(MRC CASE) Assessment of human placental barrier pharmacokinetics of biomolecular therapeutics

About the Project

Biopharmaceuticals are increasing in prominence as targeted therapies to address chronic healthcare conditions. Women of childbearing age with chronic inflammatory and other conditions would benefit enormously from being able to continue to medicate throughout pregnancy (1), but there are concerns of potential effects on fetal growth and development. The interface between the maternal and fetal circulatory systems includes the capacity to selectively transport IgGs and albumin across the placental barrier (2). This transfer involves specialist receptor-mediated uptake process, which might also be utilised by albumin bound therapeutics, including monoclonal antibody and engineered albumin-binding drug-carrier formats, potentially exposing the fetus to maternal medications.

The Food and Drug Administration of North America, a regulatory agency, recently announced a directive to encourage the ending of animals used in pharmaceutical toxicology testing (3). The first tranche of consideration will be the removal of non-human primates, which is the only current regulated model capable of evaluating the safety of monoclonal antibody therapies in pregnancy.

This PhD project focuses on understanding the capacity and uptake mechanisms of different formats of monoclonal antibody therapeutics, with special focus on albumin-associated therapeutics within and across the human placental barrier, using ex vivo fresh human placental tissue explants and ex vivo dual perfusion (4,5). It offers an excellent opportunity to work with industry, providing experience in the design and exploration of the relationship between differing monoclonal antibody and albumin structural formats and receptor-mediated placental pharmacokinetic capacity (6). Applied mathematical modeling will be drawn from real human tissue experimental data. In addition, the study could possibly include the use of spatial transcriptomics to assess the landscape of expression and polarity of receptor mediated mechanisms involved in albumin-binding molecular formats within the placental barrier. The successful candidate will work closely with a team from UCB comprising antibody and disease area experts (Dr Anthony Shock & Dr Joe Rastrick) and clinical pharmacologists (Dr Rocio Lledo-Garcia and Dr Pinky Dua), as well as a Dr Paul Brownbill (Placental Physiologist) and Dr Eleanor Doman (Applied Mathematician) at the Division of Developmental Biology & Medicine, University of Manchester (St Mary’s Hospital). An industrial placement at UCB (Slough, UK) will form part of this program to undertake the molecular design and preparation of tool antibodies and other reagents for physiological and modelling investigations. This innovative industrial project would be suited to a candidate interested in pursuing a career in bioengineering and pharmacology.

Entry Requirements

Applicants should hold (or be about to obtain) a First or Upper Second class (2:1) UK honours degree, or international equivalent, in a relevant subject.

Application Guidance

Candidates must contact the primary supervisor before applying to discuss their interest in the project and assess their suitability.

Apply directly via this link: OAA Applicant Portal or on the online application portal, select MRC DTP PhD as the programme of study.

You may apply for up to two projects within this scheme. To do so, submit a single online application listing both project titles and the names of both main supervisors in the relevant sections.

Please ensure that your application includes all required supporting documents: Curriculum Vitae (CV), Supporting Statement, Academic Certificates and Transcripts.

Incomplete or late applications will not be considered.