Development of Cancer Immunotherapeutics Targeting Complement Regulatory Protein CD55

Bradley, Richard Grayson (2007) Development of Cancer Immunotherapeutics Targeting Complement Regulatory Protein CD55. PhD thesis, University of Nottingham.

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Abstract

CD55 is one of the complement regulatory/inhibitory proteins and is over-expressed on a wide range of solid tumours. CD55 is also known to be deposited within tumour stroma and is secreted in an active soluble form, mediated by matrix metalloproteinase-7. The complement cascade forms part of the innate immune system and culminates in cell lysis of targeted cells. As a complement regulatory protein, the primary function of CD55 is to accelerate the decay of complement components preventing formation of the membrane attack complex.

CD55 is also known to be a ligand for the T cell early activation antigen CD97, and their interaction has been shown to inhibit the proliferation of activated T cells.

This project aimed to develop anti-tumour immunotherapeutics aimed at exploiting CD55 as a tumour associated antigen. Initial strategies were to develop monoclonal antibodies, specific to identified epitopes from within the CD55 protein sequence, capable of binding, and neutralising CD55s decay accelerating activity. Developed antibodies would also have the potential to induce antibody dependent cell cytotoxicity, thus blocking CD55 protection of tumours and mediating an active anti-tumour response. Antibodies were raised specific to CD55 derived linear peptides, which have been used for the assessment of CD55 expression in breast tumour sections. Monoclonal antibodies failed to recognise natively expressed protein on viable tumour cells and alternate strategies were developed.

An effective immunotherapy for the treatment of cancer would engage both cellular and humoral mediated responses for effective clearance of target cells. In order to achieve this, a DNA vaccine incorporating a human IgG Fc tail was developed expressing the active sites of CD55, containing HLA-A*201 restricted heteroclitic epitopes. The vaccines were used to immunise HLA-A*201 HHDII transgenic mice and CD55 specific responses were assessed. One of the vaccines analysed, elicited CD55 specific antibodies capable of recognising tumour cells in vitro and also generated epitope specific CD8+ T cell mediated lysis of epitope bearing cells. The frequency of CD55 specific T cells was obtained via antigen specific IFN gamma release ELISPOT assays and the cytokine profile of responses generated was assessed via luminex analysis.

In conclusion, CD55 remains a viable target for immunotherapies aimed at CD55 bearing tumours. DNA vaccines encoding modified epitopes are capable or raising cellular and humoral responses to this antigen and further studies should be completed in order to determine anti-cancer effects in tumour bearing models.

Item Type:Thesis (PhD)
Supervisors:Durrant, Lindy
Uncontrolled Keywords:CD55, Complement Regulatory Proteins, DAF, Decay Accelerating Factor, Cancer Vaccines, Immunotherapy, Tumour Vaccines, Tumor Vaccines, Therapeutic Antibodies
Faculties/Schools:UK Campuses > Faculty of Medicine and Health Sciences > School of Molecular Medical Sciences
ID Code:258
Deposited By:Richard Bradley
Deposited On:22 Jun 2007
Last Modified:06 Feb 2009 14:43

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