Engineering to Reposition the Fc Carbohydrate Chain Eliminates Effector Function in mAbs

Engineering to Reposition the Fc Carbohydrate Chain Eliminates Effector Function in mAbs

A key structural feature of antibody therapeutics is their ability to both bind to antigen and to recruit effector functions of the immune system such as antibody dependent cell mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).  These effector functions result from the interaction of immunoglobulin Fc with the Fc gamma receptor.  It is often desirable in the design of antibody therapeutics to separate binding from effector function, if for example, the clinical use of the mAb therapeutic is to block the biological activity of an antigen but not to activate the immune system.  In these circumstances, it is necessary to have an immunoglobulin for which effector function is absent. This can be achieved by selecting one immunoglobulin subclass over another (e.g., IgG2 or 4 over IgG1) or by antibody engineering methods.

Antibody interactions with Fcγ receptors (FcγR) initiate cytokine release, degranulation, phagocytosis and cell death.  Previous attempts to interrupt this interaction have often resulted in altered properties of the antibodies. A research group lead by Qun Zhou from Sanofi recently published work describing a modification to engineer an antibody to eliminate immune effector function.  Dr. Zhou and colleagues chose simply to move the single Fc glycosylation site from a position at Asn 297 to 298 by altering three adjacent residues (S298N/T299A/Y300S).  In making this change from NSTY (at postions 297-300) to create a “NNAS” mutant, the investigators achieved ablation of FcgR binding and silencing of ADCC and CDC without impacting antigen or FcRn binding, while retaining normal purification yields, thermal stability and half life in mice and a non-human primate. This finding introduces a novel engineering approach to eliminate antibody effector function and improve targeted effects of antibody treatments that do not stimulate activity of the immune system, but that otherwise retain beneficial attributes of a whole antibody.

Please find the full article, “Engineered Fc-glycosylation switch to eliminate antibody effector function,” authored by Qun Zhou, Julie Jaworski, Yanfeng Zhou, Delphine Valente, Joanne Cotton, Denise Honey, Ekaterina Boudanova, Jochen Beninga, Ercole Rao, Ronnie Wei, Christine Mauriac, Clark Pan, Anna Park and Huawei Qiu in MABs, 12:1, e1814583 (13 pages) (2020) at the following link: https://www.tandfonline.com/doi/abs/10.1080/19420862.2020.1814583

Chamow & Associates, an Alira Health company, assists companies to develop biologics for clinical testing and welcomes your inquiry.

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