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Derivatives of Human Complement Component C3 for Therapeutic Complement Depletion: A Novel Class of Therapeutic Agents

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Book cover Current Topics in Complement II

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 632))

Abstract

To obtain proteins with the complement-depleting activity of Cobra Venom Factor (CVF), but with less immunogenicity, we have prepared human C3/CVF hybrid proteins, in which the C-terminus of the α-chain of human C3 is exchanged with homologous regions of the C-terminus of the β -chain of CVF. We show that these hybrid proteins are able to deplete complement, both in vitro and in vivo. One hybrid protein, HC3-1496, is shown to be effective in reducing complement-mediated damage in two disease models in mice, collagen-induced arthritis and myocardial ischemia/reperfusion injury. Human C3/CVF hybrid proteins represent a novel class of biologicals as potential therapeutic agents in many diseases where complement is involved in the pathogenesis.

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References

  • Andrä, J., Halter, R., Kock, M. A., Niemann, H., Vogel, C.-W., and Paul, D. (2002). Generation and characterization of transgenic mice expressing cobra venom factor. Mol Immunol 39, 357–365

    Article  PubMed  Google Scholar 

  • Brand, D. D., Myers, L. K., Terato, K., Whittington, K. B., Stuart, J. M., Kang, A. H., and Rosloniec, E. F. (1994). Characterization of the T cell determinants in the induction of autoimmune arthritis by bovine alpha 1(II)-CB11 in H-2q mice. J Immunol 152, 3088–3097

    Google Scholar 

  • Carroll, M. C. (2004). The complement system in B cell regulation. Mol Immunol 41, 141–146

    Article  PubMed  CAS  Google Scholar 

  • Cochrane, C. G., Müller-Eberhard, H. J., and Aikin, B. S. (1970). Depletion of plasma complement in vivo by a protein of cobra venom: its effect on various immunologic reactions. J Immunol 105, 55–69

    PubMed  CAS  Google Scholar 

  • Costa, C., Zhao, L., Burton, W. V., Rosas, C., Bondioli, K. R., Williams, B. L., Hoagland, T. A., Dalmasso, A. P., and Fodor, W. L. (2002). Transgenic pigs designed to express human CD59 and H-transferase to avoid humoral xenograft rejection. Xenotransplantation 9, 45–57

    Article  PubMed  Google Scholar 

  • de Bruijn, M. H. and Fey, G. H. (1985). Human complement component C3: cDNA coding sequence and derived primary structure. Proc Natl Acad Sci U S A 82, 708–712

    Article  PubMed  CAS  Google Scholar 

  • Fodor, W. L., Rollins, S. A., Guilmette, E. R., Setter, E., and Squinto, S. P. (1995). A novel bifunctional chimeric complement inhibitor that regulates C3 convertase and formation of the membrane attack complex. J Immunol 155, 4135–4138

    PubMed  CAS  Google Scholar 

  • Fritzinger, D. C., Petrella, E. C., Connelly, M. B., Bredehorst, R., and Vogel, C.-W. (1992). Primary structure of cobra complement component C3. J Immunol 149, 3554–3562

    PubMed  CAS  Google Scholar 

  • Fritzinger, D. C., Bredehorst, R., and Vogel, C.-W. (1994). Molecular cloning and derived primary structure of cobra venom factor. Proc Natl Acad Sci U S A 91, 12775–12779

    Article  PubMed  CAS  Google Scholar 

  • Fritzinger, D. C., Hew, B. E., Thorne, M., and Vogel, C.-W. (2004). Functional characterization of cobra venom factor/cobra C3 hybrid proteins. Mol Immunol 41, 230

    Google Scholar 

  • Fritzinger, D. C., Hew, B. E., Pangburn, M. K., and Vogel, C.-W. (2008). Generation of human C3 derivatives with CVF-like function for therapeutic complement depletion. FASEB J 19, A324

    Google Scholar 

  • Fritzinger, D. C., Hew, B. E., Pangburn, M. K., Janssen, B. J. C., Gros, P., and Vogel, C.-W. (2008). Human C3/cobra venom factor hybrid proteins with potential therapeutic applications. Mol Immunol 43, 141–142

    Article  Google Scholar 

  • Fritzinger, D. C., Hew, B. E., Lee, J. Q., and Vogel, C.-W. (2007). Human C3/cobra venom factor hybrid proteins for therapeutic complement depletion: in vivo activity and fine mapping of important domains. Mol Immunol 44, 3945

    Article  Google Scholar 

  • Fritzinger, D. C., Hew, B. E., Thorne, M., Pangburn, M. K., Janssen, B. J., Gros, P., and Vogel, C.-W. (2007b). Human C3 derivatives with Cobra venom factor-like functions for therapeutic complement depletion. Dev Comp Immunol, in press

    Google Scholar 

  • Fujita, T., Matsushita, M., and Endo, Y. (2004). The lectin-complement pathway – its role in innate immunity and evolution. Immunol Rev 198, 185–202

    Article  PubMed  CAS  Google Scholar 

  • Gowda, D. C., Schultz, M., Bredehorst, R., and Vogel, C.-W. (1992). Structure of the major oligosaccharide of cobra venom factor. Mol Immunol 29, 335–342

    Article  PubMed  CAS  Google Scholar 

  • Gowda, D. C., Petrella, E. C., Raj, T. T., Bredehorst, R., and Vogel, C.-W.. (1994)Immunoreactivity and function of oligosaccharides in cobra venom factor. J Immunol 152, 2977–2986

    PubMed  CAS  Google Scholar 

  • Gowda, D. C., Glushka, J., Halbeek, H., Thotakura, R. N., Bredehorst, R., and Vogel, C.-W. (2001). N-linked oligosaccharides of cobra venom factor contain novel alpha(1-3)galactosylated Le(x) structures. Glycobiology 11, 195–208

    Article  PubMed  CAS  Google Scholar 

  • Grier, A. H., Schultz, M., and Vogel, C.-W. (1987). Cobra venom factor and human C3 share carbohydrate antigenic determinants. J Immunol 139, 1245–1252

    PubMed  CAS  Google Scholar 

  • Guo, R. F. and Ward, P. A. (2005). Role of C5a in inflammatory responses. Annu Rev Immunol 23, 821–852

    Article  PubMed  CAS  Google Scholar 

  • Hebell, T., Ahearn, J. M., and Fearon, D. T. (1991). Suppression of the immune response by a soluble complement receptor of B lymphocytes. Science 254, 102–105

    Article  PubMed  CAS  Google Scholar 

  • Hew, B. E., Thorne, M., Fritzinger, D. C., and Vogel, C.-W. (2004). Humanized cobra venom factor (CVF): Generation of Human C3 derivitives with CVF-like function. Mol Immunol 41, 244–244

    Google Scholar 

  • Hillmen, P., Hall, C., Marsh, J. C., Elebute, M., Bombara, M. P., Petro, B. E., Cullen, M. J., Richards, S. J., Rollins, S. A., Mojcik, C. F., and Rother, R. P. (2004). Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 350, 552–559

    Article  PubMed  CAS  Google Scholar 

  • Jacobson , M. P., Pincus, D. L., Rapp, C. S., Day, T. J., Honig, B., Shaw, D. E., and Friesner, R. A. (2004). A hierarchical approach to all-atom protein loop prediction. Proteins 55, 351–367

    Article  PubMed  CAS  Google Scholar 

  • Janssen, B. J., Huizinga, E. G., Raaijmakers, H. C., Roos, A., Daha, M. R., Nilsson-Ekdahl, K., Nilsson, B., and Gros, P. (2005). Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 437, 505–511

    Article  PubMed  CAS  Google Scholar 

  • Janssen, B. J., Christodoulidou, A., McCarthy, A., Lambris, J. D., and Gros, P. (2006). Structure of C3b reveals conformational changes that underlie complement activity. Nature 444, 213–216

    Article  PubMed  CAS  Google Scholar 

  • Kock, M. A., Hew, B. E., Bammert, H., Fritzinger, D. C., and Vogel, C. W. (2004). Structure and function of recombinant cobra venom factor. J Biol Chem 279, 30836–30843

    Article  PubMed  CAS  Google Scholar 

  • Kölln, J., Spillner, E., Andrä, J., Klensang, K., and Bredehorst, R. (2004a). Human C3 derivatives engineered for decomplementation by forming stable C3 convertases. Mol Immunol 41, 259

    Article  Google Scholar 

  • Kölln, J., Spillner, E., Andrä, J., Klensang, K., and Bredehorst, R. (2004b). Complement inactivation by recombinant human C3 derivatives. J Immunol 173, 5540–5545

    Google Scholar 

  • Kölln, J., Bredehorst, R., and Spillner, E. (2005). Engineering of human complement component C3 for catalytic inhibition of complement. Immunol Lett 98, 49–56

    Article  PubMed  Google Scholar 

  • Lachmann, P. J. and Halbwachs, L. (1975). The influence of C3b inactivator (KAF) concentration on the ability of serum to support complement activation. Clin Exp Immunol 21, 109–114

    PubMed  CAS  Google Scholar 

  • Maillard, J. L., and Zarco, R. M. (1968). [Decomplementization by a factor extracted from cobra venom. Effect on several immune reactions of the guinea pig and rat]. Ann Inst Pasteur (Paris) 114, 756–774

    CAS  Google Scholar 

  • Medicus, R. G., Götze, O., and Müller-Eberhard, H. J. (1976). The serine protease nature of the C3 and C5 convertases of the classical and alternative complement pathways. Scand J Immunol 5, 1049–1055

    Article  PubMed  CAS  Google Scholar 

  • Mollnes, T. E. and Kirschfink, M. (2006). Strategies of therapeutic complement inhibition. Mol Immunol 43, 107–121

    Article  PubMed  CAS  Google Scholar 

  • Morgan, B. P. and Harris, C. L. (2003). Complement therapeutics; history and current progress. Mol Immunol 40, 159–170

    Article  PubMed  CAS  Google Scholar 

  • Nagaki, K., Iida, K., Okubo, M., and Inai, S. (1978). Reaction mechanisms of beta1H globulin. Int Arch Allergy Appl Immunol 57, 221–232

    Article  PubMed  CAS  Google Scholar 

  • Nelson, R. A., Jr. (1966). A new concept of immunosuppression in hypersensitivity reactions and in transplantation immunity. Surv Ophthalmol 11, 498–505

    PubMed  Google Scholar 

  • Pangburn, M. K., Schreiber, R. D., and Müller-Eberhard, H. J. (1977). Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein beta1H for cleavage of C3b and C4b in solution. J Exp Med 146, 257–270

    Article  PubMed  CAS  Google Scholar 

  • Pangburn, M. K. and Müller-Eberhard, H. J. (1986). The C3 convertase of the alternative pathway of human complement. Enzymic properties of the bimolecular proteinase. Biochem J 235, 723–730

    PubMed  CAS  Google Scholar 

  • Sahu, A. and Lambris, J. D. (2000). Complement inhibitors: a resurgent concept in anti-inflammatory therapeutics. Immunopharmacology 49, 133–148

    Article  PubMed  CAS  Google Scholar 

  • Shernan, S. K., Fitch, J. C., Nussmeier, N. A., Chen, J. C., Rollins, S. A., Mojcik, C. F., Malloy, K. J., Todaro, T. G., Filloon, T., Boyce, S. W., Gangahar, D. M., Goldberg, M., Saidman, L. J., and Mangano, D. T. (2004). Impact of pexelizumab, an anti-C5 complement antibody, on total mortality and adverse cardiovascular outcomes in cardiac surgical patients undergoing cardiopulmonary bypass. Ann Thorac Surg 77, 942–949; discussion 949–950

    Article  PubMed  Google Scholar 

  • Till, G. O., Johnson, K. J., Kunkel, R., and Ward, P. A. (1982). Intravascular activation of complement and acute lung injury. Dependency on neutrophils and toxic oxygen metabolites. J Clin Invest 69, 1126–1135

    Article  PubMed  CAS  Google Scholar 

  • Till, G. O., Morganroth, M. L., Kunkel, R., and Ward, P. A. (1987). Activation of C5 by cobra venom factor is required in neutrophil-mediated lung injury in the rat. Am J Pathol 129, 44–53

    PubMed  CAS  Google Scholar 

  • Vogel, C.-W. (1991). Cobra venom factor, the complement-activating protein of cobra venom. In: Anthony Tu (ed.). Handbook of Natural Toxins: Reptile and Amphibian Venoms, Marcel Dekker, New York, pp. 147–188Vol. 5.

    Google Scholar 

  • Vogel, C.-W., and Müller-Eberhard, H. J. (1982). 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 257, 8292–8299

    PubMed  CAS  Google Scholar 

  • Vogel, C.-W., and Müller-Eberhard, H. J. (1984). Cobra venom factor: improved method for purification and biochemical characterization. Journal of Immunology Methods 73, 203–220

    Article  CAS  Google Scholar 

  • Vogel, C.-W. and Fritzinger, D. C. (2007). Humanized cobra venom factor: experimental therapeutics for targeted complement activation and complement depletion. Curr Pharm Des 13, 2916–2926

    Article  PubMed  CAS  Google Scholar 

  • Vogel, C.-W., Smith, C. A., and Müller-Eberhard, H. J. (1984). Cobra venom factor: structural homology with the third component of human complement. J Immunol 133, 3235–3241

    PubMed  CAS  Google Scholar 

  • Vogel, C.-W., Bredehorst, R., Fritzinger, D. C., Grunwald, T., Ziegelmüller, P., and Kock, M. A. (1996). Structure and function of cobra venom factor, the complement-activating protein in cobra venom. Adv Exp Med Biol 391, 97–114

    Article  PubMed  CAS  Google Scholar 

  • Vogel, C. W., Fritzinger, D. C., Hew, B. E., Thorne, M., and Bammert, H. (2004). Recombinant cobra venom factor. Mol Immunol 41, 191–199

    Article  PubMed  CAS  Google Scholar 

  • Walsh, M. C., Bourcier, T., Takahashi, K., Shi, L., Busche, M. N., Rother, R. P., Solomon, S. D., Ezekowitz, R. A., and Stahl, G. L. (2005). Mannose-binding lectin is a regulator of inflammation that accompanies myocardial ischemia and reperfusion injury. J Immunol 175, 541–546

    PubMed  CAS  Google Scholar 

  • Wehrhahn, D., Meiling, K., Fritzinger, D. C., Bredehorst, R., Andrä, J., and Vogel, C.-W. (2000). Analysis of the structure/function relationship of Cobra Venom Factor (CVF) and C3: generation of CVF/cobraC3 hybrid proteins. Immunopharmacology 49, 94

    Article  Google Scholar 

  • Weisman, H. F., Bartow, T., Leppo, M. K., Marsh, H. C., Jr., Carson, G. R., Concino, M. F., Boyle, M. P., Roux, K. H., Weisfeldt, M. L., and Fearon, D. T. (1990). Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 249, 146–151

    Article  PubMed  CAS  Google Scholar 

  • Whaley, K., and Ruddy, S. (1976). Modulation of the alternative complement pathways by beta1H globulin. J Exp Med 144, 1147–1163

    Article  PubMed  CAS  Google Scholar 

  • Zhou, C. Y., McInnes, E., Copeman, L., Langford, G., Parsons, N., Lancaster, R., Richards, A., Carrington, C., and Thompson, S. (2005). Transgenic pigs expressing human CD59, in combination with human membrane cofactor protein and human decay-accelerating factor. Xenotransplantation 12, 142–148

    Article  PubMed  Google Scholar 

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Acknowledgments

Part of the research was supported by Incode Biopharmaceutics Corporation, Lahaina, Hawaii, USA.

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Authors and Affiliations

  1. Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, HI 96813, USA

    David C. Fritzinger

  2. Maui High Performance Computing Center, Kihei, HI 96753, USA

    James Newhouse

  3. Advanced Studies in Genomics, Proteomics, and Bioinformatics, University of Hawaii at Manoa, Honolulu, HI 96822, USA

    Maqsudul Alam

  4. Melior Discovery Corporation, Exton, PA 19341, USA

    John R. Ciallella

  5. Brigham and Women’s Hospital, Center for Experimental Therapeutics and Reperfusion Injury, Harvard University, Boston, MA 02115, USA

    William B. Gorsuch

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  1. David C. Fritzinger
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  2. Brian E. Hew
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  3. June Q. Lee
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  4. James Newhouse
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  11. Carl-Wilhelm Vogel
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    Fritzinger, D.C. et al. (2008). Derivatives of Human Complement Component C3 for Therapeutic Complement Depletion: A Novel Class of Therapeutic Agents. In: Lambris, J. (eds) Current Topics in Complement II. Advances in Experimental Medicine and Biology, vol 632. Springer, New York, NY. https://doi.org/10.1007/978-0-387-78952-1_21

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