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

Shan, Lu; Dyk, Nydia Van; Haskins, Nantaporn; Cook, Kimberly M.; Rosenthal, Kim L.; Mazor, Ronit; Dragulin-Otto, Sonia; Jiang, Yu; Wu, Herren; Dall’Acqua, William F.; Borrok, Martin J.; Damschroder, Melissa M.; Oganesyan, Vaheh

doi:10.1038/s42003-021-02565-5

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

Journal Article · Wed Sep 08 00:00:00 EDT 2021 · Communications Biology

DOI:https://doi.org/10.1038/s42003-021-02565-5· OSTI ID:1903975

^[1]; ^[2]; Haskins, Nantaporn ^[2]; Cook, Kimberly M. ^[3]; Rosenthal, Kim L. ^[2]; Mazor, Ronit ^[4]; Dragulin-Otto, Sonia ^[5]; Jiang, Yu ^[6]; Wu, Herren ^[2]; Dall’Acqua, William F. ^[2]; Borrok, Martin J. ^[7]; Damschroder, Melissa M. ^[2]; ^[2]

AstraZeneca, Gaithersburg, MD (United States). Antibody Discovery and Protein Engineering. R&D; Denali Therapeutics, South San Francisco, CA (United States); OSTI
AstraZeneca, Gaithersburg, MD (United States). Antibody Discovery and Protein Engineering. R&D
AstraZeneca, Gaithersburg, MD (United States). Early Oncology. R&D
AstraZeneca, Gaithersburg, MD (United States). Antibody Discovery and Protein Engineering. R&D; FDA Center for Biologics Evaluation and Research, Silver Spring, MD (United States). Division of Cellular and Gene Therapies
AstraZeneca, Gaithersburg, MD (United States). Dosage Form Design and Development. R&D
AstraZeneca, Gaithersburg, MD (United States). Clinical Pharmacology and Safety Science. R&D
Janssen Research and Development, Spring House, PA (United States). Janssen BioTherapeutics

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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1903975

Journal Information:: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 4; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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