Unlocking new drug targets through antibody-targeted protein degradation

Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although PROTACs can be highly effective against a wide variety of targets, most degraders reported to date display limited intrinsic tissue selectivity, and do not discriminate between cells of different types. We recently reported a novel strategy for selective protein degradation in a specific cell type with one of the first antibody-PROTAC conjugates, demonstrating antigen-dependent degradation of a target protein specifically in HER2-positive breast cancer cells (ACS Chem. Biol. 2020, 1306). These studies demonstrated proof-of-concept for tissue-specific degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.

This project brings together innovations in targeted protein degradation with the world-leading expertise of ADC Therapeutics in preclinical and clinical antibody-drug conjugate (ADC) development (https://www.adctherapeutics.com/) to discover a new generation of targeted protein degraders as novel ADC payloads. You will push the boundaries of ADC design, exploiting new modalities including high-affinity peptide-based degraders for intractable targets, molecular glues, and autophagy- or lysosome-targeting compounds. You will combine these payloads with clinical grade ADC linker design and monoclonal antibodies to enable precise release of degraders targeted to specific tissue types across a range of disease indications, with an initial focus on cancer.

This studentship would suit a talented and motivated chemist or chemical biologist who is passionate about research at the interface with biomedicine, and with a strong interest in targeted protein degradation and novel drug modalities. Applicants should have an outstanding academic background in chemistry or a closely related area. Training will be provided in all relevant areas (synthesis, bioconjugations, cell biology, etc.), but previous lab experience in synthesis, chemical biology or protein chemistry would an advantage. The successful applicant will undertake research at the £170M state-of-the-art Molecular Sciences Research Hub and with ADC Therapeutics at the I-HUB, co-located at Imperial's new White City Campus.

Addressing UK skills demand: The most important impact of the CDT will be to train a new generation of Chemical Biology PhD graduates (~80) to be future leaders of enterprise, molecular technology innovation and translation for academia and industry. They will be able to embrace the life science's industrialisation thereby filling a vital skills gap in UK industry. These students will be able to bridge the divide between academia/industry and development/application across the physical/mathematical sciences and life sciences, as well as the human-machine interfaces. The technology programme of the CDT will empower our students as serial inventors, not reliant on commercial solutions.
CDT Network-Communication & Engagement: The CDT will shape the landscape by bringing together >160 research groups with leading players from industry, government, tech accelerators, SMEs and CDT affiliates. The CDT is pioneering new collaboration models, from co-located prototyping warehouses through to hackathons-these will redefine industry-academic collaborations and drive technology transfer.
UK plc: The technologies generated by the CDT will produce IP with potential for direct commercial exploitation and will also provide valuable information for healthcare and industry. They will redefine the state of the art with respect to the ability to make, measure, model and manipulate molecular interactions in biological systems across multiple length scales. Coupled with industry 4.0 approaches this will reduce the massive, spiralling cost of product development pipelines. These advances will help establish the molecular engineering rules underlying challenging scientific problems in the life sciences that are currently intractable. The technology advances and the corresponding insight in biology generated will be exploitable in industrial and medical applications, resulting in enhanced capabilities for end-users in biological research, biomarker discovery, diagnostics and drug discovery.
These advances will make a significant contribution to innovation in UK industry, with a 5-10 year timeframe for commercial realisation. e.g. These tools will facilitate the identification of illness in its early stages, minimising permanent damage (10 yrs) and reducing associated healthcare costs. In the context of drug discovery, the ability to fuse the power of AI with molecular technologies that provide insight into the molecular mechanisms of disease, target and biomarker validation and testing for side effects of candidates will radically transform productivity (5-10 yrs). Developments in automation and rapid prototyping will reduce the barrier to entry for new start-ups and turn biology into an information technology driven by data, computation and high-throughput robotics. Technologies such as integrated single cell analysis and label free molecular tracking will be exploitable for clinical diagnostics and drug discovery on shorter time scales (ca.3-5 yrs).
Entrepreneurship & Exploitation: Embedded within the CDT, the DISRUPT tech-accelerator programme will drive and support the creation of a new wave of student-led spin-out vehicles based on student-owned IP.
Wider Community: The outreach, responsible research and communication skill-set of our graduates will strengthen end-user engagement outside their PhD research fields and with the general public. Many technologies developed in the CDT will address societal challenges, and thus will generate significant public interest. Through new initiatives such as the Makerspace the CDT will spearhead new citizen science approaches where the public engage directly in CDT led research by taking part in e.g hackathons. Students will also engage with a wide spectrum of stakeholders, including policy makers, regulatory bodies and end-users. e.g. the Molecular Quarter will ensure the CDT can promote new regulatory frameworks that will promote quick customer and patient access to CDT led breakthroughs.