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At least 19 recordsLinked to original sources
PubMed2026

Distinct HLA Associations for Antibody Multireactivity With Citrulline-Containing Type II Collagen Epitopes Versus More Limited Antibody Reactivity With Citrulline-Containing IgG Epitopes in Rheumatoid Arthritis.

OBJECTIVE: Anticitrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) can be promiscuous, with cross-reactive binding to many antigens containing short motifs, or private with little cross-reactivity. Also, ACPA reactivity patterns differ among patients with RA, including for motif-containing epitopes in important self-antigens like collagen and IgG (bound by RA-associated rheumatoid factors [RFs]), with limited understanding of the underlying mechanism. The objective of this study was to determine if HLA alleles associate with ACPA reactivity patterns. METHODS: For 100 ACPA+RF+ participants with RA, serum IgG binding was quantified by enzyme-linked immunosorbent assay to 10 citrulline-containing peptides derived from Type II collagen and IgG1 (nine with motifs), and HLA loci were genotyped. Also, antibody and serum multireactivity were evaluated. HLA alleles present differentially in RA participants with high versus low IgG binding to specific peptides, as well as with multireactivity versus limited reactivity were identified by Fisher's exact test. RESULTS: Serum IgG multireactivity for citrulline-glycine motif-containing collagen peptides was high, at least partially due to promiscuous antibodies. HLA-DQA1*01:02 was present in more participants with anticitrullinated collagen antibodies and multireactive sera. In contrast, serum multireactivity was low for IgG1-derived peptides due at least in part to more private antibodies. Shared epitope-containing HLA-DRB1*04:01 was present more frequently in participants with RA-associated RFs irrespective of the citrulline-serine motif and less frequently in participants with anticitrullinated collagen antibodies. Several HLA alleles associated with specific antibody reactivities. CONCLUSION: Different HLA alleles may contribute to the different reactivity patterns of promiscuous anticitrullinated collagen antibodies and more private RA-associated RFs.

Humans↗
PubMed2026

Nonclinical investigation of the potential of MHAA4549A, an anti-influenza A therapeutic antibody, to mediate antibody-dependent enhancement.

Antibody-dependent enhancement (ADE) of infection and disease is a theoretical safety risk for antiviral antibodies against seasonal viruses with antigenic drift, such as influenza. ADE of infection may occur if virus-specific antibodies at subtherapeutic, nonneutralizing concentrations facilitate virus uptake, thus potentially enhancing virus replication. In contrast, ADE of disease reflects exacerbation of viral disease severity through viral replication-dependent or -independent mechanisms. Because of the theoretical concern of ADE, nonclinical safety assessment of therapeutic anti-influenza antibodies includes a thorough evaluation of ADE potential. The current set of studies was conducted to investigate the potential of MHAA4549A-a broadly specific, neutralizing, therapeutic anti-influenza A antibody-to elicit ADE of infection and disease of influenza H3N2 A/Aichi/2/68 (X31) across a broad dose range. Assessment of ADE was based on totality of results from both in vitro and mouse influenza studies with integration across study endpoints. In vitro studies demonstrated that MHAA4549A can mediate increased X31 entry into human and murine monocytic cells, but increased uptake did not result in enhanced viral replication or release under physiologic conditions. In a mouse model of X31 infection, intravenous administration of MHAA4549A resulted in delayed body weight recovery, but no exacerbation in orthogonal endpoints including mortality, lung viral titers or genomes, lung weights, or severity of influenza pneumonia. Overall, the totality of nonclinical data did not demonstrate any clear indication of ADE of infection at nonneutralizing concentrations, suggesting a low risk for MHAA4549A to cause enhanced influenza A-mediated disease at subtherapeutic doses.

Animals↗
PubMed2026

MET-Aberrant non-small cell lung cancer: from kinase dependence to cell-surface targetability-mechanistic basis and biomarker framework for bispecific antibodies and antibody-drug conjugates.

MET-aberrant non-small cell lung cancer (NSCLC) is not a uniform therapeutic entity. Its biology, diagnostic pathways, and treatment sensitivity differ across MET exon 14 skipping alteration (METex14), MET amplification, and MET overexpression. This heterogeneity cannot be fully explained by conventional event-based classification and is reflected in the distinct clinical activity of MET tyrosine kinase inhibitors (MET-TKIs), bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). With the emergence of antibody-based therapies, MET has evolved from a signaling driver to a cell-surface target for receptor modulation and payload delivery. We therefore propose a clinically anchored two-dimensional framework for interpreting therapeutic relevance in MET-aberrant NSCLC: kinase dependence and cell-surface targetability. Neither dimension should be regarded as a directly measurable binary variable. Kinase dependence is inferred from genomic and treatment-contextual proxies, most strongly METex14 and, more conditionally, high-level focal MET amplification. Cell-surface targetability is approximated by drug-specific IHC assessment of assay-defined c-MET protein expression; however, receptor internalization, intracellular trafficking, and payload delivery capacity remain incompletely measurable in routine clinical practice. Within this framework, MET-TKIs have the most evidence-supported established role in tumors with evidence of MET-driven kinase dependence. EGFR × MET BsAbs have demonstrated clinical activity in broad post-osimertinib EGFR-mutant NSCLC, while EGFR/MET co-dependence or MET-mediated bypass activation provides a mechanistic rationale for their use; MET-defined preferential benefit remains to be prospectively established. MET-directed antibody-drug conjugates (MET-ADCs) are supported in drug- and assay-defined populations with high c-MET protein overexpression, although the predictive relevance of delivery-related factors remains hypothesis-generating. Accordingly, MET testing should shift from single-event detection to platform-oriented stratification: next-generation sequencing (NGS) for driver alterations and resistance profiles, fluorescence in situ hybridization (FISH) for high-level focal amplification, and immunohistochemistry (IHC) for surface expression relevant to antibody-based therapies. This framework is intended to organize current biological and clinical evidence rather than to replace drug-specific companion diagnostics, regulatory indications, or prospectively validated treatment-selection algorithms. Precision treatment of MET-aberrant NSCLC is thus moving from event-based drug selection toward mechanism-based therapeutic matching. Future priorities include standardizing biomarkers, defining optimal target populations, and aligning biological subtypes, diagnostic strategies, and therapeutic platforms.

Antibody-drug conjugate↗
PubMed2026

Long-term follow-up of a phase 1/2 trial of anti-GDF-15 antibody visugromab plus anti-PD-1 antibody nivolumab in anti-PD-1/-L1 relapsed/refractory solid tumors.

BACKGROUND: Resistance to anti-PD-1/PD-L1 therapy is a major unmet need. Growth Differentiation Factor 15 (GDF-15) has been identified as a key resistance factor for anti-PD-1/PD-L1 immunotherapy. Visugromab, a neutralizing anti-GDF-15 antibody, plus the anti-PD-1 antibody nivolumab (V+N) was evaluated in the first-in-human phase 1/2a GDFATHER-01 trial in heavily pretreated participants with locally advanced/metastatic non-squamous non-small-cell lung cancer (nsq NSCLC), urothelial carcinoma (UC), or hepatocellular carcinoma (HCC), stringently defined as anti-PD-1/PD-L1-relapsed/refractory, and showed encouraging objective responses. This analysis reports long-term follow-up of these three phase 2 expansion cohorts of the GDFATHER-01 trial. METHODS: Seventy-seven participants with nsq NSCLC (N=22), UC (N=27), and HCC (N=28) received visugromab (10 mg/kg) plus nivolumab (240 mg) every two weeks until disease progression or unacceptable toxicity. RESULTS: Objective response rates (RECIST v1.1) were 18.2% for nsq NSCLC (4/22; 95%CI 5.2-40.3), 18.5% for UC (5/27; 95%CI 6.3-38.1), and 14.3% for HCC (4/28; 95%CI 4.0-32.7). Median duration of response (DoR) was 32.2 months (95%CI 5.5-38.0), 28.8 months (95%CI 7.4-39.4), and 19.4 months (95%CI 5.8-39.7; with protracted recruitment), respectively, with 7/13 responses (53.8%) ongoing. Confirmed complete response or complete metabolic response (CR or CMR) among responders was 61.5% (8/13), with 7/8 ongoing. In addition, 46.2% (6/13) of responders achieved a deeper response on V+N per RECIST v1.1 than with the prior anti-PD-(L)1 therapy; median DoR on V+N was 28.8 months (95%CI 7.4-38.0) versus 12.0 months (95%CI 8.0-24.0) on initial anti-PD-1/PD-L1 treatment. V+N was generally well tolerated. CONCLUSIONS: In heavily pretreated, advanced/metastatic participants with nsq NSCLC, UC, or HCC who were anti-PD-1/PD-L1-relapsed/refractory, V+N achieved deep and durable objective responses. The observed DoR, depth of response, and CR+CMR rate among responders exceeded those reported for their initial anti-PD-1/PD-L1 therapy. These findings suggest that GDF-15 blockade with visugromab can overcome resistance and enhance the magnitude and durability of anti-PD-1/PD-L1 responses, and warrant further exploration in randomized trials. REGISTRY: ClinicalTrials.gov, TRN: NCT04725474, Registration date: 25 January 2021; EudraCT, TRN: 2020-002103-19, Registration date 16 Dec 2020.

Humans↗
PubMed2025

Serum proteomics reveals high-affinity and convergent antibodies by tracking SARS-CoV-2 hybrid immunity to emerging variants of concern.

The rapid spread of SARS-CoV-2 and its continuing impact on human health has prompted the need for effective and rapid development of monoclonal antibody therapeutics. In this study, we investigate polyclonal antibodies in serum and B cells from the whole blood of three donors with SARS-CoV-2 immunity to find high-affinity anti-SARS-CoV-2 antibodies to escape variants. Serum IgG antibodies were selected by their affinity to the receptor-binding domain (RBD) and non-RBD sites on the spike protein of Omicron subvariant B.1.1.529 from each donor. Antibodies were analyzed by bottom-up mass spectrometry, and matched to single- and bulk-cell sequenced repertoires for each donor. The antibodies observed in serum were recombinantly expressed, and characterized to assess domain binding, cross-reactivity between different variants, and capacity to inhibit RBD binding to host protein. Donors infected with early Omicron subvariants had serum antibodies with subnanomolar affinity to RBD that also showed binding activity to a newer Omicron subvariant BQ.1.1. The donors also showed a convergent immune response. Serum antibodies and other single- and bulk-cell sequences were similar to publicly reported anti-SARS-CoV-2 antibodies, and the characterized serum antibodies had the same variant-binding and neutralization profiles as their reported public sequences. The serum antibodies analyzed were a subset of anti-SARS-CoV-2 antibodies in the B cell repertoire, which demonstrates significant dynamics between the B cells and circulating antibodies in peripheral blood.

Humans↗
PubMed2026

Mapping antibody sequences and effector functions across spatial niches.

Antibodies are fundamental to human health but can also drive pathology. Each antibody has a molecular specificity, encoded by their clonally heritable B cell receptor (BCR). Recent advances in spatial transcriptomics coupled with repertoire sequencing have enabled capturing antibody-secreting cells (ASCs) and their clonal BCR within their tissue microenvironment. However, our understanding of antibody production niches remains limited. Furthermore, where antibodies are produced can be distinct from where antibodies exert their effector function. Here, we propose a conceptual spatial framework to distinguish between 'antibody production niches', defined by the ASC, BCR, and niche composition, versus 'antibody functional niches', composed of the antibody, antigen, and effector landscape. We then examine the possibilities and challenges to map and link antibody-encoding sequences and antibody effector functions using current and emerging technologies. Combined, we argue that integrating spatial sequence data with the antibody functional context is essential to decode the architecture of antibody-mediated immunity.

Humans↗
PubMed2025

Increased immunogen valency improves the maturation of vaccine-elicited HIV-1 VRC01-like antibodies.

Antibodies belonging to the VRC01-class display broad and potent neutralizing activities and have been isolated from several people living with HIV (PLWH). A member of that class, monoclonal antibody VRC01, was shown to reduce HIV-acquisition in two phase 2b efficacy trials. VRC01-class antibodies are therefore expected to be one component of an effective HIV-1 vaccine elicited response. In contrast to the VRC01-class antibodies that are highly mutated, their unmutated forms do not engage HIV-1 envelope (Env) and do not display neutralizing activities. Hence, specifically modified Env-derived proteins have been designed to engage the unmutated forms of VRC01-class antibodies, and to activate the corresponding naïve B cells. Selected heterologous Env must then be used as boost immunogens to guide the proper maturation of these elicited VRC01-class antibodies. Here we examined whether and how the valency of the prime and boost immunogens influences VRC01-class antibody-maturation. Our findings indicate that, indeed the valency of the immunogen affects the maturation of elicited antibody responses by preferentially selecting VRC01-like antibodies that have accumulated somatic mutations present in broadly neutralizing VRC01-class antibodies isolated from PLWH. As a result, antibodies isolated from animals immunized with the higher valency immunogens display broader Env cross-binding properties and improved neutralizing potentials than those isolated from animals immunized with the lower valency immunogens. Our results are relevant to current and upcoming phase 1 clinical trials that evaluate the ability of novel immunogens aiming to elicit cross-reactive VRC01-class antibody responses.

AIDS Vaccines↗
PubMed2026

Antiadalimumab Antibodies in Patients With Inflammatory Ocular Diseases: Incidence and Clinical Outcomes.

PURPOSE: To determine the incidence, effect on adalimumab drug levels, and clinical consequences of antiadalimumab antibody formation, and to assess potential risk factors. DESIGN: Retrospective clinical cohort study. PARTICIPANTS: One hundred twenty-eight patients treated with adalimumab who underwent antiadalimumab antibody monitoring. METHODS: Beginning October 2023, regularly scheduled antiadalimumab antibody and adalimumab level testing was begun. Using staggered entry analysis, anchored observation to treatment initiation, incidence was calculated. Time-updated models evaluated risk factors for antiadalimumab antibody formation. MAIN OUTCOME: Incidence of antiadalimumab antibodies. RESULTS: Antiadalimumab antibodies developed in 37 of 128 patients for a rate of 0.077 per person-year (PY) (95% confidence interval [CI] 0.055/PY, 0.104/PY). Median serum adalimumab concentrations were significantly lower in antiadalimumab antibody-positive blood samples (2.6 &#xb5;g/mL; interquartile range 0.8, 7.0) than in antibody-negative samples (10.2 &#xb5;g/mL; interquartile range 6.9, 15.1), P < .00001. In time-updated analyses, there was a suggestion that concomitant immunosuppression was associated with a reduced risk of antiadalimumab antibodies (odds ratio [OR] 0.64; 95% CI 0.37, 1.10; P = .10) and weekly adalimumab dosing was associated with a reduced risk (OR 0.62; 95% CI 0.42, 0.91; P = .01). Antiadalimumab antibodies were associated with active ocular inflammation (OR 3.68; 95% CI 1.99, 6.82; P < .00001). CONCLUSIONS: Antiadalimumab antibodies occur commonly among patients treated with long-term adalimumab, with a cumulative incidence of nearly 50% by 8 years of therapy. Antibody formation was associated with lower serum adalimumab levels and active ocular inflammation.

Humans↗
PubMed2025

Antibody responses in Klebsiella pneumoniae bloodstream infection: a prospective cohort study.

BACKGROUND: Klebsiella pneumoniae is a leading cause of infection-related deaths globally, yet little is known about human antibody responses to invasive K&#xa0;pneumoniae. We sought to determine whether the O-specific polysaccharide antigen is immunogenic in humans with K&#xa0;pneumoniae bloodstream infection. We also sought to define the cross-reactivity of human antibody responses among structurally related K&#xa0;pneumoniae O-specific polysaccharide subtypes and to assess the effect of capsule production on O-specific polysaccharide-targeted antibody binding and function. METHODS: In this prospective cohort study, we compared plasma antibody responses to O-specific polysaccharide in a cohort of consecutively enrolled patients with K&#xa0;pneumoniae bloodstream infection with controls, specifically a cohort of healthy individuals and a cohort of individuals with Enterococcus spp bloodstream infection. Patients were enrolled at the Massachusetts General Hospital, a tertiary hospital with affiliated clinics in the USA. We excluded patients whose isolates were not confirmed to be K&#xa0;pneumoniae by whole-genome sequencing. The primary outcome was the measurement of plasma IgG, IgM, and IgA antibody responses. We performed flow cytometry to measure the effects of K&#xa0;pneumoniae capsule production on O-specific polysaccharide antibody binding and O-specific polysaccharide antibody-mediated complement deposition, using patient isolates with variable levels of capsule production and isogenic capsule-deficient strains derived from these isolates. FINDINGS: We enrolled 129&#xa0;consecutive patients with suspected K&#xa0;pneumoniae bloodstream infection between July 24, 2021,&#xa0;and August 4, 2022, of whom 69&#xa0;patients (44 [64%] male and 25 [36%] female) with confirmed K&#xa0;pneumoniae bloodstream infection were eligible for immunological evaluation. Common O-specific polysaccharide serotypes (O1,&#xa0;O2, O3, and O5) accounted for 57 (83%) of 69&#xa0;infections. O-specific polysaccharide was immunogenic in patients with K&#xa0;pneumoniae bloodstream infection, and peak O-specific polysaccharide-IgG antibody responses in patients were ten-fold to 30-fold higher than antibody responses detected in healthy controls, depending on the serotype. There was cross-reactivity among similar O-specific polysaccharide subtypes, including the O1v1 and O1v2, O2v1 and O2v2, and O3 and O3b subtypes, as well as between the O1 and O2 types. Capsule produced by both hyperencapsulated and non-hyperencapsulated K&#xa0;pneumoniae inhibited O-specific polysaccharide-targeted antibody binding and function. INTERPRETATION: O-specific polysaccharide was immunogenic in patients with K&#xa0;pneumoniae bloodstream infection, supporting its potential as a candidate vaccine antigen. The cross-reactivity observed between similar O-specific polysaccharide subtypes in patients with K&#xa0;pneumoniae bloodstream infection suggests that it might not be necessary to include all subtypes in an O-specific polysaccharide-based vaccine. However, these observations are tempered by the fact that capsule production, even in non-highly encapsulated strains, has the potential to interfere with O-specific polysaccharide antibody binding. This finding could limit the effectiveness of vaccines that exclusively target O-specific polysaccharide. FUNDING: National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

Humans↗
PubMed2025

One thousand SARS-CoV-2 antibody structures reveal convergent binding and near-universal immune escape.

Understanding antibody recognition and adaptation to viral evolution is central to vaccine and therapeutic development. Over 1,100 SARS-CoV-2 antibody structures have been resolved, marking the largest structural biology effort for a single pathogen. We present a comprehensive analysis of this landmark dataset to investigate the principles of antibody recognition and immune escape. Human immunoglobulins and camelid single-chain antibodies dominate, collectively mapping 99% of the receptor-binding domain. Despite remarkable sequence and conformational diversity, antibodies exhibit convergence in their paratope structures, revealing evolutionary constraints in epitope selection. Analyses reveal near-universal immune escape of antibodies, including all clinical monoclonals, by advanced variants such as KP3.1.1. On average, over one-third of antibody epitope residues are mutated. These findings support pervasive immune escape, underscoring the need to effectively leverage multi-epitope-targeting strategies to achieve durable immunity. To support community accessibility, we developed an interactive web server for visualization and analysis of antibody-antigen complexes and mutational data.

SARS-CoV-2↗
PubMed2026

Design of a modified platelet immunofluorescence test to assess platelet-reactive antibody burden and its association with platelet functional exhaustion and clinical features in chronic immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by platelet destruction and dysfunction associated with anti-platelet antibodies. This study evaluated the relationship between total anti-platelet antibody burden, measured using a modified platelet immunofluorescence test (PIFT), platelet functional responses and clinical features in chronic ITP. Thirty-one patients with chronic ITP and 20 healthy controls were included. Bleeding severity was assessed, and platelet function was analysed in peripheral blood by measuring P-selectin expression, PAC-1 binding (antibody against active conformation of GPIIb/IIIa)&#xa0;and reactive oxygen species (ROS) generation at baseline and following agonist stimulation. Relative platelet-reactive antibody burden was assessed using a ratio-based PIFT assay. ITP patients demonstrated significantly higher antibody burden compared with controls. Increased platelet-reactive immunoglobulin G (IgG) signals were associated with reduced platelet responsiveness to agonist stimulation. Antibody burden correlated with bleeding severity (p&#x2009;<&#x2009;0.01) but not with platelet count. Non-responders exhibited significantly higher antibody levels than responders. receiver operator characteristic (ROC) analysis demonstrated discrimination between responder groups at a PIFT cut-off &#x2265;3.85 (area under the curve [AUC] 0.877, sensitivity 80%; specificity 87%). Patients above this threshold showed attenuated platelet functional responses. Taken together, this study concluded that quantitative assessment of total antibody burden against platelets using modified PIFT is associated with platelet dysfunction, bleeding severity and treatment response status in chronic ITP.

Humans↗
PubMed2026

Biofilm-derived curli and Z-DNA shape anti-DNA antibody responses during Salmonella infections.

Antibodies to Z-DNA, a non-canonical DNA conformation with a left-handed zigzag backbone, are abundant in the serum of patients with systemic lupus erythematosus (SLE), with levels increasing with disease activity and flares. As SLE is associated with bacterial infections, and as extracellular DNA (eDNA) within biofilms of several bacterial species has been shown to adopt the Z-DNA conformation, bacterial Z-DNA may represent a source of immunogenic Z-DNA in SLE and other related autoimmune conditions. In these studies, we investigated whether eDNA in Salmonella biofilms also contained Z-DNA and whether such Z-DNA could elicit an antibody response. Using antibody-based staining approaches, we observed abundant eDNA in Salmonella enterica serovar Typhimurium (STm) biofilms in both the Z- and canonical B-DNA configurations, consistent with the highly Z-prone nature of the GC-rich Salmonella genome. To assess the functional contribution of these DNA conformations to biofilm integrity, biofilms were treated with DNase I, which lacks enzymatic activity against Z-DNA, or with benzonase, a nonspecific nuclease that degrades both B- and Z-DNA. DNase I treatment applied after biofilm maturation was less effective at thinning biofilms than treatment during early biofilm formation, a pattern also observed with benzonase treatment. Purified curli:DNA complexes contained Z-DNA and, when administered intraperitoneally to mice, elicited robust anti-Z-DNA antibody responses. Similarly, infection with invasive STm induced the production of anti-Z-DNA antibodies in vivo. Moreover, STm infection in mice fed a diet that promotes biofilm development was associated with increased Z-DNA levels in the cecal lumen and elevated anti-DNA antibody responses. Collectively, these findings suggest that Z-DNA, likely formed by extruded Salmonella genomic DNA, and embedded within curli:DNA complexes of STm biofilms, triggers a host immune response and drives anti-Z-DNA antibody production. This work provides mechanistic insight into how bacterial infections and diet-dependent modulation of biofilm formation may contribute to anti-Z-DNA antibody responses in autoimmune diseases like SLE.

Animals↗
PubMed2026

Immunoproteomic Profiling of Autoantibodies and Antibodies against Infectious Agents in Autoimmune Diseases.

Prior research investigated limited antibody sets within individual autoimmune diseases. Using the Nucleic-Acid Programmable Protein Array platform, we measured antibodies against 280 human, 40 viral, and 15 bacterial antigens in serum from 237 patients with 8 autoimmune diseases, including autoimmune gastritis (AG), autoimmune thyroiditis (AT), celiac disease (CD), idiopathic inflammatory myopathies (IIM), type 1 diabetes mellitus (T1D), rheumatoid arthritis (RA), Sj&#xf6;gren's disease (SjD), and systemic lupus erythematosus (SLE), and 112 controls. Candidate antibodies were identified by combining Firth logistic regression and machine learning. We identified disease-specific antibodies, ranging from 3 in IIM to 13 in SLE for IgG and 1 in CD to 13 in AG for IgA. Additionally, 63 IgG and 44 IgA antibodies were shared across two or more diseases. Notably, two IgG autoantibodies overlapped in up to five diseases: directed against STNM4 (SLE, SjD, T1D, CD, and RA) and TRIM21 (SLE, SjD, IIM, CD, and RA); and three IgA antibodies in up to seven diseases: directed against H1N1 Influenza A virus NP (IIM, SjD, AG, T1D, CD, RA, and AT) and Coxsackievirus B3MK012537 and Enterovirus C PVgp1 (IIM, SjD, AG, T1D, CD, SLE, and RA). These findings underscore the potential of antibody profiling in autoimmune disease characterization and biomarker discovery.

Humans↗
PubMed2026

Antibody repertoire associated with clinically diverse presentations of pediatric SARS-CoV-2 infection.

Pediatric SARS-CoV-2 infection can give rise to a range of clinical presentations, from asymptomatic or mild cases to severe pulmonary COVID-19, and to multisystem inflammatory syndrome in children (MIS-C). The latter is characterized by hyperinflammation and involvement of multiple organs. Although various aspects of antibody responses to pediatric SARS-CoV-2 infection have been reported, there has been limited research on the parallel antibody responses to both viral and self-antigens. We examined whether clinical phenotypes were linked to particular antiviral antibody and autoantibody profiles. By using custom arrays, we discovered that all manifestations of SARS-CoV-2 infection were linked to increased autoantibody production when compared to uninfected subjects, suggesting that pediatric SARS-CoV-2 infection may predispose to immune dysregulation. We observed subtle differences in autoantibody patterns among infection groups, with some autoantibodies being more associated with mild symptoms and others linked to severe disease manifestations. In particular, subsets of subjects with MIS-C and/or severe COVID-19 exhibited elevated autoreactive antibody responses against thyroperoxidase, IL-13, and IFN-epsilon, although differences across clinical groups did not reach statistical significance. When we compared subjects with MIS-C to those with severe COVID-19, we noted differences in the abundance of IgG (primarily IgG1), but no differences in Fc-mediated effector functions. Our study shows that the antibody repertoire in children varies with the clinical presentation of SARS-CoV-2. Moreover, MIS-C may be linked to abnormal antibody function, indicating that this syndrome-and potentially other post-acute sequelae of SARS-CoV-2 infection-could be related to antibody dysfunction.

Humans↗
PubMed2025

Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma.

Monoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). Although they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor-cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, we analyzed whole-genome and whole-exome sequencing data from patients 701 newly diagnosed MM, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse after anti-CD38 antibodies. We report a loss of CD38 in 10 of 50 patients (20%) after CD38 therapy, 3 of whom exhibited a loss of both copies. Two of these cases showed convergent evolution in which distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that 2 variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies daratumumab and isatuximab. However, a third mutation, R140G, conferred selective resistance to daratumumab, while retaining sensitivity to isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies after disease progression and these data suggest that next-generation sequencing may play a role in subsequent treatment selection for a subset of patients.

Humans↗
PubMed2026

A guide to selecting high-performing antibodies for TMEM175 (UniProt ID: Q9BSA9) for use in western blot, immunoprecipitation, and immunofluorescence.

TMEM175 is the pore-forming subunit of a lysosomal K+ channel complex that regulates lysosomal pH stability and membrane potential. To further investigate its cellular functions and implications in neurodegenerative diseases, antibody reagents are needed. Here we have characterized six TMEM175 commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

Humans↗
PubMed2025

Structures of respiratory syncytial virus G bound to broadly reactive antibodies provide insights into vaccine design.

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease in infants and older adults. The attachment glycoprotein (RSV G) binds to the chemokine receptor CX3CR1 to promote viral entry and modulate host immunity. Antibodies against RSV G are a known correlate of protection. Previously, several broadly reactive, high-affinity anti-RSV G human monoclonal antibodies were isolated from RSV-exposed individuals and were shown to be protective in vitro and in vivo. Here, we determined the structures of three of these antibodies in complex with RSV G and defined distinct conformational epitopes comprised of highly conserved RSV G residues. Binding competition and structural studies demonstrated that this highly conserved region displays two non-overlapping antigenic sites. Analyses of anti-RSV G antibody sequences reveal that antigenic site flexibility may promote the elicitation of diverse antibody germlines. Together, these findings provide a foundation for next-generation RSV prophylactics, and they expand concepts in vaccine design for the elicitation of germline lineage-diverse, broadly reactive, high-affinity antibodies.

Humans↗