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Design and characterization of novel dual Fc antibody with enhanced avidity for Fc receptors.

07:00 EST 8th November 2019 | BioPortfolio

Summary of "Design and characterization of novel dual Fc antibody with enhanced avidity for Fc receptors."

Monoclonal antibodies (mAbs) have become an important class of therapeutics, particularly in the realm of anti-cancer immunotherapy. While the two antigen-binding fragments (Fabs) of a mAb allow for high-avidity binding to molecular targets, the crystallizable fragment (Fc) engages immune effector elements. mAbs of the IgG class are used for the treatment of autoimmune diseases and can elicit anti-tumor immune functions by several mechanisms including direct antigen engagement via their Fab arms, but also by Fab binding to tumors combined with Fc engagement of complement component C1q and Fc γ receptors. Additionally, IgG binding to the neonatal Fc receptor allows for endosomal recycling and prolonged serum half-life. To augment the effector functions or half-life of an IgG1 mAb, we constructed a novel "2Fc" mAb containing two Fc domains in addition to the normal two Fab domains. Structural and functional characterization of this 2Fc mAb demonstrated that it exists in a tetrahedral-like geometry and retains binding capacity via the Fab domains. Furthermore, duplication of the Fc region significantly enhanced avidity for Fc receptors FcγRI, FcγRIIIa, and FcRn which manifested as a decrease in complex dissociation rate that was more pronounced at higher densities of receptor. At intermediate receptor density, the dissociation rate for Fc receptors was decreased 6- to 130-fold, resulting in apparent affinity increases of 7- to 42-fold. Stoichiometric analysis confirmed that each 2Fc mAb may simultaneously bind two molecules of FcγRI or four molecules of FcRn, which is double the stoichiometry of a wild-type mAb. In summary, duplication of the IgG Fc region allows for increased avidity to Fc receptors that could translate into clinically relevant enhancement of effector functions or pharmacokinetics. This article is protected by copyright. All rights reserved.

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Name: Proteins
ISSN: 1097-0134
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