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Antibody-drug conjugates (ADCs) for the treatment of solid tumours


Project Description

An Antibody-Drug Conjugate (ADC) comprises an antibody targeted toward a tumour cell surface antigen, coupled through a chemical linker to a highly-cytotoxic drug. ADCs take advantage of the selectivity of monoclonal antibodies for their antigens to deliver a highly-toxic chemical agent directly to cancer cells. Once the ADC complex is internalized, the toxic payload is released, killing the cancer cells. Six ADCs are approved, five for the treatment of hematopoietic cancers and one for breast cancer. Approved ADCs are coupled through a chemical linker to a highly-cytotoxic small-molecule payload (e.g. tubulin inhibitor). However, cancer cells are frequently resistant to these drugs. We hypothesize that if a toxic drug could be selected to be one that cancer cells are highly-susceptible, and it can be delivered specifically to tumours, effectiveness may be enhanced.

The aim of this PhD project will be to design novel ADCs combining monoclonal antibodies seeking out melanoma cells, with cancer-toxic drugs which attack vital cancer cell signals. ADCs will recognise chondroitin sulfate proteoglycan 4 (CSPG4), a cell surface glycoprotein highly-expressed by >70% of melanomas. CSPG4 has restricted and low normal tissue distribution, important for limiting on-target toxicities of ADCs, and participates in melanoma pathogenesis and progression through activation of key signalling pathways. We hypothesise that we conjugate small doses of inhibitors targeting cancer-promoting pathways (e.g. RAS), which, guided by antibody specificity to CSPG4, can be delivered more specifically to tumours, reducing drug exposure in other organs and improving the drug’s therapeutic index by concentrating inhibitors inside cancer cells with ADC internalisation.

Project details
Year 1: Bioengineering antibodies linked to cancer pathway inhibitors, confirming antigen specificity (antibody:antigen binding by ELISA against recombinant antigens and flow cytometry on tumour antigen-expressing and non-expressing cancer cells and non-malignant cells) and antibody/ADC internalisation studies using reporter assays and confocal microscopy.
Year 2: In vitro efficacy and safety assays, cell viability (MTT/MT), clonogenic (e.g. crystal violet), cell invasion/migration (transwell), and IncuCyteTM live-cell assays.
Years 3-4: In vivo efficacy and the impact of ADCs on cancer signalling pathways, e.g. molecular, proteomic and cell biology assays (e.g. RT-PCR, Western blotting, Proteome Profiler Human Phospho-Kinase Arrays). ADCs displaying combined cytotoxicity, selectivity and interfering with cancer pathways will be evaluated for anti-tumour activity in human tumour xenograft mouse models and in immune competent mouse cancer models.

We aim to identify the most-promising ADC to be developed towards clinical testing. This project is designed to train the next generation of antibody and ADC therapeutics specialists and would suit graduates in chemistry, biomolecular sciences (e.g. biochemistry, immunology) and molecular biology who are interested in antibody engineering, functional analyses and translational science.

Potential research placements

1.Tumour selective targeting of oncogene mutant cancers, supervised by Julian Downward and senior lab members (Miriam Molina-Arcas and David Hancock), Francis Crick Institute

2.Monitoring kinetics and tumour localization of antibodies and antibody-drug conjugates in mouse cancer models. Biological Research Facility Science Technology Platform, supervised by Thomas Snoeks and Julian Downward, Francis Crick Institute

3.Conjugation chemistry and novel linking of novel payloads to antibodies. the Peptide Chemistry Science Technology Platform supervised by Nicola O’Reilly and Julian Downward, Francis Crick Institute.

Funding Notes

Only EU / UK students are eligible for this funding

References

1. Cheung, A. et al. Anti-Folate Receptor Alpha-Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer. Clin Cancer Res; 2018, 24(20): 5098-5111.
2. Hoffmann, R. M. et al. Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs). Oncoimmunology; 2017, Nov 20, 7(3).
3. Cheung, A. et al. Targeting folate receptor alpha for cancer treatment. Oncotarget; 2016, 7(32): 52553-52574.
4. Ilieva, K. M. et al. Functionally Active Fc Mutant Antibodies Recognizing Cancer Antigens Generated Rapidly at High Yields. Front Immunol; 2017, 8: 1112.
5. Lionarons, D.A., et al. RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance. Cancer Cell; 2019, 36 (7): 68-83.

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