Cancer-induced bone pain is a common symptom among patients with metastatic cancer, and health professionals can face challenges in managing the associated pain. The study focused on eNAMPT, a damage-associated molecular pattern described as overexpressed in metastatic breast carcinoma. According to the proposed mechanism, eNAMPT binds to Toll-like receptor 4 and triggers a nuclear factor kappa B signaling cascade associated with inflammation, osteoclastogenesis and pain. The researchers investigated whether neutralizing eNAMPT could reduce pain-related behavior and bone loss in experimental models.

To examine eNAMPT production, the investigators used enzyme-linked immunosorbent assays to measure eNAMPT synthesis and secretion by EO771 mouse breast adenocarcinoma cells. Levels increased over time and reached a maximum at 48 hours. ALT-100 reduced the measured eNAMPT signal, consistent with the antibody’s function as an eNAMPT-neutralizing monoclonal antibody. These results characterized the antibody’s effect in the EO771 cell-culture system rather than in human cancer cells or patients.

The researchers next examined osteoclast differentiation using RAW 264.7 osteoclast precursor cells. Recombinant eNAMPT significantly increased tartrate-resistant acid phosphatase activity, which the researchers used as a measure of osteoclastogenesis. Adding ALT-100 alongside recombinant eNAMPT significantly reduced that increase. The cell experiment therefore showed that eNAMPT promoted an osteoclast-associated response in this model and that the antibody inhibited the response. It did not by itself determine the antibody’s effectiveness in human osteoclasts or establish a treatment dose.

For the in vivo experiment, female C57BL/6J mice underwent intramedullary femoral injection of EO771 cells to establish cancer-induced bone pain, while other mice received sham surgery. One week later, the animals received either ALT-100 at 4 mg/kg by intraperitoneal injection or saline control. The researchers then assessed pain-related behaviors longitudinally and examined the femurs through radiographic analysis. These procedures modeled aspects of breast-cancer-associated bone pain in mice.

Compared with cancer-bearing mice that received saline, mice treated with ALT-100 showed significantly reduced pain-related behaviors. Radiographic analysis also showed that ALT-100 mitigated cancer-induced bone loss. The observed effects came from a controlled murine experiment using a specific administration schedule and dose. The study therefore provides evidence of activity against pain-related behavior and bone loss in the model, rather than proof of benefit for people with cancer-induced bone pain.

Together, the cell and animal findings suggest that ALT-100 can interfere with two measured features of the investigated disease process: eNAMPT-induced osteoclast differentiation and pain-related behavior in mice. Its broader significance is that the study provides experimental support for targeting eNAMPT in cancer-induced bone pain. The authors present this approach as a potential alternative therapeutic strategy, but the reported evidence comes from cultured cells and a murine breast-cancer model, not from a human clinical trial.

The results remain preclinical. The study used EO771 cells, RAW 264.7 cells and female C57BL/6J mice to examine a proposed inflammatory and bone-remodeling pathway associated with eNAMPT. ALT-100 reduced eNAMPT-related assay signals, inhibited the rise in tartrate-resistant acid phosphatase activity caused by recombinant eNAMPT, and improved measured pain-related behavior and radiographic bone loss in the mouse model. Whether the antibody can safely and effectively treat cancer-induced bone pain in humans cannot be determined from these findings alone.

Subject of Research: Preclinical testing of an eNAMPT-neutralizing antibody for cancer-induced bone pain in cells and mice

Article Title: A humanized eNAMPT -neutralizing monoclonal antibody reduces cancer-induced bone pain and osteoclastogenesis in murine breast cancer model

Article References: Mathur, N. C., Villarroel, E., Villarroel, I., Liktor-Busa, E., Karlage, K. L., Kaur, M., Kempf, C., Gudaite, B., Ding, Z., Garcia, J. G. N., Largent-Milnes, T., & Vanderah, T. W. (2026). A Humanized eNAMPT -Neutralizing Monoclonal Antibody Reduces Cancer-induced Bone Pain and Osteoclastogenesis in Murine Breast Cancer Model. Frontiers in Pain Research, 7, 1955262. https://doi.org/10.3389/fpain.2026.1955262

Image Credits: AI Generated

DOI: 10.3389/fpain.2026.1955262

Keywords: eNAMPT, ALT-100, cancer-induced bone pain, breast cancer, osteoclastogenesis, monoclonal antibody, mouse model, bone loss, pain-related behavior, humanized, neutralizing, monoclonal

FCoV is a non-segmented, single-stranded positive-sense RNA virus with a genome of approximately 29 kilobases. The disease it causes was first described in 1963, but the viral aetiology was only established in 1966, when healthy animals inoculated with tissues from diseased cats developed infection, and the agent was confirmed as a coronavirus in 1968. Two biologically distinct pathogenic forms circulate in cat populations. Feline enteric coronavirus (FECV) is highly contagious in multi-cat environments and infects nearly all exposed animals, yet it usually produces only mild, transient diarrhoea or no symptoms at all. Feline infectious peritonitis virus (FIPV), by contrast, is not transmitted by the faecal-oral route; it arises from mutations in FECV within a small proportion of infected cats, shifting viral tropism from intestinal epithelial cells to monocytes and macrophages. Once FIPV replicates inside peritoneal macrophages, it disseminates through the body and produces high-titre progeny virus, culminating in the fatal systemic disease known as feline infectious peritonitis.

The mutations that drive this transition remain incompletely mapped, which makes accurate and early diagnosis of FCoV infection a critical prerequisite for antiviral intervention. The spike (S) protein, a Type I transmembrane glycoprotein divided into an N-terminal S1 receptor-binding domain and a C-terminal S2 domain containing the fusion peptide, sits at the centre of both pathogenesis and immunity. It mediates fusion of the viral envelope with the host cell membrane, determines antigenic classification, and carries abundant epitopes that elicit neutralizing antibodies in infected hosts. FCoV strains are divided into Type I and Type II serotypes on the basis of their S proteins, with Type I being the most primitive and most prevalent serotype worldwide. Because early coronavirus detection strategies have repeatedly benefited from targeting the S protein, the researchers reasoned that S-specific monoclonal antibodies could anchor a robust antigen-detection platform, even though few such assays had previously been reported for FCoV.

Existing diagnostic options each carry drawbacks. RT-qPCR is sensitive and experimentally straightforward, but false negatives can arise with novel variants, false positives from sample contamination, and the technique requires fully equipped laboratories, limiting its use in large-scale clinical screening. Serological assays detect immunoglobulin G antibodies, which only appear days after infection and vary between individuals, so they are poorly suited to early diagnosis. Virus isolation, the classical reference method, is hampered by the difficulty of culturing FCoV in vitro, long turnaround times and demanding operating conditions. Against this backdrop, the team set out to build a sandwich ELISA in which a rabbit polyclonal capture antibody and a mouse monoclonal detection antibody bracket the spike antigen, combining broad binding capacity with high specificity.

To generate the immunogen, the researchers expressed and purified a recombinant fragment of the Type I FCoV spike protein, designated FCoV-SP. Six-week-old BALB/c mice received weekly subcutaneous injections of 50 micrograms of the protein emulsified in Freund’s complete adjuvant for three weeks, while three adult rabbits were immunized with 200 micrograms each following the same schedule. Antibody titres were monitored by indirect ELISA using tail vein blood from mice and auricular artery blood from rabbits. After the final immunization, immunoglobulin G was purified from the rabbit serum with the highest titre on a protein A Sepharose column and stored at minus 80 degrees Celsius for use as the capture antibody.

Monoclonal antibodies were produced by fusing myeloma cells with splenocytes from the immunized mice at a 1:8 cell ratio using 50 percent PEG3350. Hybridomas were cultured in 96-well plates under standard HAT and HT selection regimens, and culture supernatants were screened by an indirect ELISA optimized through checkerboard titration. Positive clones were subcloned by limiting dilution until 100 percent positivity was achieved, and ascites fluid was raised in pristane-primed mice injected with hybridoma cells. A subclone designated E5, whose isotype was identified as IgG2b, emerged as the working monoclonal. Western blotting confirmed that both the E5 monoclonal antibody and the rabbit polyclonal serum specifically recognized the recombinant FCoV-SP at its predicted molecular weight of approximately 32 kilodaltons, validating the reagents at the heart of the assay.

Checkerboard titration established the optimal working conditions: microplates were coated overnight at 4 degrees Celsius with the polyclonal capture antibody at 0.15 micrograms per millilitre, blocked, then incubated with samples or controls for 45 minutes at room temperature. The E5 monoclonal was added at 1.0 micrograms per millilitre for 30 minutes, followed by horseradish peroxidase-conjugated goat anti-mouse IgG diluted 1:10,000 for one hour. The colour reaction was developed with tetramethylbenzidine, stopped with 2 M sulphuric acid, and read at 450 nanometres. Serial twofold dilutions of purified antigen from 3.25 down to 0.0127 micrograms per millilitre generated a standard curve with a coefficient of determination of 0.991, and the analytical limit of detection was calculated as approximately 0.15 micrograms per millilitre, defined as the concentration corresponding to the mean optical density of 20 negative faecal samples plus three standard deviations.

The cut-off value was set at 0.85, derived from the mean OD450 of 0.33 plus three standard deviations of 0.17 among 20 RT-PCR-confirmed negative faecal samples, which were pretreated with 1 percent Triton X-100 and 0.3 percent tri-n-butyl phosphate to inactivate any virus. Repeatability testing across five samples analysed in duplicate over three days yielded intra-assay coefficients of variation between 3.90 and 14.10 percent and inter-assay coefficients between 2.55 and 11.09 percent. One high-signal positive sample exceeded the conventional 10 percent intra-assay threshold at 14.07 percent, likely because small pipetting or washing inconsistencies are proportionally amplified at elevated absorbance, but all values remained below the 20 percent limit generally accepted for exploratory immunoassays. Specificity testing on 48 faecal samples, 12 each from cats infected with feline panleukopenia virus, feline calicivirus, feline herpesvirus and FCoV, produced positive signals only for FCoV-infected samples and the purified spike protein, with no cross-reactions against the other three feline viruses.

For clinical validation, 62 faecal samples were collected from cats in Longyan, Xiamen and Fuzhou with informed owner consent and tested in parallel by DAS-ELISA and RT-qPCR. Of 32 PCR-positive samples, 26 were correctly identified by the ELISA, a positive coincidence rate of 81.3 percent, while 25 of 30 PCR-negative samples were correctly classified, or 83.3 percent. Receiver operating characteristic analysis yielded a sensitivity of 81.3 percent, a specificity of 80.0 percent and an area under the curve of 0.861, indicating clinically useful discriminatory power. The six discordant samples that were PCR-positive but ELISA-negative likely reflect low viral antigen loads early in infection or during recovery, when faecal antigen concentrations fall below the assay threshold even though viral RNA remains detectable. Conversely, five samples were ELISA-positive but PCR-negative; their OD values clustered just above the cut-off, suggesting low-level matrix interference, possibly from endogenous peroxidase contaminants in faeces, rather than genuine antigen binding. The authors note that adding a peroxidase-blocking step or inhibitors to the sample diluent could reduce such false positives, and that equivocal results should be confirmed by RT-PCR.

The study has acknowledged limitations. Because no commercial FCoV antigen-detection ELISA exists, the assay could only be compared against published PCR results rather than a reference kit, and the specificity panel of 12 samples per competing virus is too small to compute robust confidence intervals or definitively exclude cross-reactivity; cohorts of 30 or more per pathogen are recommended for reliable specificity estimates. Cross-reactivity with Type II FCoV strains and canine coronavirus was not systematically tested, and the analytical limit of detection was established with purified antigen in buffer rather than in the faecal matrix, so the true clinical detection limit may be higher. Even so, the combination of acceptable repeatability, strong analytical linearity, no cross-reactivity with the major feline enteric viruses, and agreement with RT-qPCR in clinical samples positions this DAS-ELISA as a promising, affordable front-line tool for FCoV surveillance in multi-cat households, catteries and veterinary clinics, pending larger validation studies and matrix-adjusted sensitivity benchmarks.

Subject of Research: Development and validation of a double-antibody sandwich ELISA for detecting feline coronavirus spike protein antigen

Article Title: Double‐Antibody Sandwich Enzyme‐Linked Immunosorbent Assay for Detecting Feline Coronavirus Infection

Article References: Dong, B., Zou, W., Hu, W., Wu, H., Jing, Y., Xie, F., Zhang, S., & Lin, W. (2026). Double‐Antibody Sandwich Enzyme‐Linked Immunosorbent Assay for Detecting Feline Coronavirus Infection. Veterinary Medicine and Science, 12(6), Article e71289. https://doi.org/10.1002/vms3.71289

Image Credits: AI Generated

DOI: 10.1002/vms3.71289

Keywords: feline coronavirus, DAS-ELISA, spike protein, monoclonal antibody, polyclonal antibody, feline infectious peritonitis, RT-qPCR, veterinary diagnostics, faecal samples, antigen detection, cross-reactivity, diagnostic sensitivity

Zolbetuximab is a chimeric monoclonal antibody that targets claudin-18 isoform 2, or CLDN18.2, a protein found on gastric cancer cells but also on the normal mucosal lining of the stomach. Approved in combination with platinum- and fluoropyrimidine-based chemotherapy as a first-line treatment for patients with CLDN18.2-positive advanced gastric cancer, the drug has a distinctive safety profile dominated by nausea and vomiting. But as the new study makes clear, another adverse event—hypoalbuminemia and the peripheral edema it causes—has increasingly been recognized as a characteristic and potentially treatment-derailing complication of zolbetuximab-based therapy.

The discrepancy between trial data and clinical reality is striking. In an integrated analysis of the SPOTLIGHT and GLOW phase III trials, hypoalbuminemia was reported in 19.3 percent of patients for all grades combined, and in only 3.8 percent for grade 3 or higher events. In the Aichi cohort, by comparison, all 39 patients developed hypoalbuminemia of any grade, 24 patients—61.5 percent—reached grade 2, and seven patients, or 17.9 percent, reached grade 3. Serum albumin levels declined in all but one patient, with the median time to reach the lowest level during treatment being 34 days. Peripheral edema of any grade occurred in 46.1 percent of patients, and diuretics were administered to 41 percent.

The researchers, led by Taro Mizuno and Yukiya Narita, conducted their single-center retrospective study among patients with advanced gastric cancer who initiated zolbetuximab plus chemotherapy between July 2024 and August 2025 and received at least two cycles of treatment. Eligibility required immunohistochemical confirmation of HER2-negative, CLDN18.2-positive gastric or esophagogastric junction adenocarcinoma. The median age of the cohort was 61 years, most patients had a gastric primary tumor, and the peritoneum was the most common metastatic site, present in 84.6 percent of cases. Ascites—fluid accumulation in the abdomen—was present in 64.1 percent of patients, and 79.5 percent had diffuse-type adenocarcinoma, a histological subtype known for aggressive behavior.

To capture clinically meaningful albumin deterioration, the team defined severe hypoalbuminemia as a minimum serum albumin level below 2.0 grams per deciliter—the threshold for grade 3 events under the Common Terminology Criteria for Adverse Events—or a decrease of at least 1.0 grams per deciliter from baseline to the nadir during treatment. The second criterion was adopted because absolute grading alone can miss significant deterioration in patients who start with relatively high albumin levels. Using this definition, 20 patients, or 51.3 percent, developed severe hypoalbuminemia.

The search for risk factors produced two clinically important findings. Patients who experienced nausea, vomiting, or both persisting from the completion of the first treatment cycle to the initiation of the second had a significantly higher incidence of severe hypoalbuminemia than those without these symptoms—63.0 percent versus 25.0 percent. More striking still, no cases of severe hypoalbuminemia were observed among the five patients who had undergone prior total gastrectomy, compared with 58.8 percent among those whose stomach remained intact. Nausea, vomiting, or abdominal pain severe enough to require interruption of the first zolbetuximab infusion, and anorexia during the first cycle, showed trends toward association but did not reach statistical significance.

The gastrectomy finding carries particular mechanistic weight. Because zolbetuximab targets CLDN18.2, which is expressed not only on cancer cells but also on the normal gastric mucosa, the drug may damage the stomach lining itself, causing a protein-losing enteropathy—a syndrome in which plasma proteins leak through the gastrointestinal wall. This hypothesis is supported by an emerging case report describing zolbetuximab-induced protein-losing enteropathy characterized by diffuse gastric mucosal redness and edema, mucous cell detachment and fundic gland disruption on biopsy, and direct visualization of albumin leakage on technetium-99m albumin scintigraphy. The absence of severe hypoalbuminemia in patients without a stomach strongly suggests that CLDN18.2-expressing normal gastric mucosa is central to susceptibility to the drug’s albumin-depleting effects.

Perhaps the most actionable finding concerns reversibility. Recovery of serum albumin from the nadir back to baseline was observed in 18 patients, or 46.2 percent, with a median time to recovery of 64.5 days. No patients received albumin supplementation. Critically, patients who temporarily interrupted treatment for any reason after reaching their albumin nadir were significantly more likely to recover than those who continued treatment—66.7 percent versus 28.6 percent. Treatment was interrupted in 18 patients, with both zolbetuximab and chemotherapy withheld in 16 cases and zolbetuximab alone in two, for a median duration of 14 days. This pattern suggests that zolbetuximab-induced mucosal injury may be at least partially reversible when the drug is withheld, though the study could not determine whether such recovery translates into clinical benefit, nor whether edema improvement was attributable to interruption or to the diuretics most edema patients received.

Importantly, the presence of severe hypoalbuminemia did not appear to compromise treatment efficacy. Among the 10 patients with measurable lesions assessed by RECIST version 1.1 criteria, the objective response rate was 20.0 percent in patients without severe hypoalbuminemia and 60.0 percent in those with it, a difference that was not statistically significant given the small numbers. Among the 25 patients with baseline ascites, ascites response rates were 50.0 percent and 40.0 percent respectively. Survival analyses, with a median follow-up of 7.1 months, showed no significant differences in progression-free or overall survival according to severe hypoalbuminemia in either first-line or later-line settings, though the authors caution that these exploratory analyses were limited by wide confidence intervals, immature data, and potential time-dependent bias.

The study’s authors conclude that severe hypoalbuminemia is common during zolbetuximab plus chemotherapy in routine clinical practice, and that the absence of prior total gastrectomy and the presence of persistent post-infusion nausea or vomiting may help identify patients at increased risk of profound albumin decline. They also note that all patients in the cohort received acid-suppressive agents and gastric mucosal protectants under an institutional protocol, yet hypoalbuminemia still occurred universally—suggesting these measures alone are insufficient for prevention, and that careful monitoring with timely treatment modification may be a more appropriate strategy than excessive prophylactic medication. Limitations include the small sample size, the retrospective single-institution design, the possibility that disease progression contributed to albumin decline, and the lack of routine endoscopic assessment to directly correlate clinical findings with mucosal injury. Further validation, the team emphasizes, is needed to determine the optimal management of zolbetuximab-associated hypoalbuminemia without compromising the treatment’s anticancer efficacy.

Subject of Research: Zolbetuximab-associated hypoalbuminemia in CLDN18.2-positive advanced gastric cancer

Article Title: Retrospective Analysis of Zolbetuximab‐Associated Hypoalbuminemia in Claudin 18.2‐Positive Advanced Gastric Cancer

Article References: Mizuno, T., Narita, Y., Ando, T., Ishizuka, Y., Umegaki, S., Honda, K., Masuishi, T., Taniguchi, H., Kadowaki, S., Ando, M., Tajika, M., & Muro, K. (2026). Retrospective Analysis of Zolbetuximab‐Associated Hypoalbuminemia in Claudin 18.2‐Positive Advanced Gastric Cancer. Cancer Reports, 9(10), Article e70709. https://doi.org/10.1002/cnr2.70709

Image Credits: AI Generated

DOI: 10.1002/cnr2.70709

Keywords: zolbetuximab, gastric cancer, hypoalbuminemia, CLDN18.2, protein-losing enteropathy, peripheral edema, monoclonal antibody, advanced gastric cancer, treatment interruption, albumin recovery, chemotherapy, real-world study

The research team, led by Kaifei Yuan, Xianhong Hu, Qi Fang, Siyuan Li, Ping Lin, Baijing Ding, and Tongyuan Lin, analyzed 61 patients with Crohn’s disease treated between April 2022 and May 2025. Twenty-one patients were biologic-naïve, meaning ustekinumab was their first biologic therapy, while 40 were biologic-experienced, having previously failed treatment with agents such as infliximab, adalimumab, or vedolizumab. The investigators tracked clinical data, laboratory markers, disease activity scores, and endoscopic findings at baseline, week 8, and week 32, and separately assessed quality of life and psychological well-being at the start and end of the observation period.

Ustekinumab works by selectively binding the p40 subunit shared by interleukin-12 and interleukin-23, preventing these cytokines from engaging the IL-12Rβ1 receptor on immune cells. This disrupts downstream signaling that would otherwise activate natural killer cells and T cells, reducing the secretion of inflammatory mediators that drive chronic intestinal inflammation. The drug is recommended as a first-line biologic for induction and maintenance of remission in moderate to severe Crohn’s disease, yet questions have persisted about how prior biologic exposure shapes its real-world effectiveness.

At baseline, the two groups were statistically comparable in gender, age, disease duration, laboratory values, Crohn’s Disease Activity Index (CDAI) scores, and Simplified Endoscopic Score for Crohn’s Disease (SES-CD) scores. Most patients in the cohort were diagnosed between ages 17 and 40, and the majority had ileocolonic disease with non-stricturing, non-penetrating behavior. Dosing followed European Crohn’s and Colitis Organisation guidelines, with weight-based intravenous induction followed by 90 milligram subcutaneous injections every eight weeks.

Laboratory results revealed distinct response patterns between the groups. By week 8, erythrocyte sedimentation rate had fallen significantly in both cohorts, but the biologic-naïve group showed larger reductions in C-reactive protein and ESR than the biologic-experienced group. By week 32, the naïve group had achieved statistically significant improvements in CRP, platelet count, hemoglobin, and ESR, while the experienced group showed significant gains in albumin, platelets, red blood cells, hemoglobin, and ESR but no significant CRP improvement. The authors suggest that prior biologic exposure may alter ustekinumab trough concentrations, and that intestinal fibrosis or structural damage in previously treated patients may blunt the apparent decline in systemic inflammatory markers.

Clinical and endoscopic outcomes favored earlier intervention. At week 32, the biologic-naïve group achieved a mean CDAI reduction of 136.25 points compared with 102.28 points in the experienced group, and their mean SES-CD score fell by 5.48 points versus 3.80 points, both differences statistically significant. Despite these gaps, the overall clinical response rates were 61.9 percent in the naïve group and 52.5 percent in the experienced group, with remission rates of 42.9 percent and 40.0 percent respectively. The overlapping 95 percent confidence intervals indicate no statistically significant difference in short-term clinical efficacy between the two treatment strategies.

The study then reclassified all 61 patients into clinical responders and non-responders based on CDAI decline at week 32. Thirty-four patients achieved a clinical response, defined as a reduction of at least 100 points from baseline, while 27 did not. Quality of life, measured with the 32-item Inflammatory Bowel Disease Questionnaire, improved significantly in both groups, but the gain was markedly larger in responders, whose IBDQ scores rose by an average of 38.11 points compared with 20.56 points in non-responders. This finding underscores that effective control of intestinal inflammation remains the central driver of improved daily functioning in Crohn’s disease.

Psychological outcomes told a more nuanced story. Using the Hospital Anxiety and Depression Scale, the researchers found that anxiety scores fell significantly only in the clinical response group, dropping from a mean of 6.72 to 5.44, while depression scores showed no significant change in either group. The authors attribute the anxiety benefit to successful symptom control breaking the vicious cycle of gut-brain axis inflammation, in which persistent intestinal inflammation feeds back through neuroendocrine and autonomic pathways to sustain psychological distress. Depression, they note, is influenced by genetic and psychosocial factors beyond disease activity, and a 32-week follow-up may simply be too short to capture meaningful improvement.

The study has important limitations. As a single-center retrospective analysis with a modest sample size and unbalanced group allocation, it is vulnerable to selection bias and reduced statistical power. Only a subset of patients completed week-32 endoscopy, fecal calprotectin and therapeutic drug monitoring data were unavailable, and the investigators could not stratify outcomes by Montreal classification phenotype. Larger, multi-center prospective studies will be needed to confirm these findings and to identify which patients benefit most from early ustekinumab initiation.

Nevertheless, the results carry practical weight for clinicians managing a disease whose prevalence in China has climbed to an estimated 60 to 70 cases per 100,000 people and continues to rise. The data support a treatment philosophy already embedded in the 2023 Chinese national guidelines, which emphasize not only symptom control and normalization of inflammatory markers but also psychological health and overall quality of life. For patients with Crohn’s disease, the message is clear: ustekinumab can deliver meaningful benefit whether it is the first biologic tried or a rescue after failure of another agent, but the deepest and most durable improvements in inflammation, mucosal healing, and emotional well-being appear to belong to those who reach it earliest.

Subject of Research: Real-world comparative effectiveness of ustekinumab in biologic-naïve versus biologic-experienced Crohn's disease patients

Article Title: Retrospective analysis of ustekinumab in Crohn’s disease between biologic-naïve and biologic-experienced

Article References: Yuan, K., Hu, X., Fang, Q., Li, S., Lin, P., Ding, B., & Lin, T. (2026). Retrospective analysis of ustekinumab in Crohn’s disease between biologic-naïve and biologic-experienced. Frontiers in Gastroenterology, 5, Article 1926425. https://doi.org/10.3389/fgstr.2026.1926425

Image Credits: AI Generated

DOI: 10.3389/fgstr.2026.1926425

Keywords: ustekinumab, Crohn's disease, biologic-naïve, biologic-experienced, inflammatory bowel disease, CDAI, SES-CD, quality of life, anxiety, depression, IL-12/23, retrospective study

The context for this work is enormous. Alzheimer’s disease accounts for roughly 60 to 80 percent of dementia cases worldwide, affecting an estimated 57 million people today, a figure projected to exceed 150 million by 2050. China alone carries nearly 17 million cases of Alzheimer’s and other dementias. For decades, treatment relied on symptomatic drugs such as acetylcholinesterase inhibitors and memantine, which ease symptoms but do nothing to halt the underlying neurodegeneration. Lecanemab changed that calculus. In the pivotal Phase III Clarity AD trial, involving 1,795 patients with early disease, the antibody slowed cognitive decline by 27 percent over 18 months and significantly reduced amyloid plaque burden on PET imaging. That success earned accelerated FDA approval in January 2023, full approval in July 2023, and Chinese regulatory approval in January 2024.

But clinical trials, however rigorous, are not real life. Trial populations are carefully selected, typically younger and healthier than the patients clinicians actually see, and rare adverse events or those with long latency periods often only surface after a drug reaches a broad population. That is precisely why the research team, led by investigators at the First Affiliated Hospital of Anhui Medical University and collaborating institutions, chose a dual approach. They prospectively followed every patient receiving lecanemab at their center from July 2024 to February 2026, and in parallel they ran a disproportionality analysis on FAERS, the FDA’s spontaneous reporting database, using two standard signal-detection metrics: the reporting odds ratio and the proportional reporting ratio.

The prospective cohort tells a relatively encouraging story. Ninety-one patients with mild-to-moderate Alzheimer’s disease were enrolled, with a median treatment duration of 185 days. Thirteen adverse events were recorded, corresponding to an exposure-adjusted incidence of 56.48 events per 100 patient-years. The most frequent were amyloid-related imaging abnormalities with hemosiderin deposition, known as ARIA-H, at 12.39 per 100 patient-years, and infusion-related reactions at 8.85 per 100 patient-years. All seven ARIA-H cases were graded mild or moderate, and none required permanent discontinuation of the drug. Notably, the cohort recorded zero cases of ARIA-E, the edema form of the abnormality, likely reflecting the team’s decision to exclude APOE ε4 homozygotes, the subgroup at highest risk, along with strict imaging-based exclusion criteria borrowed from the Clarity AD protocol.

The FAERS analysis, drawing on 2,969 reports identifying lecanemab as the primary suspect drug, largely mirrored the cohort findings. The most frequently reported events were headache, ARIA-E, ARIA-H, and infusion-related reactions, all of which appear in the drug’s official prescribing information. The signal strengths for ARIA-E and ARIA-H were extraordinarily high, with reporting odds ratios exceeding 13,000, reflecting how tightly these imaging abnormalities are associated with anti-amyloid therapy in the pharmacovigilance record. Infusion-related reactions also showed a robust signal, with a reporting odds ratio of 45.71 across 263 cases, consistent with the known immunological profile of a large-molecule exogenous protein triggering fever, chills, and blood pressure fluctuations during intravenous administration.

Then came the finding that stands out. Cerebral infarction, or ischemic stroke, is not listed in lecanemab’s prescribing information, yet the FAERS analysis revealed a strong signal with a reporting odds ratio of 22.31 across 55 reported cases. The researchers dug deeper, mapping concomitant medications and medical histories for those 55 patients. They found that 17 of them, roughly 31 percent, had at least one identifiable traditional stroke risk factor or were taking antithrombotic drugs such as aspirin or clopidogrel. Hypertension was documented in 11 patients and diabetes in two. Strikingly, 91 percent of the cases listed concomitant medications as being used for an unknown indication, underscoring how poorly baseline comorbidities are captured in spontaneous reporting systems. The authors are careful to frame this as a hypothesis-generating signal rather than proof of causation, noting that underlying cerebral amyloid angiopathy, combined with antithrombotic use and preexisting cardiovascular disease, could plausibly explain many of these ischemic events without lecanemab being the direct trigger.

Timing emerged as another key theme. A time-to-onset analysis of 898 FAERS reports with valid onset dates showed that nearly 46 percent of adverse events occurred within the first one to two months of treatment. A Weibull shape parameter below 1 classified the temporal profile as an early-failure curve, meaning the hazard of experiencing an adverse event is highest early on and declines thereafter, though a persistent fraction, about 13.7 percent, occurred more than a year after initiation. The prospective cohort showed a qualitatively similar pattern, with the highest proportion of events also clustering in the first two months. Infusion-related reactions tended to strike during the first one or two infusions, while ARIA, both the edema and the hemorrhage forms, could appear at any point in the treatment course, reinforcing the need for ongoing MRI surveillance rather than a fixed early window of vigilance.

Demographics added further nuance. In the FAERS data, patients aged 65 to 85 accounted for nearly 65 percent of reports, and in the prospective cohort the same age group made up 77 percent of those experiencing adverse events. Women were overrepresented in the spontaneous reports, consistent with the higher prevalence of Alzheimer’s disease in females. The authors suggest that this age bracket represents both the bulk of the treated population and a particularly vulnerable group, warranting prioritized monitoring of safety parameters in clinical practice.

Some findings were quietly reassuring. Despite gastrointestinal disorders ranking fifth in report volume, the disproportionality analysis yielded a protective signal, with a reporting odds ratio of 0.65, suggesting lecanemab does not meaningfully elevate the risk of nausea or diarrhea beyond what would be expected by chance. Infections and infestations, ranking seventh, similarly showed a protective signal at 0.49, indicating no significant increase in infection risk. These results diverge from what one might expect from the prescribing information and likely reflect reporting biases inherent to spontaneous systems, where only unusual or unexpected events tend to be filed.

The study is not without limitations, and the authors are candid about them. The prospective cohort is single-center and modest in size, with a median exposure of just 185 days, which limits conclusions about long-term safety beyond one year. The FAERS analysis cannot calculate true incidence rates because spontaneous reporting lacks a denominator, and the time-to-onset subset, representing about 30 percent of reports, may be biased toward medically attended events with precise dates. Still, the convergence of two independent data sources, a carefully phenotyped real-world cohort and a large pharmacovigilance database, offers a more textured picture than either alone. The overall message is one of cautious optimism: lecanemab’s safety profile in routine practice appears broadly manageable and consistent with trial data, provided clinicians remain vigilant during the first two months of therapy, monitor for ARIA throughout the entire treatment course, and interpret the emerging stroke signal with the cardiovascular context of each individual patient firmly in mind. Larger, multicenter prospective studies will be needed to confirm these signals and refine risk-mitigation strategies as anti-amyloid therapy becomes a routine part of Alzheimer’s care.

Subject of Research: Real-world safety of the Alzheimer's drug lecanemab assessed through a prospective patient cohort and FDA adverse event database signal analysis

Article Title: Safety of lecanemab in real-world patients with Alzheimer’s disease: a prospective, observational case series supported by FAERS signal analysis

Article References: Ji, H., Yang, Y., Wu, X., & Bao, E. (2026). Safety of lecanemab in real-world patients with Alzheimer’s disease: a prospective, observational case series supported by FAERS signal analysis. Frontiers in Neuroinformatics, 20, Article 1977226. https://doi.org/10.3389/fninf.2026.1977226

Image Credits: AI Generated

DOI: 10.3389/fninf.2026.1977226

Keywords: lecanemab, Alzheimer's disease, ARIA, FAERS, drug safety, pharmacovigilance, cerebral infarction, infusion-related reactions, amyloid-beta, monoclonal antibody, adverse events, real-world evidence

Respiratory syncytial virus, or RSV, is the leading cause of bronchiolitis, a viral infection of the small airways that sends hundreds of thousands of infants to hospitals across Europe each winter. For decades, pediatricians had little to offer beyond supportive care, since a previous antibody product, palivizumab, was reserved for high-risk infants because of its high cost and the need for monthly injections. Nirsevimab changed that calculus. A single dose provides protection lasting at least five months, covering an entire RSV season, and clinical trials demonstrated strong efficacy against medically attended lower respiratory tract infection in healthy term and preterm infants alike.

When nirsevimab finally became available in Europe in late 2023, national and regional health authorities adopted it at different speeds and with different strategies. Some countries launched universal immunization programs targeting all infants entering their first RSV season, while others restricted initial campaigns to infants born during or just before the season, and a few had no program at all during the study window. This patchwork of implementation created an unintended natural experiment, and a large consortium of European pediatric emergency researchers seized the opportunity to measure what happened.

The research team, led by Léa Lenglart and Naim Ouldali with the EPISODES Study Group, assembled routinely collected data from 27 pediatric emergency departments spanning 12 European countries, covering the period from January 2018 through March 2024. They included every case of bronchiolitis diagnosed in infants younger than 12 months, yielding a total of 107,088 episodes. Regions were classified as intervention or control depending on whether nirsevimab had been implemented, and immunization coverage figures were drawn from official regional reports. Urinary tract infections in the same age group served as a control outcome, a standard technique to detect whether observed changes reflect a real intervention effect or some unrelated shift in emergency department attendance.

The analytical approach was a controlled interrupted time-series design, a method well suited to evaluating population-level interventions introduced at a known point in time. The models accounted for underlying seasonality and pre-existing temporal trends, allowing the researchers to estimate how much of the change in monthly bronchiolitis cases during the intervention period, from October 2023 through March 2024, could be attributed to the antibody program rather than to the ordinary rhythm of winter epidemics. Estimates were stratified by age group, separating infants aged 0 to 3 months, who face the highest risk of severe disease, from those aged 3 to 12 months.

The results were striking in both their magnitude and their heterogeneity. Reductions in bronchiolitis visits ranged from essentially no change, with one estimate of plus 0.6 percent, to a remarkable 61 percent decline, with a confidence interval stretching from minus 67.8 to minus 35.2 percent. Infants in the youngest age band generally showed the largest reductions, consistent with the biology of RSV, since the highest rates of hospitalization and intensive care admission occur in the first months of life. Meanwhile, bronchiolitis trends in control regions without nirsevimab programs remained stable, and urinary tract infection visits showed no comparable decline, strengthening the argument that the observed reductions were tied to the immunization campaigns rather than a general drop in emergency presentations.

Perhaps the most consequential finding was the strength of the statistical relationship between coverage and benefit. Across regions and age groups, the correlation between nirsevimab coverage and the percentage reduction in bronchiolitis visits was negative and pronounced, with a correlation coefficient of minus 0.86 and a p-value of 0.001. In practical terms, regions that immunized a larger share of their infant population saw proportionally larger drops in emergency department visits. The relationship held across both age strata, suggesting that the antibody’s protective effect translated into population benefit wherever it reached enough infants, whether they were immunized at birth during the season or through catch-up campaigns targeting older babies.

Why did coverage differ so much across Europe? The study points to implementation choices as the decisive variable. Countries and regions that embedded nirsevimab into routine newborn care, offering the dose in maternity wards before discharge, achieved far higher uptake than those relying on later appointments or opportunistic vaccination during other visits. Administrative hurdles, supply constraints, differences in eligibility criteria, and varying levels of parental and clinician acceptance all likely contributed. The authors emphasize that the antibody’s intrinsic efficacy, already demonstrated in randomized trials, was never in question; what varied was the fraction of the infant population that actually received it in time to be protected when the virus arrived.

The researchers are careful about the limits of their design. As an ecological study, it examines populations rather than individuals, so causality cannot be definitively inferred. Unmeasured regional differences, such as changes in testing practices, health-seeking behavior, viral circulation intensity, or concurrent public health measures, may have contributed to some of the observed variability. The interrupted time-series models adjust for seasonality and trend, and the stability of control outcomes argues against simple artifacts, but the authors acknowledge that residual confounding remains possible. Still, the consistency of the findings across 27 departments, multiple countries, and two age groups, together with the tight coverage-response relationship, makes a compelling case that immunization coverage was a key driver of the reductions.

The implications for health policy are immediate. RSV prevention has entered a new era, with nirsevimab programs now expanding and maternal RSV vaccines adding another layer of protection for newborns. This study demonstrates that the public health return on these interventions depends not only on the biology of the product but on the machinery of delivery. Regions that achieved high coverage among both season-born and out-of-season infants reaped reductions in bronchiolitis visits of a scale rarely seen for a respiratory disease, easing pressure on emergency services during the busiest weeks of the winter. For health authorities weighing how to structure their own programs, the European experience of 2023–2024 offers a clear lesson: the fastest, broadest, and earliest possible reach into the infant population is what converts a highly effective antibody into a visible decline in disease. As nirsevimab programs mature and additional seasons of data accumulate, researchers will be watching to see whether the coverage-response relationship holds, whether protection extends to severe outcomes such as intensive care admission, and whether the substantial regional variability in implementation narrows as systems learn from one another.

Subject of Research: Association between nirsevimab immunization coverage and reductions in infant bronchiolitis emergency department visits across 12 European countries

Article Title: Association between nirsevimab coverage and pediatric emergency department visits for bronchiolitis in 12 European countries: An interrupted time-series analysis

Article References: Lenglart, L., Titomanlio, L., Alberti, I., Almeida, L., Aupiais, C., Akyüz Özkan, E., Barrett, M., Basmaci, R., Birbilen, A., Borensztajn, D., Schönenberger, C. B., Bressan, S., Buonsenso, D., Campos, T., Castanhinha, S., Chiaretti, A., Claret, G., De Zan, F., Durnin, S., … the EPISODES Study Group (2026). Association between nirsevimab coverage and pediatric emergency department visits for bronchiolitis in 12 European countries: An interrupted time-series analysis. PLOS Medicine, 23(9), e1005223. https://doi.org/10.1371/journal.pmed.1005223

Image Credits: AI Generated

DOI: 10.1371/journal.pmed.1005223

Keywords: nirsevimab, RSV, bronchiolitis, infants, pediatric emergency departments, immunization coverage, interrupted time-series, Europe, PLOS Medicine, monoclonal antibody, respiratory syncytial virus, public health

Evolocumab belongs to a class of drugs known as PCSK9 inhibitors, and its mechanism is elegantly simple at the molecular level. PCSK9 is a protein produced by the liver that binds to LDL receptors on hepatocytes and tags them for destruction. Because these receptors are the primary route by which the liver clears LDL particles from the bloodstream, destroying them means cholesterol lingers in circulation, embedding itself in arterial walls. Evolocumab is a fully human monoclonal antibody that neutralises PCSK9, preventing this degradation. The result is a dramatic increase in the recycling and surface density of LDL receptors, which accelerates the clearance of LDL particles and can lower LDL cholesterol by up to 60 percent, far beyond what statins alone typically achieve.

The new analysis was conducted under PRISMA guidelines and prospectively registered, with researchers searching five major databases through April 2025. They included only randomised controlled trials of evolocumab in adults with established cardiovascular disease, defined as prior myocardial infarction, stroke, symptomatic peripheral artery disease, or coronary revascularisation. By focusing exclusively on a single PCSK9 inhibitor rather than pooling multiple agents, the investigators aimed to produce drug-specific estimates while minimising the heterogeneity that plagues broader class-level reviews. The final dataset encompassed 67,662 patients, with 34,618 receiving evolocumab and 33,044 receiving placebo or standard therapy, spanning landmark trials such as FOURIER, its open-label extension, and EVOPACS, which enrolled patients in the immediate aftermath of acute coronary syndromes.

The lipid results were striking across the board. Beyond the headline LDL reduction of 57.73 milligrams per decilitre, evolocumab lowered total cholesterol by about 52 milligrams per decilitre and triglycerides by roughly 21 milligrams per decilitre, while modestly raising HDL cholesterol by about 3.7 milligrams per decilitre. The drug also reduced lipoprotein(a), a genetically determined, pro-atherogenic particle that statins barely touch, though the pooled reduction of about 11 milligrams per decilitre narrowly missed conventional statistical significance. The authors caution that the clinical benefit should be attributed primarily to LDL lowering, which has a firmly established causal relationship with atherosclerotic risk, while the changes in HDL and triglycerides are best viewed as accompanying metabolic effects rather than independent drivers of outcome improvement.

On the clinical side, the pooled analysis found a significant reduction in major adverse cardiovascular events, with a risk ratio of 0.53. That figure, however, demands careful interpretation. The pooled estimate is considerably larger than the roughly 15 percent relative risk reduction reported in the FOURIER trial, and the researchers attribute this discrepancy to methodological differences, including the pooling of risk ratios from aggregated event counts rather than hazard ratios from time-to-event analyses, the inclusion of smaller trials with fewer events, and variation in how composite endpoints were defined across studies. When the most influential smaller trials were excluded in sensitivity analyses, heterogeneity vanished and the effect settled at a more conservative risk ratio of 0.84, which aligns closely with the landmark trial evidence.

Individual endpoints told a consistent story. Myocardial infarction risk fell by 26 percent and coronary revascularisation by 20 percent, both with high-certainty evidence and minimal heterogeneity. Stroke showed a smaller, borderline significant reduction of 14 percent. Cardiovascular mortality and hospitalisation for unstable angina did not decline significantly, which the authors attribute to the relative rarity of these individual endpoints, the limited follow-up duration of most trials, and the fact that cardiovascular death reflects many competing mechanisms beyond LDL exposure alone. Importantly, the absence of significance for these endpoints does not negate biological benefit, given the robust reductions observed in the events that most directly reflect plaque rupture and arterial obstruction.

Safety findings were equally reassuring. Across more than 56,000 patients analysed for serious adverse events, there was no difference between evolocumab and control groups, with zero heterogeneity indicating remarkably consistent results. Rates of drug discontinuation, neurocognitive complaints, muscle-related symptoms, and new-onset diabetes were all statistically indistinguishable from placebo. The only signal was a modest, non-significant increase in mild injection-site reactions. This profile contrasts favourably with statins, which do not inhibit intracellular cholesterol synthesis and therefore avoid the muscle toxicity pathway that troubles some patients. Long-term extension data from FOURIER-OLE, following patients for nearly eight years, have similarly found no accumulation of neurological, metabolic, or hemorrhagic harms.

The authors also explored how treatment effects varied across clinical contexts. LDL reductions remained significant in every subgroup examined, ranging from about 55 to 60 milligrams per decilitre whether patients had recent acute coronary syndromes or stable disease. Lipoprotein(a) reductions were significant in acute coronary syndrome populations and in event-driven trials, while the MACE benefit was concentrated in stable atherosclerotic disease populations, imaging trials, and studies with at least one year of follow-up. These patterns reinforce the idea that the magnitude of absolute benefit scales with baseline cardiovascular risk, meaning patients with recent events, polyvascular disease, diabetes, or persistently elevated cholesterol stand to gain the most from adding evolocumab to their regimen.

The clinical implications extend to health economics as well. Current guidelines from the American College of Cardiology, the American Heart Association, and the European Society of Cardiology already recommend PCSK9 inhibitors for patients whose LDL remains at or above 70 milligrams per decilitre despite maximally tolerated statin therapy. This analysis supports that guidance, but the authors note that cost remains a barrier, with earlier cost-effectiveness analyses favourable only for the highest-risk subgroups. Insurers frequently require documented very high LDL or multiple cardiovascular events before approving coverage, a practice that effectively targets the patients most likely to benefit. As prices fall and value-based pricing models mature, access is expected to broaden.

Looking forward, the researchers call for individual participant data meta-analyses to identify which patient characteristics predict the greatest benefit, dedicated trials in patients with elevated lipoprotein(a), head-to-head comparisons with alirocumab and newer agents such as inclisiran, and real-world registries to confirm the durability of benefit beyond the trial setting. For now, the evidence solidifies a central principle of modern cardiology: when it comes to LDL cholesterol, lower is better, and evolocumab offers a powerful, safe tool for pushing levels far below what statins alone can achieve in the patients who need it most.

Subject of Research: Efficacy and safety of the PCSK9 inhibitor evolocumab in patients with established atherosclerotic cardiovascular disease

Article Title: Impact of Evolocumab on LDL‐Cholesterol and Cardiovascular Outcomes in Patients With Established CVD: Systematic Review and Meta‐Analysis

Article References: Goel, A., Naveed, M. A., Tandel, H., Mahmood, A., Mukhlis, M., Reddy, K. S. V., Maloth, A. K., Chauhan, A., Ashwara, A., Verma, A., & Tahir, H. B. (2026). Impact of Evolocumab on LDL‐Cholesterol and Cardiovascular Outcomes in Patients With Established CVD: Systematic Review and Meta‐Analysis. Endocrinology, Diabetes & Metabolism, 9(6), Article e70355. https://doi.org/10.1002/edm2.70355

Image Credits: AI Generated

DOI: 10.1002/edm2.70355

Keywords: evolocumab, PCSK9 inhibitor, LDL cholesterol, cardiovascular disease, meta-analysis, FOURIER trial, myocardial infarction, coronary revascularisation, lipoprotein(a), statins, secondary prevention, monoclonal antibody

The study, led by Michael J. Peluso and Dylan Ryder of the University of California, San Francisco, together with a broad consortium of collaborators at the University of Pennsylvania, Harvard Medical School, Aerium Therapeutics, and the Patient-Led Research Collaborative, was designed as a mechanistic trial rather than a conventional efficacy study. Thirty-six participants were enrolled and randomized in a 2:1 ratio to receive either a single infusion of AER002 or a placebo, with both participants and investigators blinded to allocation. After an intensive baseline characterization that included patient-reported outcomes, objective measures of physical and neurocognitive function, and a battery of blood-, imaging-, and tissue-based biomarkers, participants were followed for a full 360 days. The primary endpoint was the PROMIS-29 Physical Health Summary Score, a validated patient-reported measure of physical health, assessed at 90 days after infusion. The trial was registered as NCT05877508 and was funded in part by the Patient-Led Research Fund, with additional support from the PolyBio Research Foundation and the National Institute of Neurological Disorders and Stroke.

The choice of AER002 reflected the specific immunological reasoning behind the trial. The antibody is a monoclonal neutralizing antibody directed against SARS-CoV-2, engineered to bind the spike protein of the virus. In theory, if residual virus or viral antigen in reservoir sites such as the gut or other tissues was driving ongoing symptoms, a potent neutralizing antibody circulating at high concentrations could bind to and help clear that antigen, interrupting the pathological feedback loop. Monoclonal antibodies of this class proved their worth during the acute phase of the pandemic, reducing viral load and hospitalization when given early in infection. The Long COVID setting, however, poses a fundamentally different problem: the target is not a rapidly replicating population of virus in the airway but a poorly characterized, possibly intracellular or sequestered reservoir, and the therapeutic window is measured in months or years rather than days.

When the results were analyzed, the trial returned a clear and largely negative verdict on those hopes. There were no significant differences between the AER002 arm and the placebo arm in physical health as measured by the primary endpoint, in quality of life, in objective measures of physical function or cognition, or in blood-based biomarkers of immune activation and viral persistence. The consistency of the null result across both subjective and objective measures is notable, because mechanistic trials of this kind often show discordance between what patients report and what laboratory assays detect. Here, neither signal moved. The investigators emphasize that the study was exploratory and small, with only 36 participants, which limits its statistical power and means that a modest treatment effect in a molecularly defined subgroup cannot be definitively excluded. Still, as a proof of concept for the idea that a single dose of a spike-specific monoclonal antibody can ameliorate Long COVID symptoms, the trial did not deliver support.

The safety data, at least, were unambiguous. AER002 was well tolerated across the follow-up period, with no significant safety concerns identified between the treatment and control arms. That finding matters for the field because it establishes that potent anti-SARS-CoV-2 antibodies can be administered to people with chronic post-acute illness without provoking unexpected adverse events, including immune-complex-mediated reactions that some theorists had worried about when antibody binds to circulating viral antigen. For a condition in which patients have been desperate for any intervention at all, and in which unproven remedies circulate widely, the demonstration that a rigorously tested biological agent can be given safely is a small but genuine contribution, even when the efficacy signal is absent.

Beneath the headline null result, however, the trial produced one of the more intriguing post-hoc observations in the Long COVID literature to date. In an analysis not specified in advance, the researchers found that participants who entered the study with lower baseline levels of SARS-CoV-2 antibodies, specifically antibodies against the spike protein, the S1 subunit, and the receptor-binding domain, and who also achieved higher drug exposure after infusion, were more likely to perceive a treatment benefit on the Patient Global Impression of Change scale, with the associations reaching statistical significance at p less than 0.05 for all three antibody measures. The pattern is biologically coherent: patients with low endogenous anti-spike titers might be those whose immune systems have been least effective at controlling a persistent viral reservoir, and who would therefore stand to gain the most from an exogenous dose of neutralizing antibody. Higher drug exposure, meanwhile, would ensure that the antibody actually reached relevant tissue compartments in sufficient concentration.

The post-hoc finding must be interpreted with considerable caution. Post-hoc analyses in small trials are exploratory by definition, and the Patient Global Impression of Change is a subjective measure that can be influenced by expectation and the natural fluctuation of symptoms over time. With 36 participants divided across two arms, the subgroup analysis rests on a handful of individuals, and the possibility of chance findings cannot be dismissed. Nevertheless, the investigators argue that the signal is valuable precisely because it is hypothesis-generating: it suggests that future trials of antiviral or antibody-based approaches in Long COVID should stratify or enrich enrollment based on baseline humoral immunity, rather than treating the syndrome as a single homogeneous entity. If viral persistence drives disease in only a subset of patients, trials that enroll unselected populations will dilute any true treatment effect into statistical invisibility, a problem that has plagued the field broadly.

The trial’s mechanistic ambition also sets a template for how Long COVID studies should be conducted. Rather than relying solely on symptom questionnaires, the investigators collected objective measures of physical function, including cardiopulmonary exercise testing, neurocognitive testing batteries, imaging procedures, and optional gut biopsies, alongside an extensive panel of blood-based biomarkers. This integrated design means that even a negative efficacy result yields a rich dataset on the natural history of the syndrome and the relationship between molecular markers and clinical status over a full year of follow-up. The involvement of the Patient-Led Research Collaborative in the design and implementation of the study, with advice from patient researchers Lisa McCorkell and Hannah Davis, also reflects a growing recognition that Long COVID research benefits from the lived expertise of the affected community, both in choosing meaningful endpoints and in sustaining recruitment.

For the viral persistence hypothesis itself, the trial is neither a confirmation nor a refutation. A single monoclonal antibody dose is a blunt instrument against a reservoir whose size, location, and biology remain unknown. If persistent virus resides intracellularly or within immune-privileged sites that antibodies penetrate poorly, or if the relevant antigen is present at vanishingly low levels, then even a highly potent neutralizing antibody may fail to change the trajectory of disease. Alternatively, if viral persistence is only one of several converging mechanisms, alongside autoimmunity, microbiome disruption, latent virus reactivation, or vascular injury, then neutralizing the virus in a mixed population would predictably produce the kind of null result observed here. The authors themselves frame the trial as a foundation rather than a conclusion, stating that although AER002 was not efficacious in this proof-of-concept study, the findings could inform future trials using monoclonal antibodies to target viral persistence in Long COVID.

What comes next will likely be shaped by the trial’s two principal lessons. First, patient selection must become molecular: enrichment strategies based on baseline anti-spike antibody levels, viral antigen detection in plasma or tissue, or other biomarkers of active persistence could dramatically increase the signal-to-noise ratio of future antiviral trials. Second, dosing and duration may need rethinking, since a single infusion may be insufficient against a reservoir that has had years to establish itself, and combination approaches, for example pairing antibodies with antiviral drugs that act intracellularly, may be required. The AER002 trial, conceived and executed with unusual rigor and community partnership, closes one door while pointing clearly toward the next: the search for the right drug, given to the right patients, at the right biological moment. For the millions living with Long COVID, that search continues, now with better maps than before.

Subject of Research: A randomized phase 2a mechanistic trial testing the SARS-CoV-2 monoclonal antibody AER002 as a treatment for Long COVID

Article Title: SARS-CoV-2-specific monoclonal antibody AER002 in Long COVID: an exploratory randomized phase 2a mechanistic trial

Article References: Peluso, M. J., Ryder, D., Dalhuisen, T., Chu, D. H. T., Williams, M. C., Rodriguez, A. E., LaFranchi, B. H., Vinden, J., Fehrman, E. A., Huang, B., Hoh, R., Asare, K. A., Bellon Pizarro, K., Rahman, M. S., de Narvaez, E., Painter, M. M., Wherry, E. J., Swank, Z. N., Hansen, L. L., … Deeks, S. G. (2026). SARS-CoV-2-specific monoclonal antibody AER002 in Long COVID: an exploratory randomized phase 2a mechanistic trial. Nature Communications. https://doi.org/10.1038/s41467-026-77925-y

Image Credits: AI Generated

DOI: 10.1038/s41467-026-77925-y

Keywords: Long COVID, SARS-CoV-2, AER002, monoclonal antibody, viral persistence, phase 2a trial, PROMIS-29, Patient Global Impression of Change, anti-spike antibodies, mechanistic trial, Nature Communications, placebo-controlled

To understand why the target is unusual, it helps to look at the immunology of the disease. Psoriasis is a chronic autoimmune skin disorder affecting roughly two percent of the global population, and about thirty percent of those patients go on to develop psoriatic arthritis, a condition that combines joint inflammation, pain, and progressive structural damage. Both diseases are driven primarily by CD4-positive T cells, the immune cells whose fate is dictated by the cytokine environment they encounter. One of the most influential of these signals is TGF-beta, a molecule with a famously dual personality: it can push naive T cells toward Th17 cells, potent drivers of inflammation, or toward regulatory T cells, or Tregs, which restrain autoimmunity and protect tissue. In psoriasis and psoriatic arthritis, this balance tips sharply toward Th17 cells, while the protective regulatory arm underperforms.

Most existing therapies attack the downstream consequences of that imbalance rather than the balance itself. Tumor necrosis factor inhibitors and antibodies against the IL-17 axis have transformed treatment for many patients, but the study’s authors note that roughly thirty-five to forty percent of people with psoriatic arthritis fail to reach a minimum level of efficacy with these drugs, and resistance emerges over time in others. Blocking BAMBI offers a conceptually different approach. BAMBI is a pseudoreceptor, a membrane-bound protein that lacks an intracellular signaling domain and acts as a decoy that modulates signaling by the TGF-beta and related pathways. By inhibiting BAMBI with an antibody, the researchers aimed to enhance the signaling that favors regulatory T cell differentiation, thereby rebuilding the immune system’s own brakes instead of merely blocking its accelerators.

The antibody itself, hB101.37, is a humanized monoclonal antibody, meaning its protein framework has been engineered to resemble human antibodies closely enough to minimize the risk that a patient’s immune system will reject it as foreign. The team evaluated its therapeutic effect in three preclinical mouse models: an imiquimod-induced model of psoriasis, an IL-21-induced model of the skin disease, and a mannan-induced model of psoriatic arthritis. These models reproduce key features of the human conditions, from scaly skin inflammation to joint swelling, and are standard tools for testing whether a candidate biologic can plausibly work in patients before any clinical trial begins.

The results were striking on several fronts. Treatment with hB101.37 reduced disease in both the psoriasis and psoriatic arthritis models, confirming efficacy across the spectrum of the disease. Flow cytometry analyses of immune cells from treated animals showed that the antibody reduced the population of pro-inflammatory Th17 cells while promoting differentiation toward the regulatory T cell lineage, exactly the rebalancing effect the researchers had predicted from the mechanism. In molecular terms, the team traced the effect to activation of the Smad2/3 pathway, the canonical intracellular signaling route downstream of the TGF-beta receptor, which they assessed by western blot. In other words, blocking the decoy receptor BAMBI allowed the genuine TGF-beta signal to flow more freely into the Smad pathway, steering T cell fate toward tolerance.

Perhaps the most commercially and clinically significant comparison in the study is head-to-head with an established drug class. The researchers report that anti-BAMBI therapy showed potentially greater clinical efficacy in psoriasis than anti-IL-17A monoclonal antibodies, one of the most successful modern treatments for the disease. If that advantage translates to humans, it would represent a meaningful advance for the many patients whose disease is incompletely controlled by IL-17 blockade. Because the antibody works upstream of the IL-17 axis, reshaping the T cell populations that generate inflammatory cytokines in the first place, it could also, in principle, address multiple inflammatory pathways simultaneously rather than a single mediator.

Safety is where many promising immunomodulators stumble, and the Spanish team devoted considerable effort to characterizing the antibody’s preclinical safety profile. They performed histological and immunofluorescence analyses of murine tissues, measured inflammatory markers by ELISA and gene expression by quantitative PCR, and, notably, conducted transthoracic echocardiography after chronic administration of the antibody to assess cardiac function. Cardiac monitoring matters because TGF-beta family signaling is implicated in fibrosis and remodeling in multiple organs, so any therapy that perturbs this pathway must demonstrate that it does not provoke cardiovascular or structural toxicity. According to the authors, the preclinical phase confirmed the safety profile of the therapeutic antibody, an essential green light for moving toward clinical development.

The work also extended beyond mice. The researchers examined the effects of hB101.37 on human CD4-positive T cells in vitro, isolating the cells from buffy coat samples of anonymous healthy donors provided by the Blood and Tissue Bank of Cantabria under ethics committee approval. Demonstrating that the antibody can modulate T cell differentiation in human cells, not just in engineered mouse models, strengthens the translational case considerably, since species differences in cytokine biology frequently derail therapies that look spectacular in rodents. The animal studies were conducted under the approval of the University of Cantabria’s Institutional Laboratory Animal Care and Use Committee and in accordance with European directives on animal welfare.

The research is the product of a collaboration that blends a small biotechnology company with academic immunology groups. Inhibitec Anticuerpos, based in Santander, developed the antibody, and several of its scientists are coauthors, while the University of Cantabria’s molecular biology and pharmacology departments and the CSIC-affiliated biomedicine institute contributed the disease models and mechanistic analyses. The work was funded by a constellation of Spanish public agencies, including the Centro para el Desarrollo Tecnológico Industrial, the Ministry of Science, Innovation and Universities, SODERCAN, and the Government of Cantabria, along with the United States National Psoriasis Foundation, reflecting the international interest in new psoriasis therapeutics. The authors note a conflict of interest: Ramón Merino is a cofounder and stockholder of Inhibitec, and several coauthors are company employees, with the company holding a license for a patent application covering monoclonal antibodies against BAMBI for inflammatory diseases.

Caveats remain. The findings are preclinical, generated in mouse models and human cells in culture, and the antibody has not yet been tested in patients, where questions of dosing, immunogenicity, long-term safety, and real-world efficacy will ultimately be decided. The published version of the paper was shared early as an accepted manuscript and remains subject to final editorial edits. Still, the study offers something the psoriasis field has lacked: a genuinely new point of intervention that does not simply block another inflammatory cytokine but instead reprograms the T cell balance itself, boosting the regulatory arm of immunity while shrinking the inflammatory one. For the large minority of patients with psoriatic arthritis who do not respond to TNF or IL-17 blockers, and for whom drug resistance looms over even successful treatments, a first-in-class antibody that teaches the immune system to regulate itself is a development worth watching closely as it advances toward the clinic.

Subject of Research: Development of a humanized anti-BAMBI monoclonal antibody for the treatment of psoriasis and psoriatic arthritis

Article Title: Humanized anti-BAMBI monoclonal antibody as a novel therapeutic strategy for psoriatic arthritis

Article References: Perez-Adrian, P., Romero, D., Cappitelli, V., Gallego, F., Ruso-Julve, F., Calvo, M., Garcia, R., Puyalto, A., Gomez, I., Merino, D., Gil-de-Gomez, L., Merino, R., & Casado-Medrano, V. (2026). Humanized anti-BAMBI monoclonal antibody as a novel therapeutic strategy for psoriatic arthritis. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09038-5

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09038-5

Keywords: psoriasis, psoriatic arthritis, BAMBI, monoclonal antibody, Th17 cells, regulatory T cells, TGF-beta, immunotherapy, biologics, Smad2/3 pathway, preclinical models, autoimmune disease

Waldenström macroglobulinemia is a rare and indolent B-cell lymphoma characterized by the accumulation of malignant lymphoplasmacytic cells in the bone marrow and, crucially, by the overproduction of monoclonal immunoglobulin M, an antibody protein that thickens the blood and can cause hyperviscosity, neuropathy, and organ damage. Because the disease is uncommon, most treatment evidence comes from small trials and single-arm studies, leaving clinicians with genuine uncertainty when patients relapse after frontline therapy. This rarity is precisely why the French group’s multicenter approach matters: by pooling patients from 17 centers, the investigators assembled one of the larger cohorts ever reported for this specific treatment strategy.

The drug at the center of the study, venetoclax, belongs to a class of agents known as BH3 mimetics. These small molecules bind to BCL-2, an anti-apoptotic protein that many B-cell cancers exploit to evade programmed cell death. By occupying the BCL-2 binding groove, venetoclax releases the cellular brakes on apoptosis, allowing malignant lymphocytes to self-destruct. The drug has already transformed the treatment landscape for chronic lymphocytic leukemia, and earlier monotherapy studies suggested promising activity in relapsed or refractory Waldenström macroglobulinemia, a population with significant unmet medical need. What remained unclear was whether venetoclax should be given alone or in combination with other agents in this disease.

The WAVE investigators turned to real-world clinical practice to answer that question. The 46 patients included in the analysis had received a median of three prior lines of treatment before starting venetoclax, and 89 percent had already been exposed to a Bruton tyrosine kinase inhibitor, the class of drugs that has become a cornerstone of Waldenström macroglobulinemia therapy. This detail is important: these were heavily pretreated patients whose disease had already evaded the most effective modern targeted therapies, meaning that any meaningful response signal carries real clinical weight. Among the cohort, 25 patients, or 54 percent, received venetoclax combined with an anti-CD20 antibody, typically rituximab or a related monoclonal antibody that targets the CD20 surface protein found on B cells and recruits the immune system to destroy antibody-coated tumor cells.

The headline finding concerns response depth. At the time of best response, patients treated with the combination achieved a deep response rate, defined as very good partial response plus uncertain complete response, of 56 percent, compared with just 24 percent among those treated with venetoclax monotherapy, a difference that reached statistical significance with a p value of 0.03. In lymphoma care, depth of response is not an academic nicety. Deeper remissions, particularly those in which the monoclonal IgM protein falls to very low or undetectable levels, are consistently associated with longer periods of disease control before relapse. For a disease in which the abnormal protein itself drives many of the symptoms, pushing IgM down as far as possible translates directly into clinical benefit.

Perhaps more striking was the result of the multivariate analysis. When the investigators adjusted for other clinical variables, anti-CD20 combination therapy emerged as the only factor independently associated with achieving a deep response, with a hazard ratio of 4.07 and a p value of 0.03. In other words, the antibody combination quadrupled the odds of a deep remission regardless of other patient characteristics. This kind of signal, emerging from a retrospective dataset where treatment assignment was not randomized, cannot prove causation on its own, but it provides a strong rationale for the prospective trials that the authors say are needed to confirm the strategy.

The progression-free survival data reinforced the same direction of benefit, though with more statistical uncertainty. At two years, 78 percent of patients treated with venetoclax plus anti-CD20 had not experienced disease progression or death, compared with 54 percent of those on monotherapy. The confidence intervals were wide, spanning 54 to 90 percent for the combination arm and 27 to 74 percent for monotherapy, and the difference did not reach statistical significance with a p value of 0.25. That lack of formal significance is unsurprising given the modest sample size, but the magnitude of the gap, nearly 25 percentage points at two years, is the kind of signal that clinicians and trial designers take seriously.

Safety, as always in combination therapy, is the counterweight to efficacy, and here the picture was more nuanced. Grade 3 or higher adverse events occurred in 17 patients, or 68 percent, of those receiving the combination, versus 7 patients, or 33 percent, of those on venetoclax alone, a difference that was statistically significant with a p value of 0.02. Three cases of febrile aplasia, episodes of fever accompanied by severe suppression of blood cell production, were reported, though these did not differ significantly between the two groups. The increased toxicity of the combination is consistent with what is known about adding antibody therapy to targeted agents: the pairing amplifies immune-mediated tumor killing but also increases the burden on the bone marrow and the immune system. For a largely elderly patient population, this trade-off between deeper remissions and higher rates of serious side effects will need careful weighing in future prospective studies.

The WAVE study also illustrates a broader shift in how rare-cancer evidence is generated. Randomized trials in diseases with incidence rates as low as Waldenström macroglobulinemia’s can take years to accrue even modest numbers of patients, and many relapsed patients cannot wait. Retrospective multicenter cohorts like this one, harmonized across 17 institutions and analyzed with multivariate statistics, offer a pragmatic middle path: they capture the messy reality of clinical practice, including heterogeneous prior treatments and variable dosing schedules, and they generate hypothesis-driving signals that can justify the prospective studies that ultimately change guidelines. The French FILO network has been particularly productive in this regard, leveraging the centralized structure of French hematology care to assemble cohorts that individual centers never could.

For patients and their physicians, the practical message is cautiously encouraging. Venetoclax, with or without an anti-CD20 antibody, is an oral, targeted, chemotherapy-free approach for a disease that has historically been treated with rituximab-based chemoimmunotherapy, proteasome inhibitors, or BTK inhibitors. The WAVE data suggest that in the relapsed or refractory setting, particularly after BTK inhibitor exposure, the combination strategy offers the best chance of a deep and durable response, at the cost of more frequent severe side effects. The authors themselves frame the findings as warranting further evaluation in prospective studies, and that is the appropriate note of restraint. Until randomized data arrive, the study gives hematologists a real-world benchmark and gives patients with few remaining options a reason for measured optimism that the next generation of trials will refine exactly who benefits most from this two-pronged attack on their cancer.

Subject of Research: Venetoclax with or without anti-CD20 antibody therapy for relapsed or refractory Waldenström macroglobulinemia

Article Title: Relapsed/refractory WAldenström macroglobulinemia patients treated by VEnetoclax with or without anti-CD20 antibody: WAVE a retrospective study of the French CLL/WM group (FILO)

Article References: Vonfeld, M., Systchenko, T., Debureaux, P.-E., Dupuis, J., Roos-Weil, D., Ysebaert, L., Dilhuydy, M.-S., Malphettes, M., Croizier, C., Aurran, T., Inchiappa, L., Willems, L., Hivert, B., Lévy, V., Bussot, L., Bouclet, F., Laribi, K., Clavert, A., Durand, A., & Tomowiak, C. (2026). Relapsed/refractory WAldenström macroglobulinemia patients treated by VEnetoclax with or without anti-CD20 antibody: WAVE a retrospective study of the French CLL/WM group (FILO). Annals of Hematology. https://doi.org/10.1007/s00277-026-07293-6

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07293-6

Keywords: Waldenström macroglobulinemia, venetoclax, anti-CD20 antibody, BTK inhibitor, relapsed refractory lymphoma, BCL-2, targeted therapy, retrospective study, hematology, monoclonal antibody, progression-free survival, FILO