Impact of antibody Fc engineering on translational pharmacology, and safety: insights from industry case studies
September 9, 2025
The Fc Review:
Continuing our series taking a closer look at recent Fc-focused papers, what they found, and why it matters for antibody discovery and development.
How does Fc engineering shape the translation of antibodies from preclinical models to the clinic?
A new industry-wide review with 15 case studies examines the impact of Fc modifications on pharmacology and safety, and the challenges of predicting human outcomes from nonclinical studies.
Background:
Fc regions do not only extend half-life, they drive functions like ADCC, ADCP, CDC, and immune modulation. Engineering the Fc can enhance, silence, or redirect these activities. But the same changes that deliver potency can also introduce risk, especially when preclinical models do not fully mirror human Fc receptor biology.
The review highlights:
- Species differences in FcγR and FcRn expression complicate translation from rodent and NHP models to humans.
- Afucosylation and amino acid substitutions can strongly boost effector functions but may also uncover safety liabilities.
- Fc silencing and half-life extension strategies require careful assessment to avoid unintended biology.
- Case studies underscore the need for multi-pronged evaluation that combines specialized in vitro human primary-cell assays, transgenic models, and orthogonal biophysical methods such as SPR.
Implications:
The paper makes clear that Fc engineering is powerful, but its impact is context dependent. Translating nonclinical data requires assays that capture human biology and anticipate both efficacy and safety outcomes.
Our perspective:
Fc engineering can deliver meaningful gains, but each modification can ripple across multiple pathways from effector function to safety. That is why broad profiling across FcγR interactions, complement pathways, and primary-cell functions is essential. Evaluating engineered antibodies in a wide panel of human-relevant functional and biophysical assays, which form the core of SeromYx' assay portfolio, provides the clearest view of both intended effects and unanticipated trade offs.
SITC - Society for Immunotherapy and Cancer 2025
The Fc Review: How does Fc engineering shape bispecific antibody function? A Frontiers in Bioengineering and Biotechnology review explores how the Fc region can be tuned to control effector function, half-life, and safety, key levers in the design of next-generation bispecific antibodies ( bsAbs ). Background: Bispecific antibodies bring new therapeutic possibilities by engaging multiple targets at once. But this complexity also brings new challenges, from unwanted immune activation to altered pharmacokinetics . The Fc region plays a central role here, acting as both a stabilizing scaffold and a regulator of immune effector engagement
Abstract: Fc engineering to enhance antibody effector functions harbors the potential to improve therapeutic effects. Understanding FcγR expression and distribution in the tumor microenvironment prior to and following treatment may help guide immune-engaging antibody design and patient stratification. In this study, we investigated FcR-expressing immune effector cells in HER2 + and triple-negative breast cancers (TNBC), including neoadjuvant chemotherapy–resistant disease. FcγRIIIa expression, FcγRIIIa + NK cells, and classically activated (M1-like) macrophages correlated with improved anti-HER2 antibody efficacy. FcγRIIIa protein and FcγRIIIa + NK cells and macrophages were present in primary TNBC and retained in treatment-resistant tumors.
Background Authorized COVID-19 vaccines require boosters for continued protection; however, the lack of crossplatform compatible boosters creates practical challenges to keeping populations protected. Methods This Phase 3, multicenter, international, randomized, active-controlled trial compared UB-612 as a thirddose heterologous booster to BNT162b2, ChAdOx1-S, or BBIBP-CorV homologous boosters in healthy subjects aged ≥16 years. Participants were randomly assigned 1:1 to receive a single intramuscular injection of UB-612 or an active comparator matching the primary dose, and were stratified for age, sex, N-protein seropositivity, and time since the last dose of their primary series COVID-19 vaccination. The primary objective was to show noninferiority of neutralizing antibody geometric mean titer (GMT) against live SARS-CoV-2 Wuhan strain after boosting with UB-612 or each of the licensed platform vaccines. Secondary and exploratory objectives covered short and long-term antibody responses. The safety analysis addressed subject and investigator reported adverse events. The study was registered on ClinicalTrials.gov, NCT05293665, and completed on September 12, 2023.
The Fc Review: Kicking off a new series where we take a closer look at recent Fc-focused papers. What they found, and why it matters for antibody discovery and development. How much does FcγR genetic variation influence an antibody’s function? A recent FDA review examines the often-overlooked role of Fcγ receptor (FcγR) polymorphisms in shaping therapeutic antibody activity, and the implications for the assays used to measure it. Background: FcγRs are the “effector arm” connection between antibodies and immune cells, driving processes like ADCC and ADCP. Genetic variation in these receptors can alter binding strength, modulate effector function, and impact clinical outcomes. Understanding this interplay is important for therapeutic design, potency assessment, and patient response prediction.
Journal Abstract: Antibodies targeting the malaria circumsporozoite protein (CSP) can prophylactically protect against malaria by targeting Plasmodium parasites before they establish symptomatic blood-stage disease. Engineering the antibody Fc region to more effectively engage immune effector functions has produced therapeutic antibodies with enhanced potency against viral and oncological targets. However, whether Fc-dependent immune effector functions can contribute to the protection of malaria CSP mAbs or be further enhanced via engineering has been limitedly tested. Here, we report that Fc-dependent effector functions are required for achieving maximal protection via prophylactic treatment with the CSP mAb 317. We further report that Fc engineering modulated the activity of multiple CSP mAbs in multiple in vitro assays of effector function. Our studies revealed that the mAbs L9 and CIS43 were more potent drivers of antibody-dependent phagocytosis, NK activation and killing, and complement deposition. In contrast, 317, but not L9 and CIS43, drove enhanced activation of CSP-responsive T-cells after DC acquisition of mAb-complexed antigens. Collectively, our data suggest that effector function represents an important mechanism of anti-CSP antibodies with the potential to enhance activity through Fc engineering.
Antibody Engineering & Therapeutics 2025
The Fc-Mediated Effector Function Summit
Authors: Kaplonek P, et al. Sci Transl Med. 2022 May 18;14(645):eabm2311.
Background Crimean-Congo hemorrhagic fever is a tick-borne febrile illness with wide geographic distribution. In recent years the geographic range of CCHFV and its tick vector have increased, placing an increasing number of people at risk of CCHFV infection. Currently there are no widely available vaccines and although the World Health Organization recommends ribavirin for treatment, its efficacy is unclear. Vaccines are critically needed for CCHFV. Methods Here we evaluated a promising replicating RNA vaccine for CCHFV in a Cynomolgus macaque model of disease. Findings In primed and boosted macaques, we found that our replicating RNA vaccine expressing the CCHFV nucleoprotein (repNP) was highly immunogenic, eliciting a robust non-neutralizing antibody response that conferred significant protection against CCHFV challenge. Macaques receiving a single repNP vaccination were partially protected against CCHFV challenge. Interpretation Our data demonstrate that our repNP vaccine and NP-specific antibody can protect against CCHFV in non-human primates. Funding This study was supported by the Intramural Research Program of the NIAID/NIH and the Medical CBRN Defense Consortium grant #MCDC2204-011.
