Therapeutic antibodies have limited access to barrier‑protected compartments such as the brain, lung and gastric mucosa, and kidney lumen, constraining their effectiveness in many diseases. Approaches using a bispecific antibody that targets a transcytosing receptor such as the polymeric Ig receptor (pIgR) can result in significant enrichment of IgG-based therapeutics across from blood into mucosal or mucosal lining. The polymeric Ig receptor is expressed in epithelial layers in many tissues, but differences in expression patterns across species represent a challenge in validating preclinical in vivo models. Here, we compare RNA and protein expression across an array of human, cynomolgus monkey, and mouse tissues. We show that pIgR expression in cynomolgus monkeys is similar to expression in humans. We further evaluate the ability of pIgR-targeted bispecific antibodies to transcytose into lung and gastrointestinal mucosa in cynomolgus monkeys. We show that pIgR-targeted bispecific antibodies rapidly deplete from serum, while enriching 5-10-fold in bronchoalveolar lavage fluid compared to normal IgG antibodies. These results support the use of anti-pIgR bispecific antibodies to treat diseases requiring targeting in mucosal areas.

Treatment with eculizumab has revolutionized the management of complement-mediated disorders such as atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH). However, this therapeutic benefit comes at the cost of compromising a key arm of the innate immune response, which plays a crucial role in defending against encapsulated bacteria, including Neisseria meningitidis. As a result, patients receiving eculizumab are at a markedly increased risk of developing life-threatening meningococcal infections, even in the presence of prior immunization. This study analyzes the clinical presentation, diagnostic workup, immunological findings, therapeutic interventions and outcomes of two clinical cases of meningococcal meningitis under chronic eculizumab therapy. These cases illustrate potential challenges associated with current preventive strategies in patients receiving sustained complement blockade. Vaccine-induced immunity may not always translate into effective protection. Complement inhibition could also influence functional aspects of the immune response, raising uncertainties regarding the durability and clinical correlates of vaccination in this setting. These observations point to areas where preventive approaches may warrant closer evaluation and individualized consideration. These findings contribute to the ongoing discussion on how best to manage infection risk in patients treated with eculizumab. While no specific strategy can be firmly established, a patient-centered approach may support safer long-term management in this vulnerable population.

Novel anti-CD20 monoclonal antibodies have been developed to optimize B-cell depletion. A key mechanism of action of these therapeutic monoclonal antibodies is the activation of immune cells via Fc receptors (FcγR). B-cell depletion with anti-CD20 monoclonal antibodies was initially developed for the treatment of B-cell lymphoma. Subsequently, its use was extended to autoimmune diseases. Rituximab has long been the main monoclonal antibody used to treat immune-mediated glomerulopathies. In glomerular diseases, rituximab was initially used to treat membranous nephropathy, demonstrating a better safety profile compared to conventional immunosuppressive therapies and a good treatment response. Therefore, other drugs targeting the same therapeutic receptor, anti-CD20, have been developed. This review aims to highlight, from a comprehensive perspective, the different anti-CD20 agents available to date.

Immune-mediated necrotizing myopathy (IMNM) is a rare and heterogeneous subgroup of idiopathic inflammatory myopathies. IMNM is broadly classified into seropositive disease, encompassing anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) and anti-signal recognition particle (anti-SRP) antibody-associated forms, and seronegative IMNM. Although seronegative IMNM has traditionally been considered largely analogous to seropositive disease, emerging evidence suggests that it may represent, at least in part, a distinct clinical entity. This review synthesizes the current evidence regarding the clinical management of seronegative IMNM.

Guillain-Barré syndrome (GBS) is a leading cause of acquired acute neuromuscular paralysis and is an immune-mediated disorder of the peripheral nervous system (PNS). Accumulating evidence indi-cates that GBS is often preceded by infectious events that trigger autoimmune responses through mechanisms such as molecular mimicry and autoantibody production. Campylobacter jejuni remains the most common bacterial agent, but viral pathogens also contribute to the development of GBS. This review summarizes the current evidence regarding viruses as triggers of GBS, including herpes-viruses, hepatotropic viruses (A, B, C, and E), human immunodeficiency virus, Zika virus, influenza virus, varicella-zoster virus, and the coronavirus SARS-CoV-2. Emphasis is placed on laboratory test results related to viral GBS, including antiganglioside antibodies, serological markers of recent in-fection, molecular diagnostic methods, and cerebrospinal fluid analysis. From the standpoint of la-boratory medicine, both the clinical diagnosis and the distinction of GBS subtypes can be supported by the identification of recent viral infections and the detection of immunological biomarkers. How-ever, cross-reactivity, extended antibody persistence, and inadequate assay standardization frequently make it difficult to interpret laboratory test results. In patients with probable viral GBS, this review shows the diagnostic significance and limitations of routine laboratory testing. It also highlights the significance of close coordination between laboratory professionals and clinicians.

Antibody-drug conjugates (ADCs) have established targeted payload delivery as an important anticancer strategy, but their efficacy remains constrained by antigen heterogeneity, incomplete internalisation, resistance and dose-limiting toxicity. Bispecific antibody-drug conjugates (BsADCs) add a second antigen- or epitope-binding specificity with the aim of broadening tumour coverage or altering receptor trafficking. The field crossed a major translational threshold in 2026, when izalontamab brengitecan (iza-bren; BL-B01D1), an EGFR×HER3 BsADC, received its first regulatory approvals in China for previously treated recurrent or metastatic nasopharyngeal carcinoma and oesophageal squamous cell carcinoma, while phase III studies also showed survival benefit in triple-negative breast cancer. These developments shift the central question from whether bispecificity can produce antitumour activity to when it can generate a clinically meaningful therapeutic window. This review evaluates BsADC development through six linked determinants: target-pair biology and co-expression, binding geometry and avidity, internalisation and lysosomal trafficking, linker-payload chemistry and drug-to-antibody ratio, intratumoural distribution and bystander activity, and biomarker-guided dosing and patient selection. We further examine how payload-mediated immunogenic cell death, Fc/Fcγ receptor-dependent uptake, suppressive tumour-immune niches and checkpoint-based combinations may modify activity beyond target recognition. Clinical programmes illustrate divergent outcomes: iza-bren provides regulatory validation of the modality, whereas experience with MEDI4276, zanidatamab zovodotin and REGN5093-M114 shows that enhanced binding or internalisation does not guarantee sustainable development. Importantly, much of the mechanistic and combination evidence for immune activation still derives from monospecific ADCs; immune benefit should therefore not be attributed to bispecificity itself without direct evidence. Future progress should integrate human pharmacokinetic/pharmacodynamic data, target-pair and immune-contexture biomarkers, dose-exposure-toxicity relationships and comparative value over optimized monospecific ADCs.

Antibody-mediated rejection (AMR) remains a major obstacle to long-term kidney allograft survival. It does not arise from a single pathway. Preformed or de novo donor-specific antibodies (DSA), endothelial injury, microvascular inflammation, complement-dependent and complement-independent mechanisms, and chronic remodeling may each contribute, often in different combinations. Recent Banff updates, biopsy-based transcriptomics, DSA assessment, and donor-derived cell-free DNA (dd-cfDNA) testing have made AMR phenotypes easier to recognize. Still, these tests are most useful when interpreted together rather than treated as separate answers. The same caution applies to treatment. Plasma exchange, intravenous immunoglobulin, B-cell or plasma-cell directed agents, complement inhibition, IL-6 pathway blockade, and optimization of maintenance immunosuppression differ in the strength of their evidence, the patients they may help, their toxicities, and their feasibility in routine practice. This review summarizes current concepts in AMR pathogenesis, diagnosis, and emerging therapy, using phenotype-guided assessment to separate expert-consensus practice from randomized evidence, observational experience, and experimental interventions.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a remarkably broad and heterogeneous autoantigen repertoire. While epitope spreading, aberrant B-cell activation, and molecular mimicry act in concert with defective apoptotic clearance and sustained type I interferon signaling to drive systemic autoreactivity, many clinical manifestations of the disease are highly localized. The involvement of neuropsychiatric, renal, cutaneous, pulmonary, vascular, and hepatic systems appears to be shaped by tissue-specific autoantigen exposure and local microenvironments, where shared immunopathogenic pathways give rise to organ-associated autoantigenic landscapes. This review develops the concept of organ-associated autoantigenic landscapes, defined here as context-dependent configurations in which autoantibody-autoantigen interactions intersect with regional microenvironments and may contribute to inflammatory cascades, complement activation, and cellular damage. Importantly, organ association does not imply strict organ specificity, as the same circulating autoantibody may acquire distinct clinical relevance across tissues depending on antigen accessibility and local effector conditions. By illustrating how specific autoantibody-autoantigen axes may translate systemic autoimmunity into restricted clinical patterns, this framework provides a unifying model for disease heterogeneity and supports the development of precision, antigen-targeted therapeutic strategies.

The avian inflammatory response is complex and requires integration of clinical examination findings alongside hematologic, biochemical, and protein electrophoretic data to best characterize the acute phase and immune response. Interpretation of protein electrophoresis in birds, however, is challenging due to methodological variability, inconsistent fraction resolution, and the lack of established species- and method-specific reference intervals. Psittacine birds represent the largest family of companion avian patients in clinical practice, emphasizing the need for reliable and clinically applicable data for diagnostic interpretation. This study compared agarose gel electrophoresis (AGE) and capillary zone electrophoresis (CZE) in 42 client-owned macaws (Ara spp.) complemented by paired serum-plasma analysis. Birds were classified as clinically normal or abnormal based on examination findings and clinicopathologic data. Capillary zone electrophoresis resolved seven protein fractions compared to six fractions resolved by AGE. Method comparison statistics demonstrated weak to moderate correlation, but poor agreement by Bland-Altman analysis, with systematic bias across all fractions, confirming results between methods are not equivalent. In an exploratory investigation, the abnormal group was found to demonstrate significantly increased total leukocyte and heterophil counts, with negative correlations between these parameters and the albumin-to-globulin ratio. Notable electrophoretic alterations were observed in select diseased birds. Agarose gel electrophoresis and CZE yielded analytically different results in the samples. These findings support the need for method-specific reference intervals and emphasize the importance of integrating protein electrophoresis results with clinical and hematologic findings.