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Temperature Dependent Motions of N-Terminal Loop in PD-1 Determine the Affinity Towards Nivolumab
Mohammad Karbalaeimahdi1, Dircia C C Marcelina1, Razvan C Stan1
1Chonnam National University Medical School, Gwangju, Republic of Korea.
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.
Insights
Higher temperatures weaken the binding of Nivolumab immunotherapy to Programmed Cell Death-1 (PD-1) receptors. This reduced binding at fever temperatures (39°C) may explain side effects observed in cancer patients undergoing immunotherapy.
Area of Science:
- Immunology
- Computational Biology
- Pharmacology
Background:
- Programmed Cell Death-1 (PD-1) receptors are crucial immune modulators on monocytes, T cells, and B cells.
- These receptors are key targets for cancer immunotherapy, particularly monoclonal antibodies like Nivolumab.
- Nivolumab-based therapies can cause side effects such as inflammation and fever in cancer patients.
Purpose of the Study:
- To investigate the impact of physiological (37°C), pathophysiological (39°C), and standard (25°C) temperatures on Nivolumab:PD-1 immune complex formation.
- To elucidate the molecular mechanisms underlying temperature-dependent binding affinity.
Main Methods:
- Surface Plasmon Resonance (SPR) was employed to measure binding kinetics.
- Molecular Dynamics (MD) simulations were conducted at relevant temperatures to analyze complex behavior.
- Analysis focused on dissociation curves and interface dynamics.
Main Results:
- The mean residence times of Nivolumab:PD-1 complexes were significantly shorter at 39°C (~7 seconds) compared to 37°C (~16 times longer) and 25°C (~125 times longer).
- Higher temperatures (39°C) induced the movement of the PD-1 N-terminal loop away from Nivolumab.
- Temperature-induced alterations in the epitope:paratope interface were observed.
Conclusions:
- Physiological and standard temperatures promote significantly more stable Nivolumab:PD-1 interactions than pathophysiological temperatures.
- The destabilization of the immune complex at higher temperatures is attributed to conformational changes in the PD-1 receptor.
- Understanding these temperature effects is vital for optimizing immunotherapy efficacy and managing side effects.
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