The high affinity Fc receptor for human IgG [Fc-gRI or CD64] is an important cytotoxic trigger molecule on monocytes, macrophages and activated neutrophils. One of the investigators' Fc-gRI-specific MAb, M22, has been humanized by CDR grafting and renamed H22. Bispecific reagents consisting of H22 linked to ligands specific for receptors that are overexpressed on tumor cells may have considerable potential as anti-cancer therapeutics. Epidermal growth factor [EGF] and heregulin [HRG] are ligands that recognized the epidermal growth factor receptor [EGFR] and the HER2/3/4 molecules, respectively, and are overexpressed on breast and ovarian carcinomas as well as other tumor cells. The overall goal is to continue the research efforts initiated in the Phase I SBIR by evaluating the clinical potential of fusion proteins consisting of EGF or HRG linked to H22, to create DNA constructs by recombinant means for the expression of H22 sFv linked covalently to EGF or to HRG, and to compare the therapeutic potential of the expressed sFv versions to the Fab' versions including testing the stability and pharmokinetics of the fusion proteins and optimization of production conditions. In addition, the investigators will create and assess a third fusion protein where H22 would be linked to a ligand termed biregulin [BRG], a chimeric molecule with properties of both EGF and HRG.
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