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

Abstract

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.

Tag-free, specific conjugation of glycosylated IgG1 antibodies using microbial transglutaminase

“…Interestingly, FcRn-mediated antibody recycling can be maintained in a bispecific antibody by introducing FcRn-binding enhancing mutations in one Fc monomer, where the second Fc monomer is non-functional with respect to FcRn binding. 28 This suggests a path forward to FcRn-mediated antibody recycling in conjunction with the I253Q substitution. Cytotoxicity and specificity of MMAE-conjugated I253Q trastuzumab are maintained.…”