4.8 Article

Human immunoglobulin G hinge regulates agonistic anti-CD40 immunostimulatory and antitumour activities through biophysical flexibility

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NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-12097-6

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资金

  1. NNSFC [31422020, 31370934, 31700806]
  2. China Postdoctoral Science Foundation [2016M591688]
  3. Shanghai Sailing Program [16YF1409700]
  4. Natural Science Foundation of Shanghai [15ZR1436400]
  5. Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (2015)
  6. Shanghai Municipal Science and Technology Commission [19431902900]
  7. Shu Guang project from Shanghai Municipal Education Commission
  8. Shanghai Education Development Foundation
  9. program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning
  10. Innovative research team of high-level local universities in Shanghai

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Human immunoglobulin G (IgG) agonistic antibodies targeting costimulatory immunoreceptors represent promising cancer immunotherapies yet to be developed. Whether, and how, human IgG hinge and Fc impact on their agonistic functions have been disputed. Here, we show that different natural human IgGs confer divergent agonistic anti-CD40 immunostimulatory and antitumour activities in Fc gamma R-humanized mice, including inactive IgG3 and superior IgG2. This divergence is primarily due to their CH1-hinges despite all human IgGs requiring Fc-Fc gamma R binding for optimal agonistic activities. Unexpectedly, biophysical flexibility of these CH1-hinges inversely correlates with, and can modulate, their agonistic potency. Furthermore, IgG Fcs optimized for selective Fc gamma R binding synergize with and still require IgG hinge, selected for rigidity, to confer improved anti-CD40 immunostimulatory and antitumour activities. These findings highlight the importance of both hinge rigidity and selective Fc gamma R binding in antibody agonistic function, and the need for newer strategies to modulate antibody agonism for improved clinical application.

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