Development of antibody-drug and antibody-protein conjugates for immunotherapy: novel linkers and release strategies
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
Theme: Bioscience for Health
The PhD will involve work on the chemistry of new linker strategies for antibody-drug conjugates for cancer therapy. Antibodies will be conjugated using these linkers to anti-neoplastic drugs or therapeutic toxins, or to cytokines to trigger immunogenic responses (immunotherapy).
Linkers will be developed that release the covalently bound drug or protein upon a light stimulus (UV/visible/near IR), or upon addition of a small-molecule triggering agent.
A new linker system developed for drug release will first be tested on a small molecule model system. After success at this level, the system will be adapted for use with cell penetrating peptides for cellular studies, before being tested on antibodies.
Additionally, work will be performed to develop non-cleavable antibody-protein conjugates between antibodies and cytokines for use in immunotherapy, to improve upon current fusion protein technology.
The student may also be involved in work to develop a CO releasing metalloantibody for cancer therapy, building upon work previously performed in the group investigating artificial CO releasing proteins.
ENWW:
- The PhD will involve detailed analysis of the kinetics of bioorthogonal labelling reactions
- Statistical analysis will be performed on all data obtained from cellular studies, for example assays to quantify toxicity of the designed linker and studies to quantify linker release at the target site (following conjugation of a fluorophore in the place of a drug/therapeutic protein)
- Molecular modelling may be performed to model whether a new design for a photo-triggered drug release strategy would be successful prior to synthesis
The PhD will involve work on the chemistry of new linker strategies for antibody-drug conjugates for cancer therapy. Antibodies will be conjugated using these linkers to anti-neoplastic drugs or therapeutic toxins, or to cytokines to trigger immunogenic responses (immunotherapy).
Linkers will be developed that release the covalently bound drug or protein upon a light stimulus (UV/visible/near IR), or upon addition of a small-molecule triggering agent.
A new linker system developed for drug release will first be tested on a small molecule model system. After success at this level, the system will be adapted for use with cell penetrating peptides for cellular studies, before being tested on antibodies.
Additionally, work will be performed to develop non-cleavable antibody-protein conjugates between antibodies and cytokines for use in immunotherapy, to improve upon current fusion protein technology.
The student may also be involved in work to develop a CO releasing metalloantibody for cancer therapy, building upon work previously performed in the group investigating artificial CO releasing proteins.
ENWW:
- The PhD will involve detailed analysis of the kinetics of bioorthogonal labelling reactions
- Statistical analysis will be performed on all data obtained from cellular studies, for example assays to quantify toxicity of the designed linker and studies to quantify linker release at the target site (following conjugation of a fluorophore in the place of a drug/therapeutic protein)
- Molecular modelling may be performed to model whether a new design for a photo-triggered drug release strategy would be successful prior to synthesis
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M011194/1 | 01/10/2015 | 31/03/2024 | |||
| 1795534 | Studentship | BB/M011194/1 | 01/10/2016 | 31/01/2021 | Lavinia Dunsmore |
| Description | New drugs for hard-to-treat cancers are urgently needed. Promising compounds from nature often remain underexploited as drugs for cancer treatment despite showing medicinal effects because of limiting side effects when the compounds are used inside the body. Compounds containing an ortho-quinone group are one such class of compounds. Ortho-quinones kill cancer cells by initiating a large build-up of reactive oxygen species in the tumour, however, typically fail clinical trials due to limiting blood-borne side effects. This funding enabled the development of new chemistry that can mask ortho-quinone compounds as they move through circulation, then enable their selective release at a target tumour site upon tumour-selective release. This new strategy can be used to target ortho-quinone containing compounds to the desired body tissue and limit their side effects. The strategy is modular so may be adapted depending on the cancer site, specificity and targeting required. Proof of concept of the developed strategy was demonstrated by the effectiveness of an antibody-drug conjugate containing a protected ortho-quinone payload at treating a cancer model. This work provides a strategy to open-up a new class of medicines for use in cancer therapy. The main outcomes of the studentship will be shortly published in a peer-reviewed journal (paper currently submitted). A PhD thesis entitled "Strategy for Controlled Protection of Redox-Cycling Ortho-Quinones with Self-Immolative Linkers" will be published on the University of Cambridge's online repository for the Department of Chemistry https://www.repository.cam.ac.uk/handle/1810/721 after degree approval. |
| Exploitation Route | The funded work developed a new, highly modular strategy for making ortho-quinone prodrugs. It is the first described method for the synthesis of redox-inactive prodrugs of ortho-quinones that can be deprotected by selective enzymatic means. This discovery will allow the design and development of prodrugs and targeted therapies with the compound class. After this proof of concept study, other researchers may combine the strategy with different ortho-quinones, pro-triggers and targeting moieties as required to develop new medicines. The discoveries will also stimulate future research into similar approaches with other compound classes. |
| Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |