May 2025: Fc Engineering - Innovations in Antibody Therapeutics

Over the past decade, the Fc domain of antibodies was thought of as a passive structural region appreciated primarily for its interaction with Fcγ receptors (FcγRs) and the neonatal Fc receptor (FcRn). Now, the Fc region is a major focus of innovation, enabling fine-tuned control over immune engagement, pharmacokinetics, and tissue targeting. This month’s developments highlight the advancements of Fc engineering and its role in creating the next generation of biologics.

Fc Mutagenesis for ADCC

Antibody-dependent cellular cytotoxicity (ADCC) remains one of the most effective mechanisms through which therapeutic antibodies mediate the clearance of diseased cells, especially in oncology and hematology. Traditionally, enhancing ADCC has relied on glycoengineering, particularly the removal of core fucosylation to boost affinity for FcγRIIIa. However, this approach introduces complexity into the manufacturing process and can limit scalability.

A recent study presents an alternative: enhancing ADCC through Fc mutagenesis. Researchers engineered point mutations into the Fc region of anti-RhD monoclonal antibodies, Brad3 and Fog1, both used to prevent hemolytic disease of the fetus and newborn (HDFN). The key achievement here is the expression of these Fc variants in standard CHO cells, preserving high yield and target-binding fidelity without the need for glycoform manipulation. The engineered antibodies exhibited significantly improved binding to FcγRIIIa and ADCC activity comparable to clinically used polyclonal RhD immunoglobulin (RhD-pIgG). These findings support Fc protein engineering as a practical and efficient strategy for tuning effector function—streamlining production while achieving clinical potency.

Engineering FcRn Interactions to Cross the Blood-Brain Barrier

As the therapeutic use of antibodies expands into neurology, the challenge of delivering large biologics across the blood-brain barrier (BBB) has taken center stage. The neonatal Fc receptor (FcRn), expressed at the endothelium of the BBB, plays a dual role in IgG recycling and transcytosis, offering a gateway for CNS delivery, but only under certain binding conditions.

A study led by University at Buffalo researchers examined how modifications to the Fc domain influence antibody trafficking into the brain. Using human FcRn (hFcRn) transgenic mice, they evaluated trastuzumab variants with altered FcRn affinity profiles. Notably, Fc mutants that bound FcRn at both neutral and acidic pH (YPY, YQAY) showed significantly enhanced brain and interstitial fluid (ISF) exposure. Conversely, the widely used YTE variant—which binds FcRn only at acidic pH—failed to improve CNS delivery, and the IHH variant lacking FcRn binding showed poor brain penetration but prolonged ISF retention.

These data indicate that FcRn binding at neutral pH is required for effective brain transcytosis, and that modifying the Fc domain to enhance such interactions can improve CNS delivery of antibodies.

Preclinical Prediction of Pharmacokinetics for Fc-Engineered mAbs

Accurate prediction of human pharmacokinetics is essential for therapeutic antibody development. Transgenic mice expressing hFcRn (Tg32) are commonly used to evaluate mAb pharmacokinetics. A recent study applied this model to predict human pharmacokinetics of Fc-engineered antibodies with increased FcRn affinity.

Clearance and distribution parameters were assessed in Tg32 mice after intravenous administration of mAbs, with or without high-dose IVIG as a competitor for FcRn binding. Fc-engineered mAbs maintained low clearance in the presence of IVIG, unlike wild-type antibodies, which exhibited increased clearance. Allometric scaling was used to derive optimal exponents for pharmacokinetic parameters, enabling accurate prediction of human plasma concentration-time profiles. These results validate the use of FcRn transgenic mice to model the pharmacokinetics of Fc-engineered mAbs and support their application in early-stage development.

Impact of Antibody Aggregation on FcγR Binding

Antibody aggregation can influence FcγR engagement and may affect therapeutic efficacy and safety. Another recent study investigated how forced aggregation of an IgG1 antibody (mAb1) altered binding to FcγRs using surface plasmon resonance (SPR) and cell-based assays.

Aggregated mAb1 fractions showed increased binding to all FcγRs in avidity-based SPR formats and in solution, with the greatest effect observed for FcγRIIa. However, when binding was measured using an antibody-down SPR format (less sensitive to avidity), FcγRIIa binding was not increased. Functionally, FcγRIIa-mediated reporter activity increased slightly with aggregates, whereas FcγRIIIa activity decreased, likely due to altered glycosylation in aggregates. These findings highlight the need to monitor and control aggregation during manufacturing and formulation, as it can significantly affect FcγR binding and downstream immune signaling.

Precision Therapeutics Targeting FcRn: A New Biotech Emerges

Merida Biosciences made headlines this month with a $121M Series A to develop antibody-like drugs that eliminate pathogenic antibodies in autoimmunity and allergy.

• Platform: Novel Fc protein engineering enables selective depletion of autoantibodies and associated B cells, without broadly suppressing the immune system.

• Targets: Graves’ disease, membranous nephropathy, severe allergies.

Fc Engineering Connection: This startup reflects the growing commercialization of Fc-based selectivity mechanisms—showing how FcRn tuning is being translated into precision biologics.

FcRn Blockade: Mechanisms & Tradeoffs

Therapeutic antagonism of FcRn is a promising strategy for treating IgG-driven diseases—but not without challenges.

• Clinical synthesis: FcRn inhibitors (e.g., for MG, ITP, CIDP) effectively lower IgG levels but can cause hypoalbuminemia.

• Mechanistic study (University of Southampton): Albumin loss is tied to FcRn degradation and competitive binding with therapeutic antibodies.

Fc Engineering Insight: Future FcRn-targeting drugs will need greater binding specificity to avoid off-target impacts on albumin metabolism.

Expanding Applications: Fc-Enhanced Antibodies Against Tuberculosis

Fc engineering isn’t limited to autoimmunity—it’s also showing promise in infectious disease.

• Study highlight: Among 52 engineered variants targeting the Mtb capsule, several promoted neutrophil-mediated bacterial clearance. Single-cell RNA-seq also confirmed activation of antimicrobial pathways.

Implication: Fc design can reprogram immune cell behavior, not just enhance binding—broadening the scope of what antibody therapies can accomplish.