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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.

SUBMITTER: Shan L 

PROVIDER: S-EPMC8426389 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Shan Lu L   Dyk Nydia Van NV   Haskins Nantaporn N   Cook Kimberly M KM   Rosenthal Kim L KL   Mazor Ronit R   Dragulin-Otto Sonia S   Jiang Yu Y   Wu Herren H   Dall'Acqua William F WF   Borrok Martin J MJ   Damschroder Melissa M MM   Oganesyan Vaheh V  

Communications biology 20210908 1


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 vari  ...[more]

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