Ligand Antibody Research Articles

Switching from ligand to receptor anti-calcitonin gene-related peptide (CGRP) antibodies or vice versa in non-responders: A controlled cohort study.

Limited options exist for migraine prevention after stopping anti-calcitonin gene-related peptide monoclonal antibodies. A systematic review examining the benefits of switching between different classes (ligand vs. receptor monoclonal antibody) is essential, alongside well-designed real-world studies. In this cohort study 67 patients were included, who discontinued their first treatment with erenumab or fremanezumab. Patients (n = 31) switched to another monoclonal antibody class within 3 months, whilst those in the control group (n = 36) received standard care. Allocation to either group relied largely on the availability of alternative monoclonal antibody treatments, introducing pseudo-random allocation. Changes in monthly migraine days were compared between groups 3 months post-discontinuation of the first monoclonal antibody or initiation of a different monoclonal antibody class. A multivariate regression model was conducted that accounted for potential confounding factors. The groups were comparable at baseline and poor treatment response was the main reason for treatment discontinuation of the first monoclonal antibody. The switching cohort experienced a reduction of 3.9 monthly migraine days (95% confidence interval -6.4, -1.3, p = 0.004) compared with the control group. Transitioning to a different anti-calcitonin gene-related peptide monoclonal class yields reduction in monthly migraine days compared to returning to standard care for patients with inadequate initial treatment response.

Phase 2b randomized clinical trial of amlitelimab, an anti-OX40 ligand antibody, in patients with moderate-to-severe atopic dermatitis

Amlitelimab, a fully human nondepleting monoclonal antibody targeting OX40 ligand on antigen-presenting cells, could prevent T-cell-driven inflammation seen in atopic dermatitis (AD). This trial evaluated the efficacy and safety of amlitelimab in adults with AD. In this 2-part, phase 2b, randomized, double-blinded placebo-controlled trial (NCT05131477), patients received subcutaneous amlitelimab every 4 weeks at doses of 250 mg with 500-mg loading dose, 250 mg, 125 mg, or 62.5 mg, or placebo for 24 weeks in Part 1 (1:1:1:1:1 randomization). In Part 2, clinical responders were reallocated 3:1 to withdraw amlitelimab or continue the previous dose regimen for 28 weeks. The primary end point was percent change in Eczema Area and Severity Index (EASI) from baseline to Week 16. 390 and 190 patients enrolled in Part 1 and Part 2, respectively. Significant percent change decreases in EASI were observed with amlitelimab vs. placebo (P<.001). Clinical responses at Week 24 (Investigator Global Assessment 0/1 and/or EASI-75) were maintained at Week 52 in patients continuing or withdrawn from amlitelimab. In patients maintaining clinical response at Week 52 while off-treatment, >80% had serum amlitelimab concentrations below a 4-μg/mL threshold for several weeks prior to Week 52. Reductions in AD-related biomarkers during Part 1 were maintained through Part 2. Amlitelimab was well tolerated over 52 weeks. Amlitelimab treatment significantly reduced clinical and biomarker responses, and was well tolerated in adults with AD through Week 52. Sustained responses were observed in the majority of patients after amlitelimab withdrawal for 28 weeks.

Robust and Sustained STING Pathway Activation via Hydrogel-Based In Situ Vaccination for Cancer Immunotherapy.

The stimulator of interferon genes (STING) pathway is crucial for tumor immunity, leading to the exploration of STING agonists as potential immunotherapy adjuvants. However, their clinical application faces obstacles including poor pharmacokinetics, transient activation, and an immunosuppressive tumor microenvironment (TME). Addressing these limitations, our study aims to develop an injectable silk fibroin hydrogel-based in situ vaccine. It incorporates a nanoscale STING agonist, an immunogenic cell death (ICD) inducer, and an immunomodulator to ensure their controlled and sustained release. cGAMP nanoparticles (cGAMPnps) with a core-shell structure ensure optimal delivery of cGAMP to dendritic cells (DCs), thereby activating the STING pathway and fostering DC maturation. ICD-associated damage-associated molecular patterns amplify and prolong STING activation via enhanced type I IFN and other inflammatory pathways, along with delayed degradation of cGAMP and STING. Furthermore, the STING-driven vascular normalization by cGAMPnps and ICD, in conjunction with immunomodulators like antiprogrammed cell death protein 1 antibody (anti-PD-1 Ab) or OX40 ligand (OX40L), effectively remodels the immunosuppressive TME. This in situ gel vaccine, when used independently or with surgery as neoadjuvant/adjuvant immunotherapy, enhances DC and CD8+ T-cell activation, suppressing tumor progression and recurrence across various immunologically cold tumor models. It revolutionizes the application of STING agonists in cancer immunotherapy, offering substantial promise for improving outcomes across a broad spectrum of malignancies.

Functionalised Ligand-Based Nanomaterial Drug Targeting Approaches for Colorectal Cancer Therapy

: Cancer refers to a condition in which abnormal cells uncontrollably divide, resulting in the destruction of tissues. In colorectal cancer, uncontrolled cell proliferation takes place in the rectum or colon. Most colorectal tumors start as adenomas, a form of polyp that can develop into cancer within the rectum or colon. Symptoms of colorectal cancer include chronic diarrhea or constipation, bleeding from the rectum, bloody stools, change in appetite, weight loss, etc. Risk factors associated with colorectal cancer are smoking, obesity, and low physical activity. Colorectal cancer can be treated depending on size, location, and the spread of the cancer. Treatment includes surgery where the lymph node is dissected and a colectomy is performed. Chemotherapy and radiation therapies are other treatment options, but the main disadvantage is that these treatments have nonspecific avenues. Apart from killing cancerous cells, they damage healthy cells, too. Therefore, with the help of nanotechnology, drug-containing nanoparticles can be created with the aid of nanocarriers, which are stronger, more durable, and site-specific. The cancerous cells can be actively targeted by formulating nanoparticles loaded with anticancer drugs and functionalising the surface by either attaching ligands (peptides, antibodies, and small molecules) or targeting molecules towards receptors that are present on the exterior surface of the cancerous cells. These surfaces functionalised nanoparticles, loaded with anticancer drugs, are significantly upregulated in cancerous cells in contrast to healthy surrounding cells and tissues. This review article is focused on ligand-based drugs targeting colorectal tumours.

Anti-RANKL Antibody For Active Charcot Foot Neuro-Osteoarthropathy in Patients with Diabetes and Chronic Kidney Disease.

Charcot neuroosteoarthropathy (CNO) is characterized with increased osteoclastic activity that can be curbed with antiresorptive agents. Chronic kidney disease (CKD) precludes bisphosphonates but anti-receptor activator of nuclear factor-B ligand (anti-RANKL) antibody, denosumab, can be contemplated in CKD. We investigated denosumab for active CNO of foot in CKD for CNO remission. During the study period, 446 persons of diabetes with unilateral, active CNO of foot and CKD were identified and 78 were finally enrolled. Patients received either 60 mg denosumab (single-dose, subcutaneous) along with standard of care (SoC) as total contact cast (TCC) (group A; n = 26) or SoC (group B; n = 52) only. Patients were followed every 4 weeks until CNO remission and subsequently every 8 weeks until 48 weeks following remission. Remission was defined as temperature difference <2 °C between 2 feet confirmed twice (4 weeks apart) with clinical resolution of signs of inflammation. The primary outcome studied was proportion of patients achieving remission within 48 weeks and the time to remission. Median age was 56.5 (48.8-65) and 57 (48.5-61.2) years, P = .57; duration of diabetes 16 (10-25.3) and 14.9 (10-19) years, P = .151; and estimated glomerular filtration rate 44.8 (21.1-65.6) and 45.7 (32.9-55.7) mL/min/1.73 m2, P = .771, in group A and B, respectively. Median temperature difference at presentation between the affected and opposite foot was 3.4 °C (2.7-6.9) and 3.2 °C (2.2-4.0), P = .119, respectively. All patients achieved remission in group A (100%) compared with 42 (80.8%) in group B (P = .006) (hazard ratio 0.52, 95% CI: 0.32-0.87; P = .012). The median time to remission was similar in the 2 groups (15 [11-25] and 17.5 [14-31.5] weeks, P = .229, respectively). 25-Hydroxyvitamin D3 >14 ng/mL was significantly associated (OR 9.5, 95% CI 1.04-87.5, P = .045) with remission. Anti-RANKL antibody added to SoC (TCC) induces remission of active foot CNO in greater proportions of patients with diabetes and CKD.

Peptide ligands for the universal purification of exosomes by affinity chromatography.

Exosomes are gaining prominence as vectors for drug delivery, vaccination, and regenerative medicine. Owing to their surface biochemistry, which reflects the parent cell membrane, these nanoscale biologics feature low immunogenicity, tunable tissue tropism, and the ability to carry a variety of payloads across biological barriers. The heterogeneity of exosomes' size and composition, however, makes their purification challenging. Traditional techniques, like ultracentrifugation and filtration, afford low product yield and purity, and jeopardizes particle integrity. Affinity chromatography represents an excellent avenue for exosome purification. Yet, current affinity media rely on antibody ligands whose selectivity grants high product purity, but mandates the customization of adsorbents for exosomes with different surface biochemistry while their binding strength imposes elution conditions that may harm product's activity. Addressing these issues, this study introduces the first peptide affinity ligands for the universal purification of exosomes from recombinant feedstocks. The peptides were designed to (1) possess promiscuous biorecognition of exosome markers, without binding process-related contaminants and (2) elute the product under conditions that safeguard product stability. Selected ligands SNGFKKHI and TAHFKKKH demonstrated the ability to capture of exosomes secreted by 14 cell sources and purified exosomes derived from HEK293, PC3, MM1, U87, and COLO1 cells with yields of up to 80% and up-to 50-fold reduction of host cell proteins (HCPs) upon eluting with pH gradient from 7.4 to 10.5, recommended for exosome stability. SNGFKKHI-Toyopearl resin was finally employed in a two-step purification process to isolate exosomes from HEK293 cell fluids, affording a yield of 68% and reducing the titer of HCPs to 68 ng/mL. The biomolecular and morphological features of the isolated exosomes were confirmed by analytical chromatography, Western blot analysis, transmission electron microscopy, nanoparticle tracking analysis.

Pharmacological Treatment of Degenerative Cervical Myelopathy: A Critical Review of Current Evidence.

Degenerative cervical myelopathy (DCM) is the leading cause of spinal cord dysfunction in adults, representing substantial morbidity and significant financial and resource burdens. Typically, patients with progressive DCM will eventually receive surgical treatment. Nonetheless, despite advancements in pharmacotherapeutics, evidence for pharmacological therapy remains limited. Health professionals from various fields would find interest in pharmacological agents that could benefit patients with mild DCM or enhance surgical outcomes. This review aims to consolidate all clinical and experimental evidence on the pharmacological treatment of DCM. We conducted a comprehensive narrative review that presents all pharmacological agents that have been investigated for DCM treatment in both humans and animal models. Riluzole exhibits effectiveness solely in rat models, but not in treating mild DCM in humans. Cerebrolysin emerges as a potential neuroprotective agent for myelopathy in animals but had contradictory results in clinical trials. Limaprost alfadex demonstrates motor function improvement in animal models and exhibits promising outcomes in a small clinical trial. Glucocorticoids not only fail to provide clinical benefits but may also lead to adverse events. Cilostazol, anti-Fas ligand antibody, and Jingshu Keli display promise in animal studies, while erythropoietin, granulocyte colony-stimulating factor and limaprost alfadex exhibit potential in both animal and human research. Existing evidence mainly rests on weak clinical data and animal experimentation. Current pharmacological efforts target ion channels, stem cell differentiation, inflammatory, vascular, and apoptotic pathways. The inherent nature and pathogenesis of DCM offer substantial prospects for developing neurodegenerative or neuroprotective therapies capable of altering disease progression, potentially delaying surgical intervention, and optimizing outcomes for those undergoing surgical decompression.

A phase Ib study of JMT103, a receptor activator of NF-kB ligand (RANKL) antibody, in patients (pts) with bone metastases from solid tumors.

e15190 Background: JMT103 is a human IgG4 monoclonal antibody against RANKL and blocks the RANK signaling in osteoclasts, thus suppressing bone resorption. This phase Ib study aims to demonstrate the activity of JMT103 in bone metastases patients with solid tumors. Methods: In this randomized, multi-center, open-label, phase Ib study, adult pts with bone metastases from solid tumors were enrolled and randomized at a 1:1:1 ratio to receive JMT103 subcutaneously at 120mg every 4 weeks (Q4W, Cohort 1), 120mg every 8 weeks (Q8W, Cohort 2) and 180mg Q8W (Cohort 3) up to 49 weeks. The primary endpoint was the percent change from baseline to week 13 in creatinine-adjusted urinary N-telopeptide (uNTx/Cr). Secondary endpoints included safety, anti-drug antibodies (ADA) positivity, the percentage of patients who experienced on-study skeletal-related events (SREs), and ≥ 2-point decreases in pain with Brief Pain Inventory – Short Form. Results: At database lock (Mar. 31, 2023), 295 pts were enrolled; 293 were treated with JMT103 and eligible for efficacy and safety evaluation (96 pts in Cohort 1, 97 pts in Cohort 2, and 100 pts in Cohort 3). The median age was 58 years (Interquartile range [IQR] 51, 66), and the primary tumor types were mainly breast (145, 50%) and prostate cancer (44, 15%). At week 13, the median (IQR) percent change in uNTx/Cr was - 80% (- 93%, - 50%) in Cohort 1, - 73% (- 94%, - 34%) in Cohort 2, and - 76% (- 92%, - 40%) in Cohort 3, respectively. The incidence of SREs in the three cohorts was 3%, 6%, and 7%, respectively. Among the 33 pts in Cohort 1, 35 pts in Cohort 2, and 37 pts in Cohort 3 with baseline pain scores ≥ 2, 61% in Cohort 1, 46% in Cohort 2, and 54% in Cohort 3 experienced ≥ 2-point decreases in pain at the first post-treatment visit (Day 15). For ADA analysis, only 1 (1%) pt in Cohort 2 with a negative result at baseline tested positive after treatment. The table shows the overall summary of the safety profile. Most of TRAEs were low in grade and resolved quickly. The most common TRAEs (any grade) were hypocalcemia (68, 23%), hypophosphatemia (67, 23%), and increased aspartate transaminase (35, 12%). Among the 40 cases of grade-5 TEAE, only 1 was reported as a TRAE (pneumonia); the rest were unrelated to JMT103. Conclusions: Our study demonstrated a promising efficacy of JMT103 in reducing bone metabolism biomarker and a good safety profile with low immunogenicity. Clinical trial information: NCT04630522 . [Table: see text]

Enhancement of anti-PD-L1 antibody plus anlotinib efficacy due to downregulation of PD-L1 in the micro-conduit endothelium within the tumor: a randomized double-blind trial.

The possible enhancing effect of anlotinib on programmed death receptor ligand (PD-L1) antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium, including lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), were determined to identify patients who would benefit from this treatment. PD-L1 positivity in LECs, BECs, and tumor cells (TCs) was assessed using paraffin sections with multicolor immunofluorescence in an investigator's brochure clinical trial of TQB2450 (PD-L1 antibody) alone or in combination with anlotinib in patients with non-small cell lung cancer. Progression-free survival (PFS) with different levels of PD-L1 expression was compared between the two groups. Among 75 patients, the median PFS (mPFS) was longer in patients who received TQB2450 with anlotinib [10 and 12 mg (161 and 194 days, respectively)] than patients receiving TQB2450 alone (61 days) [hazard ratio (HR)10 mg = 0.390 (95% confidence interval {CI}, 0.201-0.756), P = 0.005; HR12 mg = 0.397 (0.208-0.756), P = 0.005]. The results were similar among 58 patients with high PD-L1 expression in LECs and TCs [159 and 209 vs. 82 days, HR10 mg = 0.445 (0.210-0.939), P = 0.034; HR12 mg = 0.369 (0.174-0.784), P = 0.009], and 53 patients with high PD-L1 expression in BECs and TCs [161 and 209 vs. 41 days, HR10 mg = 0.340 (0.156-0.742), P = 0.007; HR12 mg = 0.340 (0.159-0.727), P = 0.005]. No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases. Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs. Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs, which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.

Antibody-displaying extracellular vesicles for targeted cancer therapy

Extracellular vesicles (EVs) function as natural delivery vectors and mediators of biological signals across tissues. Here, by leveraging these functionalities, we show that EVs decorated with an antibody-binding moiety specific for the fragment crystallizable (Fc) domain can be used as a modular delivery system for targeted cancer therapy. The Fc-EVs can be decorated with different types of immunoglobulin G antibody and thus be targeted to virtually any tissue of interest. Following optimization of the engineered EVs by screening Fc-binding and EV-sorting moieties, we show the targeting of EVs to cancer cells displaying the human epidermal receptor 2 or the programmed-death ligand 1, as well as lower tumour burden and extended survival of mice with subcutaneous melanoma tumours when systemically injected with EVs displaying an antibody for the programmed-death ligand 1 and loaded with the chemotherapeutic doxorubicin. EVs with Fc-binding domains may be adapted to display other Fc-fused proteins, bispecific antibodies and antibody–drug conjugates.

Addition and Correction to “High-Performance Concurrent Chemo-Immuno-Radiotherapy for the Treatment of Hematologic Cancer through Selective High-Affinity Ligand Antibody Mimic-Functionalized Doxorubicin-Encapsulated Nanoparticles”

Addition and Correction to “High-Performance Concurrent Chemo-Immuno-Radiotherapy for the Treatment of Hematologic Cancer through Selective High-Affinity Ligand Antibody Mimic-Functionalized Doxorubicin-Encapsulated Nanoparticles”

ASK1-mediated Apoptosis in Human Lung Fibroblasts

Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating lung disease characterized by progressive fibrosis and dysregulated wound repair that negatively affect lung function. Although lung fibroblasts are important in repair mechanisms following lung injury, differentiation into myofibroblasts in the presence of TGF-β and resistance to apoptosis can promote the progression of pulmonary fibrosis. Apoptosis signal regulating kinase 1 (ASK1) is a member of the mitogen activated protein (MAP) kinase family that is known to promote apoptosis. The objective of this study was to test the hypothesis that ASK1 is an important mediator of apoptosis in lung fibroblasts. Normal human lung fibroblasts were obtained from five donors and cultured in the presence or absence of TGF-β (1ng/mL) for 72h. Apoptosis was assessed by a Caspase-Glo® 3/7 assay following treatment with a combination of cycloheximide and Fas ligand antibody with or without the ASK1 inhibitor, selonsertib. Expression of α-smooth muscle actin (α-SMA), collagen, ASK1, and survivin (a member of the inhibitor of apoptosis protein family) were determined by western blot. Apoptosis was induced in three of the five donor lines, and selonsertib treatment reduced caspase-3/7 activity. These donor lines expressed lower levels of survivin compared with the non-responding lines. TGF-β did not significantly affect these results. As expected, TGF-β stimulated expression of collagen and α-SMA in all donor lines, but this was reduced by treatment with selonsertib. Interestingly, TGF-β caused a reduction in the expression of ASK1 which is consistent with the idea that myofibroblasts in IPF are resistant to apoptosis. These results suggest that ASK1 can promote apoptosis in normal lung fibroblasts, but this is dependent upon the expression of survivin. Supported by VA Merit Award BX005889 (CMW) and NIH grant HL131526 (CMW). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Analytical Techniques for Characterizing Tumor-Targeted Antibody-Functionalized Nanoparticles.

The specific interaction between cell surface receptors and corresponding antibodies has driven opportunities for developing targeted cancer therapies using nanoparticle systems. It is challenging to design and develop such targeted nanomedicines using antibody ligands, as the final nanoconjugate's specificity hinges on the cohesive functioning of its components. The multicomponent nature of antibody-conjugated nanoparticles also complicates the characterization process. Regardless of the type of nanoparticle, it is essential to perform physicochemical characterization to establish a solid foundation of knowledge and develop suitable preclinical studies. A meaningful physicochemical evaluation of antibody-conjugated nanoparticles should include determining the quantity and orientation of the antibodies, confirming the antibodies' integrity following attachment, and assessing the immunoreactivity of the obtained nanoconjugates. In this review, the authors describe the various techniques (electrophoresis, spectroscopy, colorimetric assays, immunoassays, etc.) used to analyze the physicochemical properties of nanoparticles functionalized with antibodies and discuss the main results.

Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET

BackgroundThe brain is a challenging target for antibody-based positron emission tomography (immunoPET) imaging due to the restricted access of antibody-based ligands through the blood–brain barrier (BBB). To overcome this physiological obstacle, we have previously developed bispecific antibody ligands that pass through the BBB via receptor-mediated transcytosis. While these radiolabelled ligands have high affinity and specificity, their long residence time in the blood and brain, typical for large molecules, poses another challenge for PET imaging. A viable solution could be a two-step pre-targeting approach which involves the administration of a tagged antibody that accumulates at the target site in the brain and then clears from the blood, followed by administration of a small radiolabelled molecule with fast kinetics. This radiolabelled molecule can couple to the tagged antibody and thereby make the antibody localisation visible by PET imaging. The in vivo linkage can be achieved by using the inverse electron demand Diels–Alder reaction (IEDDA), with trans-cyclooctene (TCO) and tetrazine groups participating as reactants. In this study, two novel 18F-labelled tetrazines were synthesized and evaluated for their potential use as pre-targeting imaging agents, i.e., for their ability to rapidly enter the brain and, if unbound, to be efficiently cleared with minimal background retention.ResultsThe two compounds, a methyl tetrazine [18F]MeTz and an H-tetrazine [18F]HTz were radiolabelled using a two-step procedure via [18F]F-Py-TFP synthesized on solid support followed by amidation with amine-bearing tetrazines, resulting in radiochemical yields of 24% and 22%, respectively, and a radiochemical purity of > 96%. In vivo PET imaging was performed to assess their suitability for in vivo pre-targeting. Time-activity curves from PET-scans showed [18F]MeTz to be the more pharmacokinetically suitable agent, given its fast and homogenous distribution in the brain and rapid clearance. However, in terms of rection kinetics, H-tetrazines are advantageous, exhibiting faster reaction rates in IEDDA reactions with dienophiles like trans-cyclooctenes, making [18F]HTz potentially more beneficial for pre-targeting applications.ConclusionThis study demonstrates a significant potential of [18F]MeTz and [18F]HTz as agents for pre-targeted PET brain imaging due to their efficient brain uptake, swift clearance and appropriate chemical stability.

Perioperative immunotherapy for esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological subtype and accounts for 85% of esophageal cancer cases worldwide. Traditional treatment for ESCC involves chemotherapy, radiotherapy, and surgery. However, the overall prognosis remains unfavorable. Recently, immune checkpoint blockade (ICB) therapy using anti-programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) antibodies have not only achieved remarkable benefits in the clinical management of ESCC but have also completely changed the treatment approach for this cancer. In just a few years, ICB therapy has rapidly advanced and been added to standard first-line treatment regimen in patients with ESCC. However, preoperative immunotherapy is yet to be approved. In this review, we summarize the ICB antibodies commonly used in clinical immunotherapy of ESCC, and discuss the advances of immunotherapy combined with chemotherapy and radiotherapy in the perioperative treatment of ESCC, aiming to provide reference for clinical management of ESCC patients across the whole course of treatment.

Performance Comparison of Aptamer- and Antibody-Based Biosensors for Bacteria Detection on Glass Surfaces

Antibodies are the most common ligands in commercial and research assay systems for detecting whole pathogen cells. On the other hand, aptamers are superior ligands with many advantages over antibodies in sensitive and robust assay development. Extensive comparisons between aptamer-based biosensors and immunosensors are limited to protein analytes. Here, we report a comparison of ligands (four antibodies and one aptamer for each bacteria) to be used as a biosensor for Escherichia coli and Staphylococcus aureus on glass surfaces through systematic experiments. We have demonstrated that anti-E. coli antibody and mouse monoclonal to S. aureus have the best performance among the compared ligands. Hence, the ligands with the best performance were further investigated within the scope of linear range, analytical sensitivity, and reproducibility of the results. We have demonstrated that anti-E. coli antibody with a capture efficiency of 89.1% and mouse monoclonal to S. aureus with a capture efficiency of 88.2% have the best performance among the compared ligands. The results suggest that antibody ligands function with higher efficiency than aptamer ligands but aptamers have strong potential as an analytical tool.

523 - Efficacy and safety of amlitelimab (an anti-OX40 ligand antibody) in patients with moderate-to-severe atopic dermatitis: 24-week results from a phase 2b trial (STREAM-AD)

Abstract Introduction/Background Targeting and binding OX40 ligand (OX40L) expressed on antigen-presenting cells may inhibit the persistent immune response that drives atopic dermatitis (AD) pathophysiology. Amlitelimab (SAR445229; KY1005) is a potential first-in-class, fully human, non-depleting anti-OX40L monoclonal antibody that blocks OX40L-OX40 interactions and has shown efficacy and an acceptable safety profile in a Phase 2a trial in adults with moderate-to-severe AD. Here, we present 24-week efficacy and safety results (Part 1) from an ongoing dose-ranging Phase 2b trial. The study remains blinded to individual patient data (Part 2 ongoing). Objectives To evaluate the efficacy and safety of amlitelimab in adults with moderate-to-severe AD. Methods STREAM-AD (NCT05131477) is a 52-week, randomised, double-blinded, placebo-controlled Phase 2b monotherapy trial. This study is designed with 2 parts (double-blind throughout): a 24-week treatment period (Part 1, completed and presented here) and a 36-week maintenance/withdrawal period (Part 2, ongoing). Adults (18 to &amp;lt;75 years; n=390) with moderate-to-severe AD were randomised 1:1:1:1:1 to receive subcutaneous amlitelimab Q4W (250 mg with 500 mg loading dose [LD], n=77; 250 mg without LD, n=78; 125 mg without LD, n=77; or 62.5 mg without LD, n=79) or placebo Q4W (n=79). The primary endpoint was percentage change in Eczema Area and Severity Index (EASI) from baseline at Week 16. Key secondary endpoints included percentage change in EASI at Week 24 and percentage of patients with at least 75% reduction from baseline in EASI (EASI-75), percentage of patients with Investigator Global Assessment response of 0 (clear) or 1 (almost clear) and a reduction from baseline of ≥2 points (IGA 0/1), and proportion of patients with a weekly average reduction of Peak Pruritus Numerical Rating Scale (PP-NRS) ≥4 points from baseline. The primary efficacy analysis included all randomised patients who completed Week 24 or discontinued treatment or study prior to Week 24 visit (n=390), whereas the safety analysis included all treated patients (n=388). Results Treatment with amlitelimab resulted in statistically significant improvements in percentage change in EASI from baseline to Week 16 compared to placebo for all four doses studied. The 250 mg with LD group had the numerically highest response versus placebo at Week 16, with a least-squares mean change from baseline of –32.1% (95% CI: –43.9, –20.3; P&amp;lt;0.0001); the remaining groups without LD had the following responses versus placebo: 250 mg, –27.3 (95% CI: –39.1, –15.6; P&amp;lt;0.0001); 125 mg, –22.2 (95% CI: –34.0, –10.4; P=0.0002); and 62.5 mg, –30.2 (95% CI: –41.9, –18.5; P&amp;lt;0.0001). There were also clinically meaningful improvements in all key secondary efficacy outcome measures, with all amlitelimab dose groups demonstrating nominally significant (P&amp;lt;0.05) efficacy versus placebo for EASI-75, IGA 0/1, and PP-NRS ≥4, except 250 mg (no LD) in IGA 0/1 at Week 16 (P=0.0562). Continued improvements were generally observed through Week 24 in primary and key secondary efficacy outcomes. Amlitelimab was well tolerated across all dose groups, with no safety concerns identified. Conclusions In this dose-ranging Phase 2b trial of amlitelimab in adults with moderate-to-severe AD, amlitelimab demonstrated clinically meaningful efficacy over 24 weeks with an acceptable safety profile across all four dose groups.

Comparison of adverse event rate of prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) with antibody or small molecule ligand targeting vector.

161 Background: PSMA-targeted radionuclide therapy (PSMA-TRT) has been established with use of either monoclonal antibodies (mAb) or small molecule ligands (SML) as the targeting vectors for delivery of 177Lu to PSMA-expressing prostate cancer. mAb and SML differ in their molecular weight, pharmacokinetics, and biodistribution which is predicted to result in different adverse effect profiles. Methods: In this study with written informed consent, we compare the adverse effects from individual patients receiving PSMA-TRT for mCRPC using mAb (J591) vs SML (PSMA-617 or PSMA I&amp;T) for delivering 177Lu in prospective clinical trials or registry. All-grade treatment-emergent adverse events (TEAEs) were extracted from trial databases. Adverse effects were graded 0-5. Pearson’s Chi-squared test was used to assess TEAEs and association with treatment type. Multivariable logistic regression was used to compare TEAEs after adjusting for administered radioactivity dose and CALGB (Halabi) prognostic score. Results: 248 patients with mCRPC were treated from March 2001 to February 2023. 166 (67.7%) received mAb (177Lu-J591), 81 received SML [76 (30.6%) 177Lu-PSMA-617, 5 (2%) 177Lu-PSMA-I&amp;T)]. The median age was 70.9 years (44.5 yrs to 93.8 yrs). At the time of trial enrollment, 137 (55.2% [68% SML and 49% mAb]) patients had exposure to chemotherapy, 112 (45.1%) had exposure to androgen-receptor pathway therapy, 193 (77.8%) had bone metastases, 120 (48.3%) LN mets, 42 (16.9%) lung mets, and 20 (8.0%) liver mets. 142 (57.2%) had Halabi score high disease. All-grade hematologic TEAEs were more common with mAb: neutropenia in 122 (74%) patients vs 16 (20%) (p&lt;0.001), anemia in 122 (73%) vs 26 (33%) (P&lt;0.001), and thrombocytopenia in 145 (87%) vs 25 (32%) (p&lt;0.001). Gr &gt;3 neutropenia occurred in 79 (47%) and Gr &gt;3 thrombocytopenia in 98 (59%) receiving mAb. All-grade non-hematologic TEAEs were generally more common with SML: fatigue in 31 (53%) vs 79 (48%) (p=0.5), pain in 32 (54%) vs 73 (44%) (p=0.2), nausea in 21 (36%) vs 34 (20%) (p=0.02) and xerostomia in 36 (61%) vs 1 (0.6%) (p&lt;0.001). After adjusting for administered dose and Halabi score, treatment with 177Lu via SML vector was associated with less neutropenia (OR 0.04, 95% CI 0.02-0.09, p&lt;0.001), anemia (OR 0.11, 95% CI 0.06-0.22, p&lt;0.001), and thrombocytopenia (OR 0.04, 95% CI 0.02-0.09, p&lt;0.001) but more nausea (OR 3.2, 95% CI 1.54-6.72, p=0.002) and xerostomia (NA due to low event rate in mAb). Conclusions: As predicted, PSMA-TRT with mAb vs SML is associated with different toxicity profiles. PSMA-TRT with the mAb 177Lu-J591 is more commonly associated with hematologic toxicities compared to the SML 177Lu-PSMA-617 and 177Lu-PSMA-I&amp;T, which are more commonly associated with non-hematologic toxicities.

C-reactive protein, pharmacological treatments and diet: how to target your inflammatory burden.

This article focuses on pharmacological agents as well as dietary changes aimed at the reduction of the inflammatory burden measured by circulating C-reactive protein concentrations. Over the last years, repurposed as well as new anti-inflammatory agents have been investigated in outcome trials in the cardiovascular field. Currently, a specific inhibition of the inflammatory cascade via the interleukin-6 ligand antibody ziltivekimab is being explored in large-scale outcome trials, after the efficacy of this agent with regard to the reduction of inflammatory biomarkers was proven recently. Next to the investigated pharmacological agents, specific dietary patterns possess the ability to improve the inflammatory burden. This enables patients themselves to unlock a potential health benefit ahead of the initiation of a specific medication targeting the inflammatory pathway. Both pharmacological agents as well as diet provide the opportunity to improve the inflammatory profile and thereby lower C-reactive protein concentrations. Whilst advances in the field of specific anti-inflammatory treatments have been made over the last years, their broad implementation is currently limited. Therefore, optimization of diet (and other lifestyle factors) could provide a cost effective and side-effect free intervention to target low-grade vascular inflammation.

ADJUBIL: A phase II study of immunotherapy with durvalumab and tremelimumab in combination with capecitabine or without capecitabine in adjuvant situation for biliary tract cancer.

TPS583 Background: Despite improvements in multidisciplinary healthcare, patients with biliary tract cancer (BTC) have a poor outcome and effective treatment options are limited. Only 20 % of patients are eligible for surgical resection with curative intent, with 5-year overall survival rates &lt; 10 % for all patients. Data on adjuvant chemotherapy alone for BTC are conflicting, and the SOC is treatment with capecitabine according to the UK BILCAP trial, even though BILCAP was formally negative. Based on the positive data for durvalumab in the TOPAZ-1 trial in BTC and for the STRIDE regimen in HCC according to the Himalaya trial data, the evaluation of the IO combination in the adjuvant setting seems promising. Also, the MediTreme trial showed promising response rates in BTC. Preclinical studies indicate that the antibody combination leads to stronger and more durable anti-tumour effects than single therapies, as it synergistically modulates the tumour's immunosuppressive microenvironment, which is particularly pronounced in cholangiocarcinoma. The aim of the ADJUBIL trial is to evaluate the clinical activity of the anti-PD-L1 (programmed-death 1 ligand) antibody durvalumab and the anti-CTLA-4 (cytotoxic T- lymphocyte-associated antigen 4) antibody tremelimumab in combination with or without capecitabine in patients with respectable BTC in the adjuvant setting. This is a randomized phase II study with a pick-the-winner design. The winner of ADJUBIL could be tested against the current SOC capecitabine in a subsequent phase 2/3 trial. Methods: The ADJUBIL trial is an open-label, multicenter phase II study, including patients with BTC after curative surgery (R0/R1) with no previous systemic treatment. Patients are randomized (1:1) to receive either tremelimumab (300 mg, one dose on C1D1) plus durvalumab (1500 mg every 4 weeks; max. 12 months), with or without capecitabine (1250 mg/m2 twice a day on day 1-14 of 3-weekly cycles; max. 8 cycles). 40 evaluable patients will be enrolled in the study to receive anticancer treatment until disease recurrence or intolerable toxicities. Primary objective is to assess the anti-tumor activity of the treatment in both arms by the recurrence-free survival rate after 12 months. Secondary endpoints are recurrence-free survival, overall survival, toxicity, and quality of life. Exploratory endpoints are to identify predictive biomarkers for recurrence-free survival and overall survival. Study start of the ADJUBIL trial was in June 2021. By September 2023, 15 centers in Germany have been activated and 23 out of 40 planned patients have been enrolled. The first 5 patients in each arm were subject to a safety lead-in phase with close monitoring of (serious) adverse events. The safety assessment revealed no concerns. The study is ongoing. Clinical trial information: NCT05239169 .