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Development of a novel plant expressed conjugate vaccine for HER2-positive breast cancer

Development of a novel plant expressed conjugate vaccine for HER2-positive breast cancer
Development of a novel plant expressed conjugate vaccine for HER2-positive breast cancer
Overexpression HER2/neu correlates with poor prognosis in many cancers, including breast cancer. HER2-specific monoclonal antibodies including Herceptin® have had significant impact on breast cancer survival rates. However, there are a number of limitations with their use, including tumour recurrence, the requirement for multiple doses and high-cost production. Vaccination, however, can provide long-term tumour specific antibodies and cellular-mediated immune responses. Here the aim was to develop a potent vaccine to target HER2.

Self-tumour antigen HER2 is poorly immunogenic due to tolerance. Previous studies using DNA vaccines demonstrated that conjugation of tumour antigens to Fragment C of tetanus toxin (FrC) broke tolerance. Here to target HER2 a novel HER2 portion ED44 was generated and conjugated to FrC. The HER2-targeting vaccine subunits were expressed using an efficient plant-based manufacturing process 'magnifection' and were available through collaboration (ICON Genetics, Germany).

Both rat and human versions were generated to study the mechanisms or for clinical application respectively. They were tested in several complementary breast cancer models including non-tolerant (TUBO, D2F2/E2) and tolerant (Balb/neuT) settings. In non-tolerant settings unconjugated ED44 was effective at inducing of protective antibody. In the tolerant model, only ED44-FrC conjugate was effective in inducing high levels of antibody and suppressing already developed tumours. Only ED44-FrC conjugate vaccine induced antibody of high affinity of a wide range of isotypes. FrC-specific T cell help induced by the conjugate vaccine was critical for effective anti-HER2 antibody.

The human ED44-FrC induced sera were able to inhibit HER2-mediated downstream signalling and induced growth inhibition of two HER2positive cell lines. Hence, the novel vaccine is a promising candidate for HER2 positive cancer treatment.

In the last chapter a novel vaccine design that included plant virus particle (PVP) was used to induce anti-HER2 cytotoxic T cells. This sets the foundation for development of this platform in the future.
Chotprakaikiat, Warayut
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Chotprakaikiat, Warayut
2f4805cc-f594-447a-b75b-25d4d2c1ebb8
Savelyeva, Natalia
804c3e15-d260-4717-9b7c-15c16ba87fc7
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Stevenson, Freda
ba803747-c0ac-409f-a9c2-b61fde009f8c

(2016) Development of a novel plant expressed conjugate vaccine for HER2-positive breast cancer. University of Southampton, Faculty of Medicine, Doctoral Thesis, 227pp.

Record type: Thesis (Doctoral)

Abstract

Overexpression HER2/neu correlates with poor prognosis in many cancers, including breast cancer. HER2-specific monoclonal antibodies including Herceptin® have had significant impact on breast cancer survival rates. However, there are a number of limitations with their use, including tumour recurrence, the requirement for multiple doses and high-cost production. Vaccination, however, can provide long-term tumour specific antibodies and cellular-mediated immune responses. Here the aim was to develop a potent vaccine to target HER2.

Self-tumour antigen HER2 is poorly immunogenic due to tolerance. Previous studies using DNA vaccines demonstrated that conjugation of tumour antigens to Fragment C of tetanus toxin (FrC) broke tolerance. Here to target HER2 a novel HER2 portion ED44 was generated and conjugated to FrC. The HER2-targeting vaccine subunits were expressed using an efficient plant-based manufacturing process 'magnifection' and were available through collaboration (ICON Genetics, Germany).

Both rat and human versions were generated to study the mechanisms or for clinical application respectively. They were tested in several complementary breast cancer models including non-tolerant (TUBO, D2F2/E2) and tolerant (Balb/neuT) settings. In non-tolerant settings unconjugated ED44 was effective at inducing of protective antibody. In the tolerant model, only ED44-FrC conjugate was effective in inducing high levels of antibody and suppressing already developed tumours. Only ED44-FrC conjugate vaccine induced antibody of high affinity of a wide range of isotypes. FrC-specific T cell help induced by the conjugate vaccine was critical for effective anti-HER2 antibody.

The human ED44-FrC induced sera were able to inhibit HER2-mediated downstream signalling and induced growth inhibition of two HER2positive cell lines. Hence, the novel vaccine is a promising candidate for HER2 positive cancer treatment.

In the last chapter a novel vaccine design that included plant virus particle (PVP) was used to induce anti-HER2 cytotoxic T cells. This sets the foundation for development of this platform in the future.

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More information

Published date: July 2016
Organisations: University of Southampton, Cancer Sciences

Identifiers

Local EPrints ID: 400684
URI: http://eprints.soton.ac.uk/id/eprint/400684
PURE UUID: dbc447f6-8faa-4787-9bb0-d5ff271efb9d
ORCID for Freda Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

Catalogue record

Date deposited: 30 Sep 2016 13:55
Last modified: 03 Jul 2018 00:35

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Contributors

Author: Warayut Chotprakaikiat
Thesis advisor: Natalia Savelyeva
Thesis advisor: Christian Ottensmeier
Thesis advisor: Freda Stevenson ORCID iD

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