Hypothetical model of crossed masked Erbitux and Matuzumab based on Donaldson et al., Cancer Biology and Therapy (2009).
While monoclonal antibodies are routinely used in the clinic, a number of these target antigens are also present on normal tissues and thus can produce severe side effects (skin rashes and cardiotoxicity). To avoid these side effects, Donaldson and co-workers have fused the domain III of the EGFR receptor (antigen) to an Erbitux scFv (antibody). The masked antibody will not bind normal or diseased tissue. The peptide linking the antigen to the antibody, however, contains a tumor specific protease site (MMP-9). Cleavage by the tumor associated protease releases the mask, allowing the therapeutic antibody to bind to the tumor associated antigen. The IgG coordinates are based on IGT.pdb. EGFR domain III is based on 1YY9.pdb.

Image courtesy of John Williams, Ph.D., and Joshua Donaldson, Department of Molecular Medicine, Beckman Research Institute, City of Hope.

Donaldson JM, Kari C, Fargoso R, Rodeck U, & Williams JC, Cancer Biology and Therapy, In press