Prof. Ermanno Gherardi, PI, Full professor
Dr. Luisa Iamele
Dr. Hugo de Jonge
Alain Patrick Peleu Ngate (PhD student)
Our laboratory is focussing on the Hepatocyte Growth Factor/Scatter Factor (HGF/SF) and its tyrosine kinase receptor c-MET as well as other growth factors structurally related to plasminogen. HGF/SF and c-MET are both large and complex multidomain proteins crucial for organ formation during embryogenesis, adult life tissue homeostasis, and regulate inflammation and immunity. Moreover, both are important drivers of tumour growth and metastasis.
The potential application in regenerative medicine for treatment of several chronic and acute diseases affecting liver, lung, heart, and many other organs including the nervous system, and the urgent need for potent c-MET inhibitors in oncology is crucially dependent on a detailed understanding of ligand-induced receptor activation. Using a combination of structural biology and protein engineering, we have obtained a molecular understanding of ligand binding and receptor activation. This formed the basis for the structure-based drug development of potent small HGF/SF mimics and agonistic monoclonal antibodies. The structural information also contributed to the development of small molecule inhibitors targeting the receptor binding site in the first kringle domain, and the development of an inhibitory antibody fragment.
Currently we are extending the use of our monoclonal antibodies and antibody fragments to develop novel CAR-T technology, improve the targeting of MET-overexpressing tumours with nanoparticles, and develop intraoperative NIRF tumour markers.
Some of the technologies our laboratory employs are:
- protein engineering - protein crystallography and x-ray diffraction
- phage-display and monoclonal antibody technology - small angle x-ray scattering
- cryo-electron microscopy
- cell-based assays and screening
- Surface Plasmon Resonance (Biacore T200)
We have ongoing collaborations with groups in Italy, France, the Netherlands, US, Hong Kong, and are working with Boehringer Ingelheim Germany on regenerative applications.
Dimerization of kringle 1 domain from HGF/SF provides a potent minimal MET receptor agonist. De Nola G, Leclercq B, Mougel A, Taront S, Simonneau C, Forneris F, Adriaenssens E, Drobecq H, Iamele L, Dubuquoy L, Melnyk O, Gherardi E, de Jonge H, and Vicogne J. In press, Life Science Alliance.
Harnessing the hERG1/β1 Integrin Complex via a Novel Bispecific Single-chain Antibody: An Effective Strategy against Solid Cancers. Duranti C, Iorio J, Lottini T, Lastraioli E, Crescioli S, Bagni G, Lulli M, Capitani C, Bouazzi R, Stefanini M, Carraresi L, Iamele L, de Jonge H, and Arcangeli A. Mol Cancer Ther 20, 1338 (2021).
A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation. Vallarola, A, Tortarolo M, Gioia R, Iamele L, de Jonge H, de Nola G, Bovio E, Pasetto L, Bonetto V, Freschi M, Bendotti C and Gherardi E. Int J Mol Sci 21, 8542 (2020).
Inhibition of the MET Kinase Activity and Cell Growth in MET-Addicted Cancer Cells by Bi-Paratopic Linking. Andres F, Iamele L, Meyer T, Stüber J, Kast F, Gherardi E, Niemann H and Plückthun A. J Mol Biol 431, 2020–2039 (2019).