Descrizione del progetto
Una nuova terapia antitumorale mirata
Lo sfruttamento della forza del sistema immunitario per combattere il cancro rappresenta un approccio terapeutico attraente. Più nello specifico, la coniugazione di farmaci chemioterapici ad anticorpi specifici al tumore migliora la somministrazione e l’efficienza dei farmaci, riducendo nel contempo gli effetti collaterali. Il progetto PAC Synthesis, finanziato dall’UE, propone di combinare i vantaggi della degradazione delle proteine e del targeting degli antibiotici in una nuova piattaforma terapeutica. Gli scienziati creeranno coniugati tra tecnologie PROTAC e anticorpi che colpiscono la proteina CD33 mieloide presente nelle cellule della leucemia mieloide acuta. La chimica impiegata garantisce la stabilità dei coniugati nel sangue e il rilascio efficiente della tecnologia PROTAC una volta interiorizzata dalle cellule tumorali.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
CB2 1TN Cambridge
Regno Unito