The potential for cancer combination therapy with multi-targeted, single-protein pharmaceuticals

Abstract

Many diseases and disorders are best treated by a combination of drugs. Unlike small molecules, engineered proteins can be designed to incorporate multiple independent drug activities. Compared with a combination of two or more proteins, the potential benefits of a single biologic that inhibits multiple targets may include lower cost, simplified clinical testing and greater patient convenience. The evolution of HIV combination therapy is a useful point of comparison, as it occurred in an unusual regulatory environment that allowed the testing of combinations when the clinical benefit of component drugs was unproven. The epidermal growth factor receptor family of cancer targets illustrates how a particular single-molecule combination therapy might be used for cancer therapy, so some attempts to construct single-protein agents with multiple activities that include anti-EGFR moieties are reviewed. Protein engineers have created an armory of multiply-targeted antibody derivatives, but such engineered molecules often have a shorter serum half-life than IgG antibodies. New protein engineering approaches may be needed to address this problem. Nonetheless, multiply-targeted single-protein agents may be an economical solution to the problem of antibody combination therapy for cancer.

Keywords::

• cetuximab
• EGFR
• protein engineering
• serum half-life
• sFv

Disclosure statement

The authors are employees of EMD Serono, which sells Erbitux^® (cetuximab) outside the US.

Acknowledgements

Special thanks to Gordon Webster and Sean McKenna for useful discussions.