Descripción del proyecto
Un novedoso tratamiento antineoplásico dirigido
Aprovechar el poder del sistema inmunitario para combatir el cáncer representa un método terapéutico interesante. Más concretamente, la conjugación de fármacos quimioterápicos con anticuerpos para tumores específicos mejora la administración y la eficacia de los fármacos, a la vez que minimiza los efectos secundarios. El proyecto PAC Synthesis, financiado con fondos europeos, propone combinar las ventajas de la degradación de las proteínas y la selección de anticuerpos en un nuevo programa terapéutico. Los científicos del proyecto generarán conjugados entre la proteólisis dirigida a las quimeras (PROTAC, por sus siglas en inglés) y los anticuerpos dirigidos a la proteína mieloide CD33 presente en las células de la leucemia mieloide aguda. La química empleada garantiza la estabilidad del conjugado en la sangre y la liberación eficiente de PROTAC una vez internalizada por las células cancerosas.
Objetivo
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.
Ámbito científico
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Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
CB2 1TN Cambridge
Reino Unido