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Therapeutic peptidomimetic strategies for costimulation blockade in multiple sclerosis and transplantation / conformational peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo

Allen, Stephanie D.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1150479940

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Ohio State Biochemistry Program.
Cognate interactions between immune effector cells and antigen presenting cells (APCs) govern immune responses. Specific signals occur between the T cell receptor, peptide and APCs as well as nonspecific signals between pairs of costimulatory molecules. Costimulation signals are required for full T cell activation and are thought to regulate T cell responses as well as other aspects of the immune system, have been extensively studied as a way to control many autoimmune diseases and downregulate inflammatory reactions. The CD28:B7 and the CD40:CD40L families of molecules are considered to be critical costimulatory molecules and have been studied extensively. Using experimental autoimmune encephalomyelitis (EAE), and transplantation models, we developed an approach that utilizes peptides for blockade of costimulatory molecules. Our laboratory has designed blocking peptide mimics that retain the functional binding area of the parent protein while reducing the overall size and are able to block signal transduction. We present data showing the ability of costimulatory molecule peptide mimics to suppress disease. HER-2/neu is the preferred dimerization partner for the ErbB receptor family. Pertuzumab (Omnitarg) is a humanized monoclonal antibody against the HER-2/neu dimerization region that inhibits HER-2/neu mediated signaling. Peptide vaccines that elicit conformation-dependent, high affinity antibodies have the added benefit of immunological memory and therefore do not require frequent dosing as monoclonal antibody treatment does, in addition to decreasing the chance of the patient developing resistance to treatment. Based on the 3-D structure of the complex of pertuzumab with HER-2/neu, we have designed a conformational peptide construct to mimic the dimerization loop of the HER-2/neu receptor. This construct was shown to elicit high affinity peptide antibodies that disrupt a number of signaling pathways including HER-2/neu specific inhibition of cellular proliferation, cytoplasmic phosphorylation, and ADCC activity. The chimeric peptide constructs were also able to abrogate transplantable tumor growth in FVB/n and Balb/c mice as well as spontaneous tumor growth in VEGF+/-Neu2-5+/- mice, suggesting a novel vaccine candidate for immunity of breast cancer.
Pravin Kaumaya (Advisor)
126 p.
Costimulation; CD28; CD40L; Multiple Sclerosis; Transplantation; Peptide Mimics; HER-2/neu; Breast Cancer; Peptide Vaccines

Recommended Citations

Citations

  • Allen, S. D. (2006). Therapeutic peptidomimetic strategies for costimulation blockade in multiple sclerosis and transplantation / conformational peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1150479940

    APA Style (7th edition)

  • Allen, Stephanie. Therapeutic peptidomimetic strategies for costimulation blockade in multiple sclerosis and transplantation / conformational peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1150479940.

    MLA Style (8th edition)

  • Allen, Stephanie. "Therapeutic peptidomimetic strategies for costimulation blockade in multiple sclerosis and transplantation / conformational peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1150479940

    Chicago Manual of Style (17th edition)

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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.
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