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