complement activation. Clin Exp Immunol 1975; 21: 109-114.
• 22 Nagaki K, Iida K, Okubo M. et al. Reaction mechanisms of beta1H globulin. Int Arch Allergy Appl Immunol 1978; 57: 221-232.
• 23 Cochrane CG, Müller-Eberhard HJ, Aikin BS. Depletion of plasma complement in vivo by a protein of cobra venom: its effect on various immunologic reactions. J Immunol 1970; 105: 55-69.
• 24 Maillard JL, Zarco RM. Décomplémentation par un facteur extrait du venin de cobra. Effect sur plusieurs reactions immunes du cobaye et du rat. Ann Inst Pasteur 1968; 114: 756-774.
• 25 Nelson Jr. RA. A new concept of immunosuppression in hypersensitivity reactions and in transplantation immunity. Surv Ophthalmol 1966; 11: 498-505.
• 26 Holers VM, Thurman JM. The alternative pathway of complement in disease: opportunities for therapeutic targeting. Mol Immunol 2004; 41: 147-152.
• 27 Lachmann PJ, Smith RA. Taking complement to the clinic - has the time finally come?. Scand J Immunol 2009; 69: 471-478.
• 28 Morgan BP, Harris CL. Complement therapeutics; history and current progress. Mol Immunol 2003; 40: 159-170.
• 29 Ricklin D, Lambris JD. Progress and trends in complement therapeutics. Adv Exp Med Biol 2013; 735: 1-22.
• 30 Fritzinger DC, Hew BE, Lee JQ. et al. Derivatives of human complement component C3 for therapeutic complement depletion: a novel class of therapeutic agents. Adv Exp Med Biol 2008; 632: 293-307.
• 31 Fritzinger DC, Hew BE, Thorne M. et al. Functional characterization of human C3/cobra venom factor hybrid proteins for therapeutic complement depletion. Dev Comp Immunol 2009; 33: 105-116.
• 32 Vogel C-W, Fritzinger DC. Humanised cobra venom factor: experimental therapeutics for targeted complement activation and complement depletion. Curr Pharm Des 2007; 13: 2916-2926.
• 33 Hebell T, Ahearn JM, Fearon DT. Suppression of the immune response by a soluble complement receptor of B lymphocytes. Science 1991; 254: 102-105.
• 34 Kock MA, Hew BE, Bammert H. et al. Structure and function of recombinant cobra venom factor. J Biol Chem 2004; 279: 30836-30843.
• 35 Vogel C-W, Fritzinger DC, Hew BE. et al. Recombinant cobra venom factor. Mol Immunol 2004; 41: 191-199.
• 36 Hew BE, Wehrhahn D, Fritzinger DC. et al. Hybrid proteins of cobra venom factor and cobra C3: tools to identify functionally important regions in cobra venom factor. Toxicon 2012; 60: 632-647.
• 37 Wehrhahn D, Meiling K, Fritzinger DC. et al. Analysis of the structure/function relationship of cobra venom factor (CVF) and C3: generation of CVF/cobra C3 hybrid proteins. Immunopharmacology 2000; 49: 94.
• 38 Hew BE, Thorne M, Fritzinger DC. et al. Humanised cobra venom factor (CVF): generation of human C3 derivatives with CVF-like function. Mol Immunol 2004; 41: 244-245.
• 39 Kölln J, Spillner E, Andrä J. et al. Complement inactivation by recombinant human C3 derivatives. J Immunol 2004; 173: 5540-5545.
• 40 de Bruijn MH, Fey GH. Human complement component C3: cDNA coding sequence and derived primary structure. Proc Natl Acad Sci USA 1985; 82: 708-712.
• 41 Fritzinger DC, Ferreira VP, Hew BE. et al. A novel concept for the treatment of paroxysmal nocturnal haemoglobinuria (PNH): complement depletion with a human C3 derivative with cobra venom factor-like activity prevents lysis of PNH erythrocytes. Mol Immunol 2008; 45: 4177.
• 42 Wang SY, Veeramani S, Racila E. et al. Depletion of the C3 component of complement enhances the ability of rituximab-coated target cells to activate human NK cells and improves the efficacy of monoclonal antibody therapy in an in vivo model. Blood 2009; 114: 5322-5330.
• 43 Fritzinger DC, Dean R, Meschter C. et al. Complement depletion with humanised cobra venom factor in a mouse model of age-related macular degeneration. Adv Exp Med Biol 2010; 703: 151-162.
• 44 Busche MN, Walsh MC, McMullen ME. et al. Mannose-binding lectin plays a critical role in myocardial ischaemia and reperfusion injury in a mouse model of diabetes. Diabetologia 2008; 51: 1544-1551.
• 45 Walsh MC, Bourcier T, Takahashi K. et al. Mannose-binding lectin is a regulator of inflammation that accompanies myocardial ischaemia and reperfusion injury. J Immunol 2005; 175: 541-546.
• 46 Gorsuch WB, Guikema BJ, Fritzinger DC. et al. Humanised cobra venom factor decreases myocardial ischaemia-reperfusion injury. Mol Immunol 2009; 47: 506-510.
• 47 Hart ML, Ceonzo KA, Shaffer LA. et al. Gastrointestinal ischaemia-reperfusion injury is lectin complement pathway dependent without involving C1q. J Immunol 2005; 174: 6373-6380.
• 48 Stahl GL, Xu Y, Hao L. et al. Role for the alternative complement pathway in is-chaemia/reperfusion injury. Am J Pathol 2003; 162: 449-455.
• 49 Zhao H, Montalto MC, Pfeiffer KJ. et al. Murine model of gastrointestinal ischaemia associated with complement-dependent injury. J Appl Physiol 2002; 93: 338-345.
• 50 Frank JA, Matthay MA. Science review: mechanisms of ventilator-induced injury. Crit Care 2003; 7: 233-241.
• 51 Takahashi K, Saha D, Shattino I. et al. Complement 3 is involved with ventilator-induced lung injury. Intern Immunopharmacol 2011; 11: 2138-2143.
• 52 Busche MN, Pavlov V, Takahashi K. et al. Myocardial ischaemia and reperfusion injury is dependent on both IgM and mannose-binding lectin. Am J Physiol Heart Circulat Physiol 2009; 297: H1853-H1859.
• 53 Huda R, Fritzinger DC, Finnegan PF. et al. Complement depletion with humanised cobra venom factor (CVF) improves the severity of experimental autoimmune myasthenia gravis (EAMG). Mol Immunol 2011; 48: 1712.
• 54 Rayes J, Ing M, Peyron I. et al. Complement depletion with humanised cobra venom factor reduces the immune response against therapeutic Factor VIII in haemophilia A. Mol Immunol. 2014 in press.
• 55 Till GO, Johnson KJ, Kunkel R. et al. Intravascular activation of complement and acute lung injury. Dependency on neutrophils and toxic oxygen metabolites. J Clin Invest 1982; 69: 1126-1135.
• 56 Till GO, Morganroth ML, Kunkel R. et al. Activation of C5 by cobra venom factor is required in neutrophil-mediated lung injury in the rat. Am J Pathol 1987; 129: 44-53.
• 57 Mulligan MS, Schmid E, Beck-Schimmer B. et al. Requirement and role of C5a in acute lung inflammatory injury in rats. J Clin Invest 1996; 98: 503-512.
• 58 Fritzinger DC, Hew BE, Lee JQ. et al. Human C3/cobra venom factor hybrid proteins for therapeutic complement depletion: in vivo activity and lack of toxicity in primates. Mol Immunol 2008; 45: 4112.
• 59 Gowda DC, Glushka J, Halbeek H. et al. N-linked oligosaccharides of cobra venom factor contain novel alpha(1-3)galactosylated Le^x structures. Glycobiol-ogy 2001; 11: 195-208.
• 60 Rayes J, Ing M, Peyron I. et al. Humanised cobra venom factor exhibits virtual absence of immunogenicity in mice compared to natural CVF. Mol Immunol. 2014 in press.
• 61 Moller-Kristensen M, Ip WK, Shi L. et al. Deficiency of mannose-binding greatly increases susceptibility to postburn infection with Pseudomonas aeruginosa . J Immunol 2006; 176: 1769-1775.
• 62 Wilson MR, Choudhury S, Goddard ME. et al. High tidal volume upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury. J Appl Physiol 2003; 95: 1385-1393