Functional characterization of human C3/cobra venom factor hybrid proteins for therapeutic complement depletion

Fritzinger, David C.; Hew, Brian E.; Thorne, Mike; Pangburn, Michael K.; Janssen, B.J.C.; Gros, Piet; Vogel, Carl‐Wilhelm

doi:10.1016/j.dci.2008.07.006

Cited by 28 publications

(43 citation statements)

References 54 publications

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“…To address this issue, we engineered a hybrid protein in which a portion of the ␣ chain at the C terminus of human C3 is replaced with homologous regions of the CVF ␤ chain crucial to activity (HC3-1496). 20,30 Using both CVF and HC3-1496, we found that depletion of complement in the 38C13 model improved the efficacy of mAb therapy. Complement depletion after CVF lasted longer than that seen with HC3-1496; however, the enhanced therapeutic response was similar for both agents, suggesting prolonged depletion of complement may not be necessary to enhance the therapeutic response to mAb therapy.…”

Section: Discussionmentioning

confidence: 99%

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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

Wang

Veeramani

Racila

et al. 2009

Blood

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124

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Section: Discussionmentioning

confidence: 99%

“…The plasmid preparation, protein expression, and purification were performed essentially as previously described. 20 …”

Section: Antibodies and Reagentsmentioning

confidence: 99%

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

Wang

Veeramani

Racila

et al. 2009

Blood

Self Cite

124

View full text Add to dashboard Cite

“…One of the limits of this treatment alternative in the clinic is the high immunogenicity of this compound (28). However, a human C3 hybrid, containing crucial regions of the CVF b chain (so-called humanized CVF or HC3-1496), has been created for this purpose (29). It will be of great interest to test other complement inhibitors currently in development in various solid tumor models to determine whether sustained treatment will favor the induction of an improved tumorspecific immune response and promote CD8 þ T-cell expansion.…”

Section: The Complement System Limits Systemic T-cell Activationmentioning

confidence: 99%

Transient Complement Inhibition Promotes a Tumor-Specific Immune Response through the Implication of Natural Killer Cells

Janelle

Langlois

Tarrab

et al. 2014

Cancer Immunology Research

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Although the role of the complement system in cancer development has been studied, its involvement in the development of an antitumoral immune response remains poorly understood. Using cobra venom factor (CVF) to inhibit the complement cascade via C3 molecule exhaustion in immunocompetent mice bearing B16gp33 melanoma tumors, we show that transient inhibition of the complement system allowed for the development of a more robust gp33-specific antitumoral CD8 þ T-cell response. This immune response proved to be natural killer (NK) dependent, suggesting an interaction of complement proteins with this cellular subset leading to T lymphocyte activation and enhanced cytotoxic T-cell activity against tumor cells. This study demonstrates for the first time the implication of the complement system in the development of NK-mediated cytotoxic T-cell-dependent antitumoral immune responses. The complement pathway could therefore be a potent therapeutic target to improve NK-dependent antitumoral immune responses in patients with cancer. Cancer Immunol Res; 2(3); 200-6. Ó2013 AACR.

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“…The structure showed that all the four modules of factor H interact with the C3b molecule in a discontinuous manner. On the basis of the structure (51) and previous studies (50,52), it was proposed that factor I inactivates C3b by interacting with the C3b-factor H complex at sites formed by the modules 1-3 of factor H, and C345C and complement C1r-C1s, UEGF, BMP1 domains of C3b. The VCP domains 1-4 are structurally and functionally similar to factor H modules 1-4.…”

Section: Vcp Domains Critical For Factor I Cfasmentioning

confidence: 99%

Domain Swapping Reveals Complement Control Protein Modules Critical for Imparting Cofactor and Decay-Accelerating Activities in Vaccinia Virus Complement Control Protein

Ahmad

Raut

Pyaram

et al. 2010

The Journal of Immunology

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Vaccinia virus encodes a structural and functional homolog of human complement regulators named vaccinia virus complement control protein (VCP). This four-complement control protein domain containing secretory protein is known to inhibit complement activation by supporting the factor I-mediated inactivation of complement proteins, proteolytically cleaved form of C3 (C3b) and proteolytically cleaved form of C4 (C4b) (termed cofactor activity), and by accelerating the irreversible decay of the classical and to a limited extent of the alternative pathway C3 convertases (termed decay-accelerating activity [DAA]). In this study, we have mapped the VCP domains important for its cofactor activity and DAA by swapping its individual domains with those of human decay-accelerating factor (CD55) and membrane cofactor protein (MCP; CD46). Our data indicate the following: 1) swapping of VCP domain 2 or 3, but not 1, with homologous domains of decay-accelerating factor results in loss in its C3b and C4b cofactor activities; 2) swapping of VCP domain 1, but not 2, 3, or 4 with corresponding domains of MCP results in abrogation in its classical pathway DAA; and 3) swapping of VCP domain 1, 2, or 3, but not 4, with homologous MCP domains have marked effect on its alternative pathway DAA. These functional data together with binding studies with C3b and C4b suggest that in VCP, domains 2 and 3 provide binding surface for factor I interaction, whereas domain 1 mediates dissociation of C2a and Bb from the classical and alternative pathway C3 convertases, respectively.

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Functional characterization of human C3/cobra venom factor hybrid proteins for therapeutic complement depletion

Cited by 28 publications

References 54 publications

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

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

Transient Complement Inhibition Promotes a Tumor-Specific Immune Response through the Implication of Natural Killer Cells

Domain Swapping Reveals Complement Control Protein Modules Critical for Imparting Cofactor and Decay-Accelerating Activities in Vaccinia Virus Complement Control Protein

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