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Temperature promotes Fab-arm exchange in Pembrolizumab
Mohammad Karbalaeimahdi1, Puneet K Singh1, Razvan C Stan1
1Department of Basic Medical Science, Chonnam National University, Hwasun 58128, Republic of Korea.
Background:
Under specific in vitro redox conditions, endogenous and therapeutic IgG4 antibodies are unusually dynamic molecules that exhibit Fab domain swapping with other IgG, resulting in hybrid antibodies with bispecificity and reduced pro-inflammatory activity.
Objective:
To probe the influence of physiologic and non-physiologic temperatures on the intramolecular rearrangements of immunotherapeutic IgG4 Pembrolizumab.
Results:
At high temperatures (38.5 °C and 40 °C), Pembrolizumab exhibits conformational changes supporting "Fab-arm exchange", compared to measurements at 37 °C or at 25 °C, and binds with a lower affinity to its antigen Programmed Death-1 receptor.
Conclusions:
Higher temperatures affect Pembrolizumab by (1) promoting binding of its Fc domain to Fc/complement receptors, (2) reducing its on-target residence time, (3) not preventing canonical S228P mutation from abrogating Fab-arm exchanges.
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