Quantitative issues in designing anti-cancer protein drugs

1 Oct 2010

Jeffrey Way
Advanced Technology Team
Wyss Institute, Harvard


The problem of delivering proteins to specific target cells is particularly acute for treating solid tumors because, unlike other tissues, tumors have no lymph node drainage. Thus, large (and small) molecules enter tumors by diffusion and penetration is almost always poor. As a result, action of drugs on normal tissues can predominate, leading to unacceptable side effects. To address this problem, we have taken a quantitative approach to minimizing the action of protein drugs on non-target tissues.

Evolution modulates the quantitative characteristics of protein interactions and often uses combinations of weak interactions to achieve a particular specificity. We addressed how quantitative optimization might be used in the design of multidomain proteins, constructing fusion proteins between EGF and interferon-alpha (IFNa), the anti-tumor antibody MR1-1 and IFNa, and the anti-glycophorin antibody 10F7 and erythropoietin (Epo). The goal was to generate proteins in which the cell binding of an "activity element" (IFNa or Epo) was driven by prior binding of a "targeting element". We connected these elements with a linker that allows each fusion partner to simultaneously bind their receptors on a cell surface, and incorporated mutations into the IFNa and Epo elements that progressively decrease the binding of these ligands to their receptors. When the activity element is appropriately mutated, the selectivity of the resulting fusion protein can be enhanced at least 10- to 20-fold compared to a fusion protein consisting of only wild-type elements. These results support a quantitative approach in the design of fusion proteins.


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