Erythropoietin: A Case Study for Understanding Cytokine Signaling and Potency

Mala Radhakrishnan, Massachusetts Institute of Technology

Erythropoietin (Epo) is a crucial hormone involved in the maturation of red blood cell precursors. Because Epo is produced in the kidney, people with renal failure must take injections of Epo in order to avoid serious anemia. Unfortunately, these external sources of Epo generally are cleared very rapidly from the body, and therefore, a current priority is to increase the potency of these drugs by increasing their in vivo half-life and by altering their signaling properties. The erythropoietin system is particularly interesting because it provides several avenues of investigation and potential mechanisms for modulation of half-life and potency. Using a combination of molecular and kinetic models, we are exploring the relative roles of binding kinetics, endocytic trafficking, and signal production and duration. Structural computations have indicated both a role for location-specific binding in biasing trafficking toward ligand recycling and specific mutations to alter this effect. In addition, we are comparatively analyzing rHuEpo and NESP, two Epo variants administered to patients, from a structural perspective in order to understand the physical basis for their differing observed thermodynamic and kinetic properties. Finally, we are developing a kinetic model applicable to general cytokine systems that captures the binding, signaling, endocytosis, recycling, and degradation of involved species. This model allows us to understand what kinetic properties of a cytokine system will generate a strong signal, a long half-life, or both. Using this model in conjunction with molecular design techniques will allow us to propose novel cytokine molecules with overall increased potency.

Abstract Author(s): Mala L. Radhakrishnan and Bruce Tidor