Temperature Dependent Motions of N-Terminal Loop in PD-1 Determine the Affinity Towards Nivolumab.

Abstract

Programmed Cell Death-1 receptors on the surface of monocytes and T and B cells modulate various immune responses and are key immunotherapy targets. Immunotherapeutic monoclonal antibodies, including Nivolumab, block the activity of this receptor and are a mainstay of cancer therapy. Use of these drugs has been associated with side effects, including local inflammation and systemic fever in some cancer patients. To understand the role of physiologic (37°C), pathophysiologic (39°C) and standard (25°C) temperatures on the formation of the immune complexes between PD-1 and Nivolumab, we used Surface Plasmon Resonance and Molecular Dynamics simulations, at appropriate temperatures. The mean lives obtained from the dissociation curves of Nivolumab:PD-1 complexes at 37°C or 25°C are ~16 times and ~125 times longer, respectively, than those at 39°C (~7 s). These discrepancies are due to N-terminal loop from PD-1 moving away from Nivolumab only at the higher temperatures, as well as due to changes in the epitope:paratope interface.