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Synthesis and Study of MUC1-Based Anti-tumor Vaccines

Karmakar, Partha
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1449750902

Abstract Details

2015, Doctor of Philosophy, University of Toledo, Chemistry.
It is important to obtain CD8+ T cell activation in the course of developing a potent anti-tumor vaccine. CD8+ T cell response to extracellular antigen is generated by processing of the extracellular antigen by antigen presenting cells (APCs). This step is followed by cross presentation of the corresponding epitope to the CD8+ T cell receptors via MHC class I molecules. Cross presentation can be facilitated by efficient antigen uptake via immune-complex-mediated maturation of the APCs. It is well known that vaccination with tumor associated cancer antigen (TACA)-containing MUC1 peptide with the variable number tandem repeat (VNTR) sequence can break self-tolerance in humanized MUC1 transgenic mice. We hypothesized that a MUC1 sequence TSAPDT(GalNAc)RPAPGSTAPPAHGV that contains a CD8+ T cell epitope delivered on a targeted liposome surface could enhance antigen uptake. Anti-rhamnose antibodies are some of the most abundant naturally occurring antibodies found in humans. Our liposomes contain L-Rhamnose (Rha) epitopes displayed on their surface that can facilitate the natural antibody-dependent immune-complex formation and antigen uptake mechanism for better antigen presentation. To test this hypothesis, synthesis of a 20 amino acid MUC1-Tn sequence, TSAPDT(GalNAc)RPAPGSTAPPAHGV was performed by solid phase peptide synthesis (SPPS) and a Toll-like receptor ligand (TLRL) was covalently attached to it by Cu(I)-assisted click chemistry. The 20 amino acid MUC1 sequence contained B cell, CD4+ T cell, and CD8+ T cell epitopes. The TLRL-MUC1-Tn vaccine was formulated onto liposomes that consisted of TEG-cholesterol or Rha-TEG-cholesterol and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) with a total lipid concentration of 30 mM. The vaccine was tested on groups of female C57BL/6 mice. Some of the groups of mice were immunized with Rha-Ficoll prior to vaccination, in order to generate anti-Rha antibodies in those mice. On vaccination, a 10 fold higher antibody production was observed against TLRL-MUC1-Tn by the anti-Rha expressing mice group that received the Rha-vaccine compared to the other groups of mice. The CD8+ T cell responses for the anti-Rha antibody expressing mice group that received the Rha-vaccine were higher compared to the others when they were evaluated by measuring CD8+ T cell proliferation, IFN¿ production and cytotoxicity against a cancer cell line. These results indicate that antigen uptake was facilitated by the anti-Rha dependent immune complex formation that resulted efficient antigen uptake and the CD8+ T cell epitope was processed and presented by the APCs.
Steven Sucheck, Prof. (Advisor)
Katherine Wall, Prof. (Committee Member)
142 p.
Chemistry; Immunology

Recommended Citations

Citations

  • Karmakar, P. (2015). Synthesis and Study of MUC1-Based Anti-tumor Vaccines [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1449750902

    APA Style (7th edition)

  • Karmakar, Partha. Synthesis and Study of MUC1-Based Anti-tumor Vaccines. 2015. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1449750902.

    MLA Style (8th edition)

  • Karmakar, Partha. "Synthesis and Study of MUC1-Based Anti-tumor Vaccines." Doctoral dissertation, University of Toledo, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1449750902

    Chicago Manual of Style (17th edition)

toledo1449750902
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© 2015, all rights reserved.
This open access ETD is published by University of Toledo and OhioLINK.