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Hidden hydrophobicity impacts polymer immunogenicity.

Zhefan Yuan1, Patrick McMullen1, Sijin Luozhong1

  • 1Meinig School of Biomedical Engineering, Cornell University Ithaca NY 14853 USA sj19@cornell.edu.

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Researchers discovered hidden hydrophobicity in polymers, linking it to immunogenicity. By minimizing this, they created protein conjugates with significantly reduced antibody responses, overcoming previous limitations.

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Area of Science:

  • Bioconjugation Chemistry
  • Polymer Science
  • Immunology

Background:

  • Antibodies against poly(ethylene glycol) (PEG) cause side reactions and reduced efficacy in PEGylated drugs.
  • The fundamental mechanisms of PEG immunogenicity and design principles for alternatives remain underexplored.

Purpose of the Study:

  • To investigate the "hidden" hydrophobicity of polymers and its correlation with immunogenicity.
  • To develop strategies for creating protein conjugates with minimal immunogenicity.

Main Methods:

  • Hydrophobic interaction chromatography (HIC) under varied salt conditions to assess polymer hydrophobicity.
  • Atomistic molecular dynamics (MD) simulations.
  • Polyzwitterion modification for creating protein conjugates.

Main Results:

  • Revealed "hidden" hydrophobicity in generally hydrophilic polymers.
  • Established a correlation between a polymer's hidden hydrophobicity and its immunogenicity when conjugated with proteins.
  • Demonstrated that this correlation holds for polymer-protein conjugates.
  • MD simulations corroborated the observed trends.

Conclusions:

  • Minimizing polymer hydrophobicity is crucial for reducing immunogenicity.
  • Polyzwitterion modification, guided by HIC, enables the creation of extremely low-immunogenic protein conjugates.
  • This approach overcomes barriers to eliminating anti-drug and anti-polymer antibodies.