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Targeting OX40 with monoclonal antibodies as a form of cancer immunotherapy

Targeting OX40 with monoclonal antibodies as a form of cancer immunotherapy
Targeting OX40 with monoclonal antibodies as a form of cancer immunotherapy
It has been well established that for an effective and controlled immune response multiple inputs are integrated. For example, the interaction of the T cell receptor (TCR) with an MHC-peptide complex alone is insufficient to cause complete T cell activation and concomitant interaction of co-stimulatory T cell receptors with their ligands is required. OX40 (CD134) and its ligand, OX40L (CD252), are members of the tumour necrosis factor receptor/tumour necrosis factor (TNFR/TNF) superfamily. Investigation into targeting such receptors with monoclonal antibodies (mAb) for use in cancer immunotherapy is ongoing, and in recent years OX40 has been shown to be a promising therapeutic target. This thesis explores the development, characterisation and therapeutic potential of a panel of novel antihOX40 mAb in a unique hOX40 knock-in (KI) mouse model.

The Antibody and Vaccine Group at the University of Southampton developed a number of anti-hOX40 mAb within the Southampton Antibody Programme (SAP) using hybridoma technology. These mAb were characterised in terms of binding domain and affinity using techniques such as flow cytometry and surface plasmon resonance (SPR) It was found that the panel of mAb all possessed a high affinity for the hOX40 receptor and binding spanned over all four extracellular domains (ECD). Their activity was then determined in vitro using proliferation assays and in vivo using a novel hOX40 KI mouse expressing human ECD and mouse intracellular domains. The immunostimulatory potential of these reagents was first assessed in an CD8+ OT-I transfer model. Subsequently, the therapeutic efficacy of these mAb were assessed using a number of mouse tumour models. Collectively the data highlighted both the importance of mAb isotype but also specific domain binding in relation to the type and strength of the anti-hOX40 mAb effector function; with mAb binding to the membrane proximal region delivering stronger agonism (T cell expansion) as mIgG1 mAb and stronger regulatory T cell (Treg) depletion as mIgG2a. Intriguingly, mAb of both isotypes were seen to eradicate established tumours, albeit through different mechanisms. Together the work in this thesis demonstrates the desired characteristics, functional effects and mechanisms of action of anti-hOX40 mAb and provides encouragement for their translation towards the clinic as potential cancer therapeutics.
University of Southampton
Griffiths, Jordana
dfd2130a-fd5b-4c17-bb7b-321dd5d24ecb
Griffiths, Jordana
dfd2130a-fd5b-4c17-bb7b-321dd5d24ecb
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Tews, Ivo
9117fc5e-d01c-4f8d-a734-5b14d3eee8dd

Griffiths, Jordana (2018) Targeting OX40 with monoclonal antibodies as a form of cancer immunotherapy. University of Southampton, Doctoral Thesis, 302pp.

Record type: Thesis (Doctoral)

Abstract

It has been well established that for an effective and controlled immune response multiple inputs are integrated. For example, the interaction of the T cell receptor (TCR) with an MHC-peptide complex alone is insufficient to cause complete T cell activation and concomitant interaction of co-stimulatory T cell receptors with their ligands is required. OX40 (CD134) and its ligand, OX40L (CD252), are members of the tumour necrosis factor receptor/tumour necrosis factor (TNFR/TNF) superfamily. Investigation into targeting such receptors with monoclonal antibodies (mAb) for use in cancer immunotherapy is ongoing, and in recent years OX40 has been shown to be a promising therapeutic target. This thesis explores the development, characterisation and therapeutic potential of a panel of novel antihOX40 mAb in a unique hOX40 knock-in (KI) mouse model.

The Antibody and Vaccine Group at the University of Southampton developed a number of anti-hOX40 mAb within the Southampton Antibody Programme (SAP) using hybridoma technology. These mAb were characterised in terms of binding domain and affinity using techniques such as flow cytometry and surface plasmon resonance (SPR) It was found that the panel of mAb all possessed a high affinity for the hOX40 receptor and binding spanned over all four extracellular domains (ECD). Their activity was then determined in vitro using proliferation assays and in vivo using a novel hOX40 KI mouse expressing human ECD and mouse intracellular domains. The immunostimulatory potential of these reagents was first assessed in an CD8+ OT-I transfer model. Subsequently, the therapeutic efficacy of these mAb were assessed using a number of mouse tumour models. Collectively the data highlighted both the importance of mAb isotype but also specific domain binding in relation to the type and strength of the anti-hOX40 mAb effector function; with mAb binding to the membrane proximal region delivering stronger agonism (T cell expansion) as mIgG1 mAb and stronger regulatory T cell (Treg) depletion as mIgG2a. Intriguingly, mAb of both isotypes were seen to eradicate established tumours, albeit through different mechanisms. Together the work in this thesis demonstrates the desired characteristics, functional effects and mechanisms of action of anti-hOX40 mAb and provides encouragement for their translation towards the clinic as potential cancer therapeutics.

Text
Jordana Griffiths FINAL Thesis - Version of Record
Restricted to Repository staff only until 15 May 2021.
Available under License University of Southampton Thesis Licence.

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Published date: September 2018

Identifiers

Local EPrints ID: 436542
URI: http://eprints.soton.ac.uk/id/eprint/436542
PURE UUID: aa3904eb-ed7f-4d5c-9e5d-223c12c0d47e
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Ivo Tews: ORCID iD orcid.org/0000-0002-4704-1139

Catalogue record

Date deposited: 12 Dec 2019 17:30
Last modified: 13 Dec 2019 01:38

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Contributors

Author: Jordana Griffiths
Thesis advisor: Mark Cragg ORCID iD
Thesis advisor: Ivo Tews ORCID iD

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