CORDIS - Forschungsergebnisse der EU
CORDIS

Synthesis of PROTAC-Antibody Conjugate for Application in Acute Myeloid Leukemia Therapy

Projektbeschreibung

Neuartige zielgenaue Krebstherapie

Die Kraft des Immunsystems zur Bekämpfung von Krebs zu nutzen, ist ein attraktiver therapeutischer Ansatz. Werden chemotherapeutische Wirkstoffe direkt an tumorspezifische Antikörper konjugiert, verbessern sich Wirkstoffabgabe und Wirksamkeit, während die Nebenwirkungen minimal bleiben. Das EU-finanzierte Projekt PAC-Synthesis will nun die Vorteile des Proteinabbaus mit gezielter Antikörpergabe kombinieren und daraus eine neue therapeutische Plattform erstellen. Das Forschungsteam wird Konjugate von sogenannten PROTAC (auf die Proteolyse abzielenden Molekülen) und Antikörpern gegen das bei akut myeolischer Leukämie in den Zellen auftretende myeloide Protein CD33 erzeugen. Die hier angewandte Chemie sorgt für Stabilität des Konjugats im Blut sowie für eine wirksame Freisetzung der PROTAC, sobald sie von den Krebszellen aufgenommen wurden.

Ziel

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.

Schlüsselbegriffe

Koordinator

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Netto-EU-Beitrag
€ 212 933,76
Adresse
TRINITY LANE THE OLD SCHOOLS
CB2 1TN Cambridge
Vereinigtes Königreich

Auf der Karte ansehen

Region
East of England East Anglia Cambridgeshire CC
Aktivitätstyp
Higher or Secondary Education Establishments
Links
Gesamtkosten
€ 212 933,76