Project description
A novel targeted anti-cancer therapy
Harnessing the power of the immune system to fight cancer is an attractive therapeutic approach. More specifically, conjugating chemotherapeutic drugs to tumour-specific antibodies improves drug delivery and efficiency while minimising side effects. The EU-funded PAC Synthesis project proposes to combine the advantages of protein degradation and antibody targeting into a new therapeutic platform. Scientists will generate conjugates between proteolysis targeting chimeras (PROTAC) and antibodies targeting the myeloid CD33 protein present in acute myeloid leukaemia cells. The employed chemistry ensures conjugate stability in the blood and efficient release of the PROTAC once internalised by cancer cells.
Objective
The field of immunotherapy has become one of the most promising strategies in fighting cancer. By using the incredible features our very own immune system already possesses, like the powerful tool of specific antibody-antigen recognition, a new generation of drugs can be generated. The idea of linking cytotoxic drugs to monoclonal antibodies with high affinities to specific tumor cells will tremendously improve drug delivery, as tumor-associated antigens can be found by antibodies and the high cytotoxicity of the conjugated drug is used to achieve efficient cancer treatment with less side effects. In this research proposal, we establish a new therapeutic platform that uniquely combines the advantages of two rapidly developing areas – immunotherapy and targeted protein degradation – by developing first class of PROTAC-Antibody Conjugates (PAC). The resulting novel therapeutic agents will help to overcome the limitations arising from lack of cell specificity of PROTACs by exploiting tissue-specificity of the antibody component. Several studies reported encouraging data for the treatment of acute myeloid leukemia (AML) with antibody drug conjugates (ADC) that target the myeloid antigen CD33. In addition, a functionalisable BET inhibitor will be employed in protein degrader construct, generating a new class of small-molecule BET protein degraders. Besides, the proposed self-immolative linker chemistry will allow the traceless realease of the PROTAC once the PAC is internalized into the target cell. Moreover, we will use novel site-selective cysteine bioconjugation approach to build homogenous conjugates that, unlike current examples built using maleimide chemistry, are fully stable in the blood. Overall, this approach will be applicable to any protein of interest and therefore has the potential to advance not only the AML treatment but also the whole field of cancer therapy.
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Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
CB2 1TN Cambridge
United Kingdom