Functional actin regulatory antibodies as in vivo expressed biologics

A fully funded AstraZeneca PhD studentship is available, commencing in October 2022, to investigate whether antibodies targeting actin regulatory proteins have potential as in vivo expressed biologics.  This project is located 50% at AstraZeneca (AZ) and will make use of AZ's considerable experience in developing antibody therapeutics.

The actin cytoskeleton is critical for cell function and alterations in its regulation are implicated in multiple disease pathways, including immunological diseases, kidney disease, neurodevelopmental defects and cancer.  Actin filaments are highly dynamic, assembling into multiple distinct networks that includes filopodia; thin actin rich finger-like protrusions essential for sensing and responding to external stimuli.  The studentship project builds on a successful collaboration between the Dobson and Gallop groups: a phage display screen on the filopodia-like structures cell-free system identified a panel of antibodies with high affinity and specificity that produce distinct changes in actin assembly in vitro [1,2].

This project aims to test the utility of the antibodies in cellular models, by optimising their design and testing efficacy on measures of actin cytoskeletal activity.  Starting with the antibodies that recognise SNX9 [2], the student will test the expression and stability of single chain and IgG antibodies and fragments in cell lines, by transient transfection or AAV methods.  The student will establish commonly used cellular assays for endocytic uptake and cell migration, such as EGF uptake, scratch and transwell migration assays.  Antibody engineering and delivery methods will take place within the AZ/Dobson lab and imaging and effects on the actin cytoskeleton will take place in the Cambridge/Gallop lab.

Year 1: Determine the expression and localisation of antibody constructs by introduction into cells followed by western blotting and high-resolution imaging.

Year 2: Measure and characterise the effect on cell migration and endocytic uptake using established markers compared to siRNA of SNX9, and on the filopodia-like structure system for novel antibody constructs.

Year 3: Test additional antibodies within a similar pipeline and consider further specific preclinical models and delivery system. 

The student will receive a tailored career development programme designed to broaden their research and professional skills and the opportunity to participate in training and cohort building events with AZ programme and other students.  In addition to her/his AZ and University supervisors, each PhD student will also have an advisor and a postgraduate thesis panel comprising three members of faculty, two of which are chosen by the student. Our PhD programmes offer many opportunities for both specialised training and the acquisition of transferable skills.

Applicants should have or shortly expect to obtain a minimum of a UK II.i Honours Degree (or equivalent) in Biochemistry or a related subject.  We are looking for highly motivated, enthusiastic and industrious individuals who are capable of thinking and working independently.  The studentships are available to students who meet the UK residency requirements.  Further information about your fee status can be found at the following website: http://www.graduate.study.cam.ac.uk/finance/fees/what-my-fee-status.

Applications: http://www.graduate.study.cam.ac.uk/how-do-i-apply. Fully completed applications (including references) must be submitted by the deadline. Please search in the Course Directory for “Biochemistry” PhD studentships, selecting course code BLBI22 as the programme of study. In addition to the application please email a covering letter (max two A4 pages) highlighting (a) your research interests, (b) what you hope to achieve from the programme, (c) your career aspirations beyond the programme, and (d) why you wish to undertake this PhD before the deadline to [Email Address Removed].

Funding: A stipend (currently £18,500 pa) will be provided for up to 3.5 years with effect from 1 October 2022. This funding also covers the University Composition Fee and Maintenance, and an allowance for consumables. 

Fixed-term: The funds for this post are available for up to 3.5 years.

If you have any questions, please in the first instance forward your enquiry to our Postgraduate Admissions Administrator at [Email Address Removed].

The closing date for applications is 12 noon on 31 January 2022.