In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance

Commun Biol. 2021 Sep 8;4(1):1048. doi: 10.1038/s42003-021-02565-5.


In a biologic therapeutic landscape that requires versatility in targeting specificity, valency and half-life modulation, the monomeric Fc fusion platform holds exciting potential for the creation of a class of monovalent protein therapeutics that includes fusion proteins and bispecific targeting molecules. Here we report a structure-guided approach to engineer monomeric Fc molecules to adapt multiple versions of half-life extension modifications. Co-crystal structures of these monomeric Fc variants with Fc neonatal receptor (FcRn) shed light into the binding interactions that could serve as a guide for engineering the half-life of antibody Fc fragments. These engineered monomeric Fc molecules also enabled the generation of a novel monovalent bispecific molecular design, which translated the FcRn binding enhancement to improvement of in vivo serum half-life.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Half-Life
  • Histocompatibility Antigens Class I / metabolism*
  • Histocompatibility Antigens Class I / pharmacology
  • Humans
  • Immunoglobulin Fc Fragments / metabolism*
  • Immunoglobulin Fc Fragments / pharmacology
  • Mice
  • Mice, Transgenic
  • Protein Engineering
  • Receptors, Fc / metabolism*


  • Histocompatibility Antigens Class I
  • Immunoglobulin Fc Fragments
  • Receptors, Fc
  • Fc receptor, neonatal