Protein Hydras: Enhancing the Cytotoxic Potential of Antibody Drug Conjugates (ADC) (360G-Wellcome-209171_Z_17_Z)

£250,000

Antibody drug conjugate (ADC) development has been hindered by synthetic strategies which result in heterogeneous mixtures of products each with their own pharmacokinetic profile. Whilst more drug per antibody molecule, the drug-to-antibody ratio (DAR), is preferable for cytotoxicity, the different aggregation potentials and pharmacokinetics of these higher DAR species typically results in reduced efficacy and non-specific toxicity. Using both chemistry and biology, my aim is to overcome the limit on DAR associated with the site-specific labelling. The project will focus on two principal areas: (a) the development of heterotrifunctional linkers, based on my previous work (Beal et al., 2012), which will enable site-specific DAR increase and investigation of drug synergies; and (b) exploitation of protein kinases as novel tools for the site-selective modification of proteins via the transfer of modified phosphates from gamma-modified ATP analogues. By combing these novel technologies with existing site-specific modification methods including disulfide bridging and unnatural amino acid incorporation, an assessment of these new materials against previous generations of ADC and commercial ADC will be undertaken. This research will be a step change in ADC development and enable a new generation of ADCs with a greater cytotoxic potential than previous iterations and therefore enhanced clinical outcomes.

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Grant Details

Amount Awarded 250000
Applicant Surname Beal
Approval Committee Basic Science Interview Committee
Award Date 2017-11-08T00:00:00+00:00
Financial Year 2017/18
Grant Programme: Title Sir Henry Wellcome Postdoctoral Fellowship
Internal ID 209171/Z/17/Z
Lead Applicant Dr David Beal
Partnership Value 250000
Planned Dates: End Date 2022-08-01T00:00:00+00:00
Planned Dates: Start Date 2018-08-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East
Sponsor(s) Prof Christopher Smales