IGF-TRAP

There is considerable current interest in targeting the IGF axis as a therapeutic strategy in oncology, with more than a dozen drug candidates undergoing clinical evaluation. Receptor-oriented strategies, targeting IGF receptor (IGF-1R) (either mabs of TKI) have been developed first. Even though clinically significant activity has been reported, some Ph3 clinical trials were disappointing and have been discontinued. Less attention has been paid to neutralizing the ligands themselves even though promising effects have been reported in pre-clinical studies using ligand-specific antibodies. IGF biding proteins are high affinity endogeneous actors of the IGF axis playing a major role in regulating IGF bioavailability. IGFBP-3 transports > 75% of serum IGF-I and –II and its activity is controlled by various proteases including MMPs active in metastatic cancer cells. Thus, IGFBPs could be used as an alternative to antibodies in targeting the IGF axis. We have produced a set of protease-resistant muteins of human IGFBP-3 (IGF-TRAP) for which a European patent application (EP 11 305 197.3) has been filed by Inserm-Transfert. In line with its in vitro anti-proliferative properties, preliminary data have been obtained indicating in vivo activity. Thus, this modified IGF binding protein could offer, a valuable alternative to receptor-oriented agents. Advantages of IGF-TRAP are i) neutralizes simultaneously IGF-I and IGF-II ii) targets both IGF-1R and IR-A signal transduction pathways iii) restores in the patient a balance destroyed by the tumor. The IGF-TRAP project seeks to further assess its properties and aims at delivering a definite proof of concept of its anti-tumor activity in vivo which will pave the way for a future biotechnology company. Our program will compare sets of tumor xenografts in mice treated or not by IGF-TRAP. We will focus on two types of “IGF-sensitive” tumor cell lines: i) IGF-II producing tumor cell lines; ii) Ewing’s sarcoma cell lines selected due to their responsiveness to anti-IGF1R therapy demonstrated in clinical trials. To generate meaningful in vivo data we need to produce adequate quantities of protein a task attributed to subcontractant 1. Read out criteria will concern signaling, cell cycle, angiogenesis and apoptosis proteins. They will encompass immunoblots (partner 1 and partner 2) evaluation of the antitumor activity on xenografts (partner 2) and immunohistochemistry (subcontractant 2). Specific in vitro experiments will concern Ewing’s sarcoma cell lines (partner 3) and other cell lines (co-coordinator). In addition, specific cell lines will be used to collect data by FDG-TEP (partner 1and in vivo fluorescence imaging (partner 2). It is our hope that this in vivo proof of concept will serve as a basis for the development of our patented set of therapeutic proteins.