Diagnostics Research Group

ABSTRACTBackgroundBispecific Antibodies (BsAbs) represent a novel class of immunoglobulins that can target and bind to two distinct antigens simultaneously. The global BsAbs market, valued at approximately USD 8.65 billion in 2023, reflects tremendous promise and substantial growth. Here, we present a comprehensive analysis of the current BsAbs research pipeline in solid tumors.MethodsData were extracted from LARVOL CLIN, an outcomes database storing over 130,000 trials, to analyze the number of BsAbs including the number of trials per company, the timeline of trial initiation, phases, specific molecules, targets, and associated biomarkers. LARVOL CLIN leverages regular expression‐based text mining to extract data from major trial registries, including ClinicalTrials.gov, EudraCT, the Australian registry ANZCTR and the Asian Registries ChiCTR and UMIN.ResultsOur analysis identified 681 registered clinical trials in ClinicalTrials.gov, a number that has doubled since 2019, each with a known target and phase, evaluating a total of 183 BsAbs. Solid tumors, particularly gastrointestinal, lung, gynecological and breast cancer, have emerged as primary focuses. A significant trend is the strong focus on immune checkpoint bispecific targets, particularly PD1‐CTLA4 (n = 216 trials, 31.7%, 4 BsAbs), PD1‐VEGF (n = 56 trials, 8.2%, 3 BsAbs), followed by oncogene targets like EGFR‐MET (n = 34 trials, 5%, 3 BsAbs). The distribution of clinical molecules also reflects such focus, with dual PD1‐CTLA4 inhibitors (Cadonilimab, Volrustomig, Danviostomig) leading the highest number of trials (n = 208, 30.5%). Other promising molecules include Ivonescimab (n = 51, 7.5%), targeting PD1‐VEGF, and Amivantamab‐vmjw (n = 29, 4.3%), targeting EGFR‐MET. Clinical trials investigating PD1‐CTLA4 BsAbs showed improved overall survival (OS) and progression‐free survival (PFS) with tolerable adverse effects when combined with standard chemotherapy. Only 38% of trials, n = 258, specified a biomarker inclusion. Among oncogene‐targeted BsAbs, EGFR is the most prevalent (n = 80, 31%), followed by HER2 (n = 77, 29.8%), and ALK (n = 41, 15.8%). Gene‐specific alterations were also represented; HER2‐positive alterations garnered the most attention in n = 35 trials. BsAbs development is primarily driven by biotechnology companies (Akesobio, Alphamab, Biokin Pharma, etc.) compared to large pharmaceutical companies (J&J, AstraZeneca, and Boehringer Ingelheim). Geographically, the United States, China and the European Union have the highest number of trials available.ConclusionSince the first BsAb approval in 2014, the field has rapidly expanded, with solid tumor oncology advancing dynamically. The major focus has been on combining BsAbs with immunotherapy strategies, followed by targeting known oncogenic pathways. The shift toward biotechnology‐led innovation underscores the growing therapeutic and financial interest in this field. Optimizing the efficacy and safety of these molecules is key to paving the way for the next era of immune and precision oncology.

Abstract Background RSV causes respiratory infections that can lead to serious respiratory complications in older adults (OA). Presently, there is no approved vaccine to prevent RSV infections. RSVPreF3 OA is an investigational vaccine containing 120 µg RSVPreF3 and the AS01E adjuvant. Here we show safety results up to month (M) 6 post-vaccination with RSVPreF3 OA. Methods This phase 3 multi-country ongoing study (NCT04732871) enrolled adults ≥ 60 years of age over a period of 3 years. Participants were randomized (3:1:1) to receive RSVPreF3 OA with different vaccination schedules. All participants received a dose of RSVPreF3 OA on day 1. Solicited and unsolicited adverse events (AEs) were evaluated within 4 and 30 days post-vaccination. All serious AEs (SAEs) and potential immune mediated diseases (pIMDs) were collected up to M6 post-vaccination. SAEs and pIMDs related to vaccination, and fatal AEs are collected up to study end but reported here up to M6. Results Overall, 1653 participants received a dose of RSVPreF3 OA and 1618 completed the M6 follow-up. The mean age was 70.0 (±6.6) years and 54.6% were women. The most frequently reported solicited injection site reaction within 4 days post-vaccination was pain (996 participants; 60.5%, 95% confidence interval [CI]: 58.1–62.9). Twenty-two participants (1.3%, 95% CI: 0.8–2.0) reported grade 3 pain (Figure). The most reported solicited systemic reactions were myalgia (551 participants; 33.5%, 95% CI: 31.2–35.8) and fatigue (517 participants; 31.4%, 95% CI: 29.2–33.7). Twenty-five participants (1.5%) reported fever (no grade 3). Most solicited AEs were transient lasting ∼2 days and were of mild to moderate intensity. Overall, 212 (12.8%, 95% CI: 11.3–14.5) participants reported at least 1 unsolicited AE within 30 days post-vaccination. At least 1 SAE was reported by 65 participants (3.9%, 95% CI: 3.0–5.0). Seven participants (0.4%, 95% CI: 0.2–0.9) reported at least 1 pIMD. Of the SAEs and pIMDs reported, 1 event (Guillain-Barre syndrome) was considered by the investigator as related to vaccination. Fatal SAEs were reported for 6 participants; none related to vaccination. Conclusion One dose of investigational RSVPreF3 OA vaccine was well tolerated and had an acceptable safety profile in adults ≥ 60 years of age. Funding GlaxoSmithKline Biologicals SA. Disclosures Tino F. Schwarz, Prof. Dr. MD, Biogen, Merck-Serono, Pfizer, Alexion, Bavarian Nordic, Janssen-Cilag, AstraZeneca, Biontech, MSD: Grants|GlaxoSmithKline Biologicals SA: Honoraria John E. Ervin, MD, The Alliance for Multispecialty Research – KCM: Contractual agreement for conduct of study protocol Charles Andrews, MD, GlaxoSmithKline Biologicals SA: Institutional grant|Merck and Boehringer Ingelheim: Consulting fees outside of the submitted work Miguel Vicco, PhD MD, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Stocks/Bonds Marc Lievens, MSc, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Stocks/Bonds Céline Maréchal, PhD, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Stocks/Bonds Phoebe Nakanwagi, Master’s in Biostatistics, GlaxoSmithKline Biologicals SA: Employee Veronica Hulstrøm, PhD MD, GlaxoSmithKline Biologicals SA: Employee.

Introduction: Current evidence indicates that gastric intestinal metaplasia (IM) of the incomplete ("colonic") type carries a greater gastric cancer risk than complete ("small intestinal") IM. Recent AGA guidelines recommend including the IM type in pathology reports. Since the only known risk factor for gastric cancer (GC) is H. pylori infection and its sequelae (chronic and multifocal atrophic gastritis), we hypothesized that if incomplete IM is a more reliable harbinger of GC than its complete counterpart, it would be more prevalent in backgrounds of H. pylori-related gastritis than in other gastritides. Methods: IDEA (Inform Diagnostics Electronic Archives) is a national clinicopathologic database of patients who had gastrointestinal biopsies diagnosed at Inform Diagnostics. We extracted all patients with gastric biopsies (2008-2020) and selected those with the following diagnoses: normal stomach (Normal); chronic inactive gastritis (CIG); H. pylori chronic active gastritis (Hp-CAG); multifocal atrophic gastritis without H. pylori infection (MAG); autoimmune atrophic gastritis (AIG); reactive gastropathy (RG); and gastric adenocarcinoma (GC). After extracting random samples of subjects with one of these seven gastric phenotypes and IM, we reviewed all original slides and determined location, extension, and type of IM. Results: There were 1,673,233 subjects with gastric biopsies; 156,969 (9.4%) had IM. The prevalence of IM by gastritis type was: Normal = 2.7%; RG = 4.5%; Hp-CAG = 17.1; CIG = 27.5%; MAG = 74%; AIG= 91.6%; and GC = 17.6%. Table 1 depicts the prevalence of incomplete IM in these conditions. Not surprisingly, the greatest prevalence of incomplete IM was found in patients with GC (50.9%), followed by those with MAG (32.8%), a sequela of long-standing H. pylori gastritis and the background most likely to predispose to GC, and those with active H. pylori gastritis (19.0%). The lowest prevalence of incomplete IM (1.7%) was found in subjects with an otherwise normal stomach and in those with RG (5.2%); neither of these situations is a known risk factor for GC. Conclusion: Incomplete IM rarely occurs in the background of gastritides not associated with high risk for GC. In contrast, MAG and active H. pylori infection are fertile backgrounds for the incomplete type. These findings further support the predictive value of incomplete IM for GC risk and emphasize the importance of stating the type of IM in gastric biopsy reports, ideally adding it to the OLGA or OLGIM stage.Table 1.: Percentage of patients with different gastric phenotypes and intestinal metaplasia with an incomplete component.

Introduction: Particulate matter smaller than 2.5 micrometers (PM2.5) is known to cause heart and lung diseases including asthma. Poor environmental quality and rural locations have been shown to be associated with eosinophilic esophagitis (EoE), but the reasons why are unknown, as is the relationship between PM2.5 and EoE. We aimed to estimate the effect of PM2.5 concentration on EoE. Methods: We performed a case control study in a large pathology database of esophageal biopsies from across the United States. Cases were defined as ≥15 eosinophils per high-powered field in the absence of other histopathologic causes; controls were all other patients with esophageal biopsies. All patient data was geocoded by home address to the census tract of residence. Exposure to PM2.5 was determined by census tract location using estimates from the EPA’s Fused Air Quality Surface Using Downscaling model, averaged over the last 5 single-year concentrations prior to case occurrence. To estimate the effect of long-term PM2.5 concentration on the prevalence of EoE, we performed logistic regression adjusting for age, census tract population per square mile, census tract race/ethnicity, and census tract age distribution, using an auto-regressive correlation structure for clustering by census tract. We estimated the case control odds ratio with 95% confidence interval (CI). Results: There were 29,956 included EoE cases and 587,381 non-EoE controls. EoE was more common in census tracts with a higher proportion of non-Hispanic White residents and in census tracts with a younger age distribution (Table 1). EoE was more common in rural populations where PM2.5 concentration was often lower (Figure 1). The case control odds ratio of EoE for each 10 additional micrograms of PM2.5 per meter cubed was 0.84 (95% CI: 0.78 – 0.90) and the matched, adjusted prevalence ratio was 0.63 (95% CI: 0.60 – 0.68). Conclusion: In this case control study, there is an inverse association between higher PM2.5 and EoE, making PM2.5 an unlikely contributor to EoE diagnosis. These results are also consistent with the previously described association between EoE and rural areas with low population density, where PM2.5 is generally lower. Further studies should be undertaken to determine different environmental risk factors for EoE.Table 1.: Individual and Census Tract Characteristics of Included Cases and Controls.Figure 1.: Choropleth Map Overlaying the Unadjusted Proportion of Upper Endoscopy Biopsies with Eosinophilic Esophagitis by Census Tract with the Micrograms of Particulate Matter Under 2.5 Micrometers per Meter Cubed.

BackgroundThis ongoing follow-up study evaluated the persistence of efficacy and immune responses for 6 additional years in adults vaccinated with the glycoprotein E (gE)-based adjuvanted recombinant zoster vaccine (RZV) at age ≥50 years in 2 pivotal efficacy trials (ZOE-50 and ZOE-70). The present interim analysis was performed after ≥2 additional years of follow-up (between 5.1 and 7.1 years [mean] post-vaccination) and includes partial data for year (Y) 8 post-vaccination.MethodsAnnual assessments were performed for efficacy against herpes zoster (HZ) from Y6 post-vaccination and for anti-gE antibody concentrations and gE-specific CD4[2+] T-cell (expressing ≥2 of 4 assessed activation markers) frequencies from Y5 post-vaccination.ResultsOf 7413 participants enrolled for the long-term efficacy assessment, 7277 (mean age at vaccination, 67.2 years), 813, and 108 were included in the cohorts evaluating efficacy, humoral immune responses, and cell-mediated immune responses, respectively. Efficacy of RZV against HZ through this interim analysis was 84.0% (95% confidence interval [CI], 75.9–89.8) from the start of this follow-up study and 90.9% (95% CI, 88.2–93.2) from vaccination in ZOE-50/70. Annual vaccine efficacy estimates were >84% for each year since vaccination and remained stable through this interim analysis. Anti-gE antibody geometric mean concentrations and median frequencies of gE-specific CD4[2+] T cells reached a plateau at approximately 6-fold above pre-vaccination levels.ConclusionsEfficacy against HZ and immune responses to RZV remained high, suggesting that the clinical benefit of RZV in older adults is sustained for at least 7 years post-vaccination. Clinical Trials Registration. NCT02723773.

Objective. To review the scientific publications reporting vagal nerve somatosensory-evoked potential (VSEP) findings from individuals with brain disorders, and present novel physiological explanations on the VSEP origin. Methods. We did a systematic review on the papers reporting VSEP findings from individuals with brain disorders and their controls. We evaluated papers published from 2003 to date indexed in PubMed, Web of Science, and Scielo databases. We extracted the following information: number of patients and controls, type of neural disorder, age, gender, stimulating/recording and grounding electrodes as well as stimulus side, intensity, duration, frequency, and polarity. Information about physiological parameters, neurobiological variables, and correlation studies was also reviewed. Representative vignettes were included to add support to our conclusions. Results. The VSEP was studied in 297 patients with neural disorders such as Parkinson's disease (PD), Alzheimer's disease, vascular dementia, mild cognitive impairment, subjective memory impairment, major depression, and multiple sclerosis. Scalp responses marked as the VSEP showed high variability, low validity, and poor reproducibility. VSEP latencies and amplitudes did not correlate with disease duration, unified PD rating scale score, or heart function in PD patients nor with cerebrospinal fluid β amyloid, phosphor-τ, and cognitive tests from patients with mental disorders. Vignettes demonstrated that the VSEP was volume conduction propagating from muscles surrounding the scalp recording electrodes. Conclusion. The VSEP is not a brain-evoked potential of neural origin but muscle activity induced by electrical stimulation of the tragus region of the ear. This review and illustrative vignettes argue against assessing the parasympathetic system using the so-called VSEP.

Green tea (Camellia sinensis) has the potential to be developed as a natural agent for therapy of iron overload in thalassemia. The purpose of this research was to observe the ability of ethanol extract of green tea as a natural iron chelating agent in animal iron overload model. Ethanol extract of green tea leave (GTLE) was prepared by maceration using 70% ethanol. Sprague-Dawley male rats were divided into three groups (5 rats each), a normal control group (group I) received daily p.o. of deionized water, the iron overload group received 100 g/Kg BW (group II) of GTLE that given two hours before ferroussulfate0.5 g/Kg BW administrations and the last group (group III) received only 0.5 g/Kg BW of ferrous sulfate. GTLE and ferrous sulfate were given orally every day for 30 days. At the end of the experimental period, rat blood serum samples were collected. Iron content and alanine aminotransferase (ALT) levels were measured using a spectrophotometer followed by observing the histologic preparation of rat liver organ. The results showed that administration of green tea leaves ethanolic extract of 100 g/Kg BW was able to keep down iron and ALT levels in the rat blood to a normal level.

The content of the rectified motor evoked potential (MEP) induced by transcranial magnetic stimulation (TMS) has ambiguously been assessed without the precision that energy calculation deserves. This fact has misled data interpretation and misguided biomedical interventions. To definitively fill the gap that exits in the neurophysics processing of these signals, we computed, inWalls (W^),thebioenergywithin the rectified MEP recorded from the human first digitorum index (FDI) muscle at rest and under isometric contraction. We also gauged thebioworkexerted by this muscle. Here we show that bioenergy and biowork can accurately and successfully be assessed, validated, and determined inW^from MEP signals induced by TMS, regardless of knowing the mathematical expression of the function of the signal. Our novel neurophysics approach represents a dramatic paradigm shift in analysis and interpretation of the content of the MEP and will give a true meaning to the content of rectified signals. Importantly, this innovative approach allowed unveiling that women exerted more bioenergy than men at the magnetic stimulations used in this study. Revisitation of conclusions drawn from studies published elsewhere assessing rectified EMG signals that have used ambiguous units is strongly recommended.