Research Projects Mechanisms of action and development of therapeutic monoclonal antibodies in hemato-oncology
In the last several years a number of humanised monoclonal antibodies directed against surface antigens expressed by tumour cells have been developed as new therapeutic tools. Surprisingly, despite the fact that a large number of potential target molecules on cancer cells are available, relatively few antibodies developed have actually reached the clinic, due to lack of activity and/or unacceptable side effects. Furthermore, even for the MAbs that have shown clear therapeutic activity in the clinic, such as the anti-CD20 antibody rituximab, resistance and relapse of treated patients do occur. From these observations, it is clear that increasing the therapeutic activity of MAbs would be beneficial. Our research in the last 10 years has therefore been aimed at more fully understanding the mechanisms of action of some of the therapeutic MAbs, and in particular of rituximab, with the view of building up the knowledge and tools necessary to improve present MAbs as well as allow the development of new therapeutic MAbs against target antigens expressed by tumour cells.
In particular we have demonstrated that complement activation, antibody dependent cytotoxicity (ADCC) and phagocytosis are all an important mechanisms of action of the anti-CD20 antibody rituximab in vitro and in vivo and that these mechanisms cooperate with each other. Thus active MAbs are likely to be those that are able to activate all these different pathways efficiently. Furthermore improving these mechanisms is likely to lead to an improvement of the activity of present day MAbs.
Current work therefore includes the study of modified MAbs or combination with immunomodulatory agents to try and improve their immune mediated activity of rirtuximab or of new therapeutic MAbs. This work takes place in collaboration with other groups in France and Switzerland.
New drugs development
New compounds potentially active in the onco-haematology field are being investigated in the laboratory in collaboration with small pharmaceutical industries. Two new compounds are at the moment the object of experimental studies in our laboratory. The first one belongs to the category of histone deacetylase inhibitors and has shown cytotoxic activity in vitro against multiple myeloma (MM) and acute myelogenous leukaemia (AML). The compound has entered phase I clinical studies in MM and AML. The activity and mechanism of action of this drug in chronic myeloproliferative disorders is presently investigated in vitro.
Main methodologies in use in the laboratory:
Cell culture, immunophenotyping and FACS analyses, Western blot, immunoprecipitation, cytotoxicity assays, colony assays |
