Descrizione del progetto
Migliorare l’affinità dei nanoanticorpi attraverso la mutagenesi chimica
L’immunoterapia antitumorale si è progressivamente affermata come una delle migliori alternative agli attuali trattamenti chemioterapici. I nanoanticorpi (o anticorpi VHH) sono anticorpi a dominio singolo variabile su una catena pesante. Gli anticorpi convenzionali presentano i domini variabili VH e VL, che forniscono stabilità e specificità di legame. I nanoanticorpi, che presentano domini VHH e sono privi di domini VL, si trovano in natura in camelidi e squali. I nanoanticorpi hanno trovato applicazione in vari ambiti medici, tra cui l’oncologico, l’infettivo e l’immunitario. Il progetto Chemical Mutagenesis, finanziato dall’UE, propone lo sviluppo di nanoanticorpi in grado di riconoscere la proteina HER-2 e i recettori di PD-1 nelle cellule tumorali. L’obiettivo è migliorare l’affinità dei nanoanticorpi con i loro bersagli mediante la mutagenesi chimica attraverso i radicali alaninici, con l’intento di risolvere il problema della resistenza dei tumori nel contesto immunoterapico.
Obiettivo
Finding a non-aggressive treatment against Cancer is one of the most important challenges that medicine has nowadays. Immunotherapy has emerged as one of the best options to overcome the current problems of chemotherapy. By the use of monoclonal antibodies (mAb), immunotherapy is able to block regulatory checkpoints and, therefore, the immune response against tumoral cells could be modulated.
Trastuzumab, pembrolizumab and nivolumab are some of the mAb approved by the Food and Drug Administration (FDA) for their use against several cancers. Trastuzumab recognizes the overexpressed protein HER2 in breast cancer, whereas the pembrolizumab and the nivolumab recognize the Programmed Cell Death-1 (PD-1) receptor and are used in several cancers such as refractory melanoma.
However, there are reported important issues concerning cancer resistance to these mAb, thus, modifying their characteristics became necessary. Unlike it happens with small molecules, there are several limitations to functionalize an antibody to improve its characteristics. In this context, chemical mutagenesis turns into a powerful tool because it allows the modification of an antibody directly with highly specific chemical reactions, and achieve changes onto its structure that would not be possible by using other techniques such as protein engineering and genetic encoding.
In this proposal I envision the use of nanobodies able to recognize HER-2 protein and PD-1 receptor in order to improve their affinity to their targets by chemical mutagenesis via alanyl radical. The success of this project would provide solutions to the cancer resistance to current immunotherapy.
Campo scientifico
- medical and health sciencesclinical medicineoncologyskin cancermelanoma
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesclinical medicineoncologybreast cancer
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- natural scienceschemical sciences
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
CB2 1TN Cambridge
Regno Unito