David C. Fritzinger, PhD
	Associate Professor (Specialist), Cancer Research Center of Hawai‘i; Associate Graduate Faculty, Cell and Molecular Biology Program Ph.D. (Biochemistry). University of Massachusetts at Amherst dfritzin@crch.hawaii.edu

Publication list via PubMed

My primary research interest is the study of protein structure/function relationships, using the third component of complement (C3) as a model system. Complement C3 is a multifunctional protein that plays a major role in all three complement activation pathways, and is the central component in the activation and regulation of the alternative pathway of complement. The active form of C3, C3b binds another complement protein, factor B (which is then proteolytically cleaved), to form the C3 converytase (C3b,Bb) that serves to activate other C3 and C5 molecules by removing a small peptide (the anaphylatoxins C3a and C5a). The activation of C3 results in a major conformational change in the C3 molecule exposing a number of protein binding sites. The C3 convertase is subject to regulation by a number of other complement proteins, such as factors H and I, and Complement receptors CR1, CF2, CR3, etc. These proteins serve to regulate complement by either causing dissociation of the C3 convertase or cleaving of C3b to inactivate it.

Cobra venom contains a structural and functional analog of C3, Cobra Venom Factor (CVF). Like the active form of C3 (C3b), CVF is able to form a C3 convertase by binding factor B. However, this convertase is several orders of magnitude more stable than the C3-containing enzyme, and is not subject to regulation by other complement proteins. Therefore, it is able to exhaustively activate serum complement, both in vitro and in vivo. We are using the relationships between CVF and C3 proteins to define the structural elements required for the unique CVF functions. For example, we have shown that the substitution of CVF sequences near the C-terminus of the large (α) chain of human C3 results in a protein with many CVF-like characteristics, including the ability to form an active, stable C3 convertase enzyme. However, unlike CVF, the hybrid protein does not activate C5, thus eliminating most, if not all of the harmful side effects of CVF treatment of animals. One protein we are studying, HC3-1496, has been shown to be non-toxic in primates, even when the dose is at least four times the dose needed to completely deplete serum complement in the animal. HC3-1496 has also been shown to be effective as a therapeutic in a number of animal models of disease, including ischemia/reperfusion injuries (such as heart attacks), age related macular degeneration, and paroxysmal nocturnal haemoglobinuria (PNH, in an in vitro model). In a mouse model, collaborators in George Weine's lab have demonstrated that treatment with HC3-1496 drastically increases the efficacy of monoclonal antibody treatment of B-cell lymphomas. Finally, we are working with a crystallography group (Piet Gros at Utrecht University, the Netherlands) that has elucidated the structure of the CVF-containing pre-convertase, which should be very similar to the C3b-containing convertase. This is a very important finding in complement biology that will increase our understanding of the structures involved in formation of this enzyme that is central to the complement cascade.

In addition, I have an interest in DNA sequencing technology and in genomics, as well as in methods for studying gene regulation and gene expression.

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Selected Publications

Fritzinger D. C., Hew B. E., Thorne M., Pangburn M. K., Janssen B. J., Gros P. and Vogel C. W. (2009) Functional characterization of human C3/cobra venom factor hybrid proteins for therapeutic complement depletion. Dev Comp Immunol 33, 105-116.

Fritzinger D. C., Hew B. E., Lee J. Q., Newhouse J., Alam M., Ciallella J. R., Bowers M., Gorsuch W. B., Guikema B. J., Stahl G. L. and Vogel C.-W. (2008) Derivatives of human complement C3 for therapeutic complement depletion: A novel class of therapeutic agents. In Current Topics in Complememnt II (Edited by Lambris J. D.). Springer, Philadelphia, USA (in press).

Vogel C. W. and Fritzinger D. C. (2007) Humanized cobra venom factor: experimental therapeutics for targeted complement activation and complement depletion. Curr Pharm Des13, 2916-26.

Fritzinger D. C., Hew B. E., Lee J. Q., St. John W., Scaife M., Wilson S. and Vogel C.-W. (2008) Human C3/cobra venom factor hybrid proteins for therapeutic complement depletion: in vivo activity and lack of toxicity in primates. Mol  Immunol45, 4112 (Abstract presented at XXII International Complement Workshop, Basel, Switzerland, Sept. 29-Oct. 3, 2008).

Wang, S.-Y., Cagley, J., Fritzinger, D.C., Vogel, C.-W., St. John, W., and Weiner, G.J. 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. (To be presented at the Annual Society of Hematology Meeting in San Francisco, CA, 12/08).

Janssen B. J., Gomes L., Fritzinger D. C., Vogel C.-W., Meeldijk H. M., Svengun D., Koning R., Koster A. and Gros P. (2008) Structure of factor B in complex with cobra venom factor gives insights into convertase formation. Mol Immunol45, 4096. (Abstract presented at the XXII International Complement Workshop, Basel, Switzerland, Sept. 29-Oct. 3, 2008).

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