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The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T cell dependent tumor immunity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
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2015 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 5, 1115-1126 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013. Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 has been investigated in human and murine in vitro models. The in vivo effect has been investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse. Results: Activation of dendritic cells (DCs) by ADC-1013 results in up-regulation of the co-stimulatory molecules CD80 and CD86, and secretion of IL-12. ADC-1013 also activates dendritic cells from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated dendritic cells induce antigen-specific T cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant anti-tumor effects and long-term tumor-specific immunity. Further, ADC-1013 demonstrates significant anti-tumor effects in a human bladder cancer transplanted into immunodeficient NSG mice. Conclusions: Our data demonstrate that ADC-1013 induces long-lasting anti-tumor responses and immunological memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.

Place, publisher, year, edition, pages
2015. Vol. 21, no 5, 1115-1126 p.
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-239514DOI: 10.1158/1078-0432.CCR-14-0913ISI: 000351982800025PubMedID: 25316820OAI: oai:DiVA.org:uu-239514DiVA: diva2:774775
Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2017-12-05Bibliographically approved
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)
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Supervisors
Available from: 2017-10-04 Created: 2017-09-07 Last updated: 2017-10-18

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Mangsbo, Sara MTötterman, Thomas H

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