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Formation ofimmune-complexes by a defined linear tetanus toxin-derived B cell epitope boosts human T cell responses to long peptides: ICs boost specific-T cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden.
Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden.
Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Enhancing T cell responses against both viral and tumor antigens requires efficient co-stimulation and directed delivery of peptide antigens into APCs. As short peptides can lead to T cell tolerance and can only be used in a specific set of patients, long peptides are considered favourable vaccine moieties from a clinical perspective as they can harbor more than one immunogenic epitope enabling a broader target population. In addition, longer peptides are not bound unselectively to MHC class I on any cell, but rather require processing and will thereby be presented to T cells in secondary lymphoid organs. However, as peptides are not actively targeted to and taken up by APCs, and the standard non-conjugated adjuvant-peptide mixtures do not ensure co-targeting of the two to the same APC. We have identified a linear tetanus-toxin derived B cell epitope that can mediate the formation of immune-complexes by the presence of circulating antibodies. Herein, we show that these complexes, improve both antigen uptake by APCs (blood monocytes and CD1c+ DCs) and thereby CD8+ T cell recall responses in a human ex-vivo blood loop system. The uptake of the peptide conjugate by blood monocytes is dependent on antibodies and the complement component C1q.  The defined linear peptide steers the immune-complex formation to a monoclonal-like complex and as a consequence we show that the number of linear tetanus sequences per T cell epitope determines the outcome of the response. We envision that this strategy can be used to facilitate active uptake of antigens into antigen-presenting cells to improve T cell responses against pathogens or cancer.

Keyword [en]
peptide conjugate, therapeutic vaccine, whole blood, immune complexes
National Category
Other Health Sciences
Research subject
Immunology; Immunology; History of Sciences and Ideas
Identifiers
URN: urn:nbn:se:uu:diva-328860OAI: oai:DiVA.org:uu-328860DiVA: diva2:1139170
Funder
Swedish Research Council
Available from: 2017-09-06 Created: 2017-09-06 Last updated: 2017-09-07
In thesis
1. Antibody- and Peptide-based Immunotherapies: Proof-of-concept and safety considerations
Open this publication in new window or tab >>Antibody- and Peptide-based Immunotherapies: Proof-of-concept and safety considerations
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of cancer immunotherapy is to eradicate tumours by inducing a tumour-specific immune response. This thesis focuses on how antibodies and peptides can improve antigen presentation and the subsequent tumour-specific T cell response. Tumour recognition by the immune system can be promoted through delivery of antigen in the form of a vaccine. One example is the development of a therapeutic peptide vaccine containing both CD4+ and CD8+ T cell epitopes. So far, peptide vaccinations have shown limited success in clinical trials and further improvements are needed, such as choice of adjuvant and T cell epitopes, as well as targeted delivery of peptides and adjuvants to the same DC.

In paper I, we describe the development of a peptide-peptide conjugate (with a tumour T cell epitope) that, via immune complex formation and FcγR binding, enhance antigen uptake and activation of DCs. The conjugate consists of three tetanus toxin-derived linear B cell epitopes (MTTE) that were identified based on specific IgG antibodies in human serum. Three MTTE peptide sequences were conjugated to a synthetic long peptide (SLP) that consists of a T cell epitope derived from the desired target tumour.

In paper II, the conjugate was evaluated in a modified Chandler loop model containing human blood, mimicking blood in circulation. The conjugate was internalised by human monocytes in an antibody-dependent manner. A conjugate containing the model CMV-derived T cell epitope pp65NLV generated recall T cell responses dependent on MTTE-specific antibodies and the covalent conjugation of the three MTTE with the SLP.

In paper III, a CD40-specific antibody was characterised for local treatment of solid tumours. The antibody eradicated bladder tumours in mice and induced T cell-mediated immunological memory against the tumour.

In paper IV, we characterised the Chandler loop model (used in paper II) for its potential use in predicting cytokine release syndrome (CRS) in response to monoclonal antibodies (mAbs). Superagonistic antibodies (e.g., OKT3) induced rapid cytokine release whereas no cytokine release was induced by antibodies (e.g., cetuximab) associated with low incidence of CRS in the clinic.

In conclusion, this thesis work demonstrates proof-of-concept of improved strategies for antibody- and peptides-based cancer immunotherapies and their potential use in multiple cancer indications.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1370
Keyword
Immune complex, conjugat, vaccine, CD40, whole blood, cytokine release syndrome
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-329038 (URN)978-91-513-0064-1 (ISBN)
Public defence
2017-10-26, Rudbecksalen, Dag hammarskjöldsväg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2017-10-04 Created: 2017-09-07 Last updated: 2017-10-18

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