Immunogenic response to anti-TNF therapeutics: defining the role of protein glycosylation

Commercial partner: Ludger Ltd

Anti-TNF therapies, in use for over 20 years in inflammatory bowel disease (IBD) management, continue to be widely regarded as first-line biological therapy in Crohn’s disease. However, almost half of the patients who respond will lose clinical benefits within the first year due to development of antibodies against the drug molecule. These anti-drug antibodies are correlated with lower drug levels and treatment failure.

It is established that genetic predisposition related to antigen-presentation to the immune system is associated with the development of antibodies to anti-TNF antibody drugs. Two extremely prevalent (40% in general population) extended genetic signatures in the HLA-DQ region have recently been implicated as associated with treatment failure, and probably causal for the development of drug immunogenicity. These gene signatures encode proteins (called human leukocyte antigens, short “HLA”) that present fragments of “foreign” proteins (here the drug molecule) to the immune system on the cell surface. Therefore, their association with the development of an antibody response suggests that particular portions of these drugs are being processed and presented by HLA to the patient’s immune systems, which in turn stimulates the production of antibodies against the drug itself.

We are aiming to decipher the mechanism of anti-TNF drug-induced antibody production, and, on the basis of these findings, suggest rational alterations to existing anti-TNF drug molecules in order to minimize drug-adverse immunogenic effects resulting in an improved efficiency and longevity of anti-TNF patient treatments. We will systematically investigate which drug fragments are presented by the HLA haplotypes indicated in treatment failure using assays that utilize primary monocyte derived dendritic cells which are pulsed with the anti-TNF drug. The identified T cell antigens will be tested for their reactivity in immune assays directly in blood of patients. Importantly, we will work closely with Ludger Ltd. In order to accurately profile the glycan-modified drug antibody residues and monitor alterations to the glycoprofile during antigen processing and presentation.

Finally, we will map the detailed IgG patient antibody profile. Together with established technology at Ludger Ltd. we will enrich drug-specific antibodies from patient blood and decode both the percentages of IgG subclasses reactive to the drug, and the associated molecular amino acid sequence, and glycan profiles. Differences in sequence and glycan profile between the patient antibodies and drug antibody will indicate drug immune reactivity and a likely associated lack of tolerance.

We will further interrogate immune reactivity of identified molecular differences in T cell assays using PBMC from patients who respond to drug treatment and those who failed.

This project will map the immune visibility of anti-TNF drugs and establish a causal relationship between the immune-reactive areas of the drug, and the associated patient drug-specific T cell and antibody response. These data will ultimately help to suggest rational alterations to the drug sequence, offering a route to improved immune tolerance of antibody therapeutics as a whole.

Apply using course: DPhil in Clinical Medicine

MRC INDUSTRIAL CASE STUDENTSHIPS 2025

Designed to nurture the academic entrepreneurs of the future, the Enterprise studentship programme offers a stimulating educational experience as part of the Oxford-MRC DTP cohort, with the additional benefit of working closely with an industrial partner. This will provide entrepreneurial training opportunities and an insight into how commercial science is conducted alongside a superb academic base within the University. Students will work for at least 3 months in the associated company.

ELIGIBILITY

They are open to both UK and non-UK nationals and will follow the UKRI student eligibility requirements. UKRI will normally limit the proportion of international students appointed each year through individual training grants to 30% of the total intake each year.

FUNDING PACKAGE

Each iCASE studentship is fully-funded – it includes four years of stipend at the UKRI stipend level + £2,500 p.a., course fees, and a generous research training support grant.

APPLICATIONS DEADLINE

Applications must be received by 12 noon (UK time) Tuesday 3 December 2024. Details on entry requirements and how to apply can be found below.

For details of entry requirements please go to the Oxford-MRC DTP iCASE 2025 Projects page.

HOW TO APPLY

Before applying for this project we recommend you contact the lead supervisors for informal discussion.

To make a formal application, please complete the University’s online application form for the DPhil course specified under the project description above. Please indicate the iCASE project clearly by inserting ‘iCASE’ before the project title and by using the reference code iCASE. You will need to provide a personal statement (500 words max if applying for a project hosted by one of Medical Sciences departments – please note that this limit might be different if a project is hosted by one of MPLS departments in which case follow their requirement) detailing your interest and fit for the studentship. Note that no project proposal is required for the iCASE studentship applications.

If you wish to apply for a combination of iCASE and other projects within the hosting department, this can be done on the same application form (max number of projects you can apply for on one application depends on the department you wish to apply to). If you wish to apply for iCASE projects within different departments, you will have to make separate applications directly through those departments.

If you have any queries about the iCASE application process (questions about the project should be directed to the lead supervisor), please email mrc@medsci.ox.ac.uk.