NextGen Biomed 2025

Abstract: RTS,S/AS01 (RTS,S) is one of two WHO-recommended malaria vaccines for children in moderate-to-high transmission settings. Yet, no validated immune correlate of protection (CoP) has been established for this vaccine. We selected 16 biomarkers to further assess as candidate CoPs, based largely on their ability to well-predict post-challenge outcomes in a integrative correlates analysis of two phase 2a controlled human malaria infection (CHMI) studies, Malaria-068 and Malaria-071. We evaluated the predictive power of these 16 biomarkers in two additional phase 2a CHMI studies, Malaria-092 and Malaria-102, to confirm these candidate CoPs in new malaria vaccine trials. In MAL092, malaria-naïve volunteers were challenged three months after a series of two or three doses of RTS,S/AS01, and in MAL102, a subset were boosted nine months later and re-challenged after three weeks. The 16 biomarkers included Plasmodium falciparum circumsporozoite protein (CSP)-specific IgG antibodies targeting the CSP NANP-repeat region (CSP IgG ELISA), NANP repeat-specific antibody binding to human Fc gamma receptors (FcγRs), CSP-specific antibody Fc effector functions, total NANP6-specific serum Ig measured by biolayer interferometry (BLI), and NANP6-specific IgG1 antibodies measured by binding antibody multiplex assay. Immunogenicity analyses confirmed that the vaccine regimens elicited robust immune responses, including multiple biomarkers not previously reported on, in both trials. I 52 n MAL092, participants clustered into two distinct immunogenicity profiles that overlapped with malaria protection status. In univariate logistic regression analyses, most biomarkers were significantly associated with protection when measured on the day of challenge in both trials. Notably, the same three biomarkers ranked as top correlates in both trials (FCGR2AH NANP6, FCGR2AR NANP6, and FCGR2B NANP6; all adjusted p-values <0.001), with similar effect sizes across studies. Despite these strong associations, no biomarker demonstrated significantly better individual-level predictive performance than CSP IgG ELISA. In MAL092, CSP IgG ELISA achieved an area under the curve (AUC) [95% confidence interval (CI)] of 0.74 (0.63, 0.84), compared with AUCs of 0.76 - 0.78 for the top five biomarkers, all of which reflected NANP6-specific FcγR binding (all adjusted p-values > 0.37 versus CSP IgG ELISA). Predictive models trained on data from two prior CHMI studies and applied to MAL092 and MAL102 identified a model based on FCGR2B NANP6 (validation AUC = 0.77 in MAL092; 0.80 in MAL102) as the best-performing univariate model for both studies. The best-performing multivariate predictive model for MAL092 was based on BLI NANP6 Dissociation AUC and ADCP NANP6 (validation AUC = 0.76), and in MAL102, it was based on CSP IgG ELISA, BLI NANP6 Dissociation AUC, and ADCP NANP6 (validation AUC = 0.82). The next approximately 10 highest-ranked models, however, had comparable performance with overlapping 95% CIs, and none were clearly superior to CSP IgG ELISA (validation AUCs 0.74 and 0.71 in MAL092 and MAL102, respectively). Collectively, these findings suggest that the majority of the previously identified candidate CoPs also hold up well in two additional malaria vaccine CHMI trials and underscore the continued utility of the CSP IgG ELISA readout as a robust marker of protection. Further studies are needed to determine whether these candidate CoPs hold in malaria-endemic field settings. Identifying validated CoPs that predict malaria vaccine efficacy would promote the development and approval of more effective and durable next-generation vaccines. These advances could also inform vaccine strategies for other infectious diseases.

Abstract: Respiratory syncytial virus (RSV) is a leading cause of respiratory illness and there is no universally accepted serological correlate of protection (CoP). We evaluated serum pre-fusion immunoglobulin G binding (preF-IgG) and RSV-A2 neutralizing antibodies (RSV-nAb) in adults aged >60 years following vaccination with investigational Ad26.RSV.preF–RSV preF vaccine. PreF-IgG and RSV-nAb measured pre-vaccination (Day 1) and Day 15 post-vaccination were assessed as CoPs against RSV-mediated acute respiratory infection (ARI) and lower respiratory tract disease (LRTD). An increase in both preF-IgG and RSV-nAb at Day 15 was significantly associated with reduced occurrence of RSV-mediated ARI and LRTD during follow-up. Based on controlled vaccine-efficacy curves and Prentice criteria, both markers were identified as CoPs for RSV-mediated ARI and LRTD. These results were validated using samples from a second randomized, phase 3 efficacy trial. Comprehensive profiling of preF-specific antibody responses showed that preF IgG3 and IgG2 may also contribute to protection from RSV.

The Fc Review: When you engineer the Fc to enhance one mechanism, what else changes? A recent Nature Cancer study takes a closer look at that question using an agonistic anti-GITR antibody, showing how Fc optimization can influence not only FcγR engagement and Treg depletion, but other immune pathways contributing to antitumor activity. Background: GITR is a stimulatory immune checkpoint receptor being explored as a target for cancer immunotherapy. While agonistic anti-GITR antibodies have shown promise preclinically, clinical efficacy has been limited. Because FcγR engagement can contribute to the activity of these antibodies, the authors used Fc protein engineering and glycoengineering to alter interactions with different human FcγRs and examine how those changes affected antitumor activity. The study highlights: Fc variants with enhanced engagement of activating FcγRIIa or FcγRIIIa increased antitumor activity, while preferentially enhancing engagement of inhibitory FcγRIIb did not improve tumor control. Combining G236A with reduced fucosylation enhanced engagement of both activating FcγRIIa and FcγRIIIa, without enhanced binding to FcγRIIb. This combined variant showed greater antitumor activity than variants enhancing either activating receptor individually in the tested model. Fc-active variants depleted Tregs within the tumor. However, the optimized variant and IgG1 produced similar Treg depletion despite differences in therapeutic activity, pointing to an additional FcγR-mediated mechanism. The Fc-optimized antibody also increased dendritic cell activation, and the authors found that conventional DCs, particularly cDC1s, were required for the Fc-mediated antitumor effect in their models. Further experiments connected this activity to CD4 T cell–DC engagement, with downstream CD4 T cell cytotoxicity and enhanced CD8 T cell activity

The Fc Review: Stepping a little outside therapeutic antibody and vaccine development this week to highlight a fascinating piece of fundamental antibody biology. A recent Science study uncovers an unexpected role for antibody-mediated complement activity in the adult mouse brain, showing that locally produced IgM and C1q work together to drive activity-dependent synapse elimination.  While this work is still early and was performed in mice, it offers an interesting look at how #antibody effector mechanisms may extend beyond the roles we typically think about. Background: Antibodies are typically viewed through the lens of infection, vaccination, or therapeutic development. Their effector functions, including complement activation, are well established as key mechanisms for eliminating pathogens and diseased cells. This study asks whether antibody-mediated complement activity also contributes to normal brain physiology. Using mouse models, the authors investigated how neuronal activity influences complement-mediated synapse remodeling and whether adaptive immune components participate in this process. The study highlights: Increased neuronal activity triggered localized C1q deposition and complement-dependent synapse loss in the adult mouse hippocampus. Activity-dependent recruitment of antibody-secreting B-lineage cells led to local production of antigen-specific IgM, which contributed to C1q deposition at synapses. Reducing neuronal hyperactivity in a mouse model of Alzheimer's disease decreased C1q deposition and partially restored synaptic density. The findings identify a previously unrecognized interaction between adaptive immunity, complement biology, and neuronal circuit remodeling in the adult brain.

The Fc Review: Can better antibody engineering improve safety, not just efficacy? A recent review in Antibody Therapeutics examines how the molecular design of antibody-drug conjugates (ADCs) influences both nonclinical and clinical toxicities, highlighting that safety is determined by far more than the payload alone. Background: ADCs are often discussed in terms of target selection and payload potency, but their safety profile is shaped by the combined properties of the antibody, linker, payload, conjugation strategy, and target biology. This review examines data from marketed ADCs and explores how each component contributes to toxicity, providing a useful framework for designing safer next-generation therapeutics. The study highlights: ADC toxicity is influenced by the combined effects of target antigen expression, antibody structure, linker stability, payload properties, and conjugation technology rather than any single design feature. The Fc region can contribute to off-target toxicity through receptor-mediated uptake. The review discusses roles for Fcγ receptors, FcRn, and C-type lectin receptors in nonspecific internalization that may influence safety. Site-specific conjugation technologies can improve homogeneity, produce more consistent drug-to-antibody ratios (DAR), and enhance stability compared with earlier random conjugation approaches. Properties such as linker stability, payload hydrophobicity, charge, and DAR all influence biodistribution, payload release, and toxicity, underscoring the importance of considering these design variables together.

The Fc Review: When does antibody bivalency help, and when can it work against you? A recent mAbs study explores the impact of antibody bivalency on antigen occupancy and cell surface opsonization, revealing that the same property can be advantageous or disadvantageous depending on the intended mechanism of action (MoA). Background: Most therapeutic antibodies are bivalent, meaning they can bind two target antigens simultaneously. This avidity effect is often viewed as beneficial because it increases apparent binding strength and can improve target engagement. However, therapeutic success is not always driven by target occupancy alone. For mechanisms that rely on Fc-mediated effector function, the number of antibodies decorating the target cell surface may be just as important. The study highlights: Bivalent antibodies achieved higher antigen occupancy than comparable monovalent antibodies across a range of affinities and antigen densities. At the same time, bivalency reduced the total number of antibodies bound per cell because a single antibody could occupy two antigens simultaneously. The authors describe an "avidity barrier," where achieving equivalent levels of cell surface opsonization requires substantially higher concentrations of a bivalent antibody. The optimal balance between occupancy and opsonization depended on factors including antibody affinity, valency, and target antigen density.

Abstract: Acute SARS-CoV-2 infection triggers the de novo production of diverse, functional autoantibodies (AABs) that remain elevated in Long COVID (LC), but their pathogenic role remains unclear. Using tissue-based immunofluorescence, ELISA, human protein array, and mass spectrometry assays, we identified a broad range of AAB targets among individuals with LC. Individuals with neurocognitive symptoms showed increased AABs against central and peripheral nervous system proteins. Purified IgG reacted with human locus coeruleus, thalamus, adrenal gland, thyroid, and cross-reacted with mouse sciatic nerve and meninges. CNS-reactive AABs correlated with several neurological symptoms. MED20-targeting IgG from patients with LC showed enhanced antibody-dependent phagocytosis. Passive transfer of IgG from individuals with LC into mice induced fatigue-like behavior, loss of balance/coordination, thermal hyperalgesia, small fiber nerve damage, and increased pain-related neuronal activity, recapitulating patients’ symptoms. These findings suggest that targeting AABs might offer therapeutic benefits for this LC subgroup. 

Type: Conference Dates: November 16th-18th, 2026 Location: Peabody, MA

The Fc Review: How much does Fc design influence the next generation of ADCs? A recent Cell review explores the rapid evolution of antibody-drug conjugates (ADCs), highlighting how advances in payloads, linker technologies, and antibody engineering are reshaping the field across both hematologic and solid tumors. Background: ADCs were originally developed as targeted delivery vehicles for highly potent payloads. But as the field matures, it is becoming increasingly clear that ADC activity is shaped by far more than antigen targeting alone. Factors such as linker stability, payload permeability, tumor microenvironment, bystander killing, and Fc-mediated interactions can all influence therapeutic performance. The study highlights: Fc-mediated mechanisms such as ADCC, ADCP, and complement activation can contribute to ADC activity beyond payload delivery. Some next-generation ADCs are intentionally engineered to enhance Fc effector function, while others incorporate Fc-silencing strategies to minimize off-tumor interactions. Payload selection, linker chemistry, and drug-to-antibody ratio all influence efficacy, safety, and bystander activity. Tumor antigen expression alone is often insufficient to predict ADC behavior, highlighting the importance of functional characterization and biological context.