Imaging Reveals Importance of Shape and Flexibility for Glomerular Filtration of Biologics.

Autor: Rafidi H; Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc., South San Francisco, California., Estevez A; Structural Biology, Genentech, Inc., South San Francisco, California., Ferl GZ; Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc., South San Francisco, California.; Biomedical Imaging, Genentech, Inc., South San Francisco, California., Mandikian D; Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc., South San Francisco, California., Stainton S; Safety Assessment, Genentech, Inc., South San Francisco, California., Sermeño L; Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc., South San Francisco, California., Williams SP; Antibody Engineering, Genentech, Inc., South San Francisco, California., Kamath AV; Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc., South San Francisco, California., Koerber JT; Antibody Engineering, Genentech, Inc., South San Francisco, California.; Research and Early Development, Genentech, Inc., South San Francisco, California., Boswell CA; Departments of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc., South San Francisco, California. boswell.andy@gene.com.; Biomedical Imaging, Genentech, Inc., South San Francisco, California.
Jazyk: angličtina
Zdroj: Molecular cancer therapeutics [Mol Cancer Ther] 2021 Oct; Vol. 20 (10), pp. 2008-2015. Date of Electronic Publication: 2021 Jul 26.
DOI: 10.1158/1535-7163.MCT-21-0116
Abstrakt: Advances in antibody engineering have enabled the construction of novel molecular formats in diverse shapes and sizes, providing new opportunities for cancer immunotherapeutic drug discovery while also revealing limitations in knowledge of structure-activity relationships. The current understanding of renal filtration originates largely from data reported for dextrans, IgG, albumin, and selected globular proteins. For a one-armed IgG-based T-cell imaging agent, we observed higher renal signal than typically observed for bivalent IgGs, prompting us to explore the factors governing renal filtration of biologics. We constructed a small representative library of IgG-like formats with varied shapes and hinge flexibilities falling broadly into two categories: branched molecules including bivalent IgG and (scFv) 2 Fc, and nonbranched molecules including one-armed IgG, one-armed IgG with stacked Fab, and one-armed IgG with a rigid IgA 2 hinge. Transmission electron microscopy revealed Y-shaped structures for the branched molecules and pseudo-linear structures for the nonbranched molecules. Single-photon emission CT imaging, autoradiography, and tissue harvest studies demonstrated higher renal uptake and catabolism for nonbranched molecules relative to branched molecules. Among the nonbranched molecules, the one-armed IgG with rigid IgA 2 hinge molecule demonstrated higher kidney uptake and decreased systemic exposure relative to molecules with a more flexible hinge. Our results show that differences in shape and hinge flexibility drive the increased glomerular filtration of one-armed relative to bivalent antibodies and highlight the practical advantages of using imaging to assess renal filtration properties. These findings are particularly relevant for T-cell-dependent bispecific molecules, many of which have nonstandard antibody structures.
(©2021 American Association for Cancer Research.)
Databáze: MEDLINE
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