A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings.

Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R).

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Properties of Rozibafusp Alfa, a Bispecific Inhibitor of BAFF and ICOSL: Analyses of Phase I Clinical Trials.

Rozibafusp alfa (AMG 570) is a first-in-class bispecific IgG2-peptide fusion designed to inhibit inducible T-cell costimulator ligand (ICOSL) and B-cell activating factor (BAFF). The pharmacokinetics (PK) and pharmacodynamics (PD) of rozibafusp alfa were investigated in two randomized, placebo-controlled clinical studies: a phase Ia single ascending-dose study (7-700 mg subcutaneously (s.c.

Efficacy of Tezepelumab in Severe, Uncontrolled Asthma: Pooled Analysis of the PATHWAY and NAVIGATOR Clinical Trials.

Tezepelumab reduced exacerbations in patients with severe, uncontrolled asthma across a range of baseline blood eosinophil counts and fractional exhaled nitric oxide levels, and irrespective of allergy status, in the phase 2b PATHWAY (Study to Evaluate the Efficacy and Safety of MEDI9929 [AMG 157] in Adult Subjects With Inadequately Controlled, Severe Asthma; NCT02054130) and phase 3 NAVIGATOR (Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; NCT03347279) trials. To examine the efficacy and safety of tezepelumab in additional clinically relevant subgroups using pooled data from PATHWAY and NAVIGATOR. PATHWAY and NAVIGATOR were randomized, double-blind, placebo-controlled trials with similar designs.

Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study.

Objective: To assess the safety and biological activity of rozibafusp alfa, a first-in-class bispecific antibody-peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA).

Methods: This phase 1b, double-blind, placebo-controlled, multiple ascending dose study included 34 patients (18-75 years; 82.4% female) with active RA (Disease Activity Score of 28 joints-C-reactive protein [DAS28-CRP] >2.

Targeting TSLP in Asthma.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine implicated in the initiation and persistence of inflammatory pathways in asthma. Released in response to a range of epithelial insults (eg, allergens, viruses, bacteria, pollutants, and smoke), TSLP initiates multiple downstream innate and adaptive immune responses involved in asthma inflammation. Inhibition of TSLP is postulated to represent a novel approach to treating the diverse phenotypes and endotypes of asthma.

Immunogenicity assessment of bispecific antibody-based immunotherapy in oncology.

With increasing numbers of bispecific antibodies (BsAbs) and multispecific products entering the clinic, recent data highlight immunogenicity as an emerging challenge in the development of such novel biologics. This review focuses on the immunogenicity risk assessment (IgRA) of BsAb-based immunotherapies for cancer, highlighting several risk factors that need to be considered. These include the novel scaffolds consisting of bioengineered sequences, the potentially synergistic immunomodulating mechanisms of action (MOAs) from different domains of the BsAb, as well as several other product-related and patient-related factors.

Immune Complex Formation Is Associated With Loss of Tolerance and an Antibody Response to Both Drug and Target.

AMG 966 is a bi-specific, heteroimmunoglobulin molecule that binds both tumor necrosis factor alpha (TNFα) and TNF-like ligand 1A (TL1A). In a first-in-human clinical study in healthy volunteers, AMG 966 elicited anti-drug antibodies (ADA) in 53 of 54 subjects (98.1%), despite a paucity of T cell epitopes observed in T cell assays.

Baseline type 2 biomarker levels and response to tezepelumab in severe asthma.

Background: Tezepelumab is a human monoclonal antibody that blocks activity of thymic stromal lymphopoietin (TSLP). In the phase IIb PATHWAY study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo in adults with severe, uncontrolled asthma. We evaluated the effects of tezepelumab in reducing type 2 (T2) inflammatory biomarker levels in the PATHWAY population, and the relationship between baseline T2 biomarker levels and AAER.

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma and Perennial Allergy.

Background: Tezepelumab is an anti-thymic stromal lymphopoietin mAb. In the PATHWAY phase IIb study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo in adults with severe, uncontrolled asthma.

Objective: This post hoc analysis assessed the efficacy of tezepelumab in PATHWAY participants with perennial allergy.

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma with and without Nasal Polyposis: A Analysis of the Phase 2b PATHWAY Study.

Background: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial cytokine implicated in asthma pathogenesis, from binding to its heterodimeric receptor. In the phase 2b PATHWAY study, tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control, in adults with severe, uncontrolled asthma. This analysis assessed the efficacy of tezepelumab in adults with severe, uncontrolled asthma with and without nasal polyposis (NP).

Tezepelumab Reduces Exacerbations Across All Seasons in Patients with Severe, Uncontrolled Asthma: A Post Hoc Analysis of the PATHWAY Phase 2b Study.

Introduction: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP), an epithelial cytokine implicated in airway inflammation in asthma, from binding to its heterodimeric receptor. In the PATHWAY phase 2b study, tezepelumab significantly reduced exacerbation rates compared with placebo in adults with severe, uncontrolled asthma, irrespective of baseline disease characteristics.

Objective: To evaluate the effect of tezepelumab on asthma exacerbations on a seasonal basis.

Pharmacokinetic and Pharmacodynamic Modeling of Tezepelumab to Guide Phase 3 Dose Selection for Patients With Severe Asthma.

Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial cytokine involved in asthma pathogenesis. In the phase 2b PATHWAY study (ClinicalTrials.gov identifier: NCT02054130), tezepelumab significantly reduced exacerbations in adults with severe, uncontrolled asthma.

Tezepelumab improves patient-reported outcomes in patients with severe, uncontrolled asthma in PATHWAY.

Background: Patients with severe, uncontrolled asthma experience frequent exacerbations and hospitalization, leading to poor health-related quality of life. In the phase 2b PATHWAY study (NCT02054130), tezepelumab reduced exacerbations by up to 71% and improved lung function, asthma control, and health-related quality of life vs placebo.

Objective: This analysis further assessed the impact of tezepelumab on patient-reported outcomes (PROs) in PATHWAY.

Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study.

Background: Refractory coeliac disease type 2 is a rare subtype of coeliac disease with high mortality rates; interleukin 15 (IL-15) is strongly implicated in its pathophysiology. This trial aimed to investigate the effects of AMG 714, an anti-IL-15 monoclonal antibody, on the activity and symptoms of refractory coeliac disease type 2.

Methods: This was a randomised, double-blind, placebo-controlled, phase 2a study of adults with a confirmed diagnosis of refractory coeliac disease type 2.

Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study.

Background: Interleukin 15 (IL-15) is implicated in the pathophysiology of coeliac disease. AMG 714 is the first anti-IL-15 monoclonal antibody to be investigated for the treatment of coeliac disease. We aimed to investigate the effects of AMG 714 in patients with coeliac disease who underwent gluten challenge.

Pharmacokinetics, Safety, and Tolerability of Tezepelumab (AMG 157) in Healthy and Atopic Dermatitis Adult Subjects.

Tezepelumab (AMG 157) is a monoclonal antibody that targets thymic stromal lymphopoietin and has shown benefits in treating asthma. We assessed the safety, tolerability, and pharmacokinetics of single-ascending and multiple-ascending doses in two randomized, double-blind, placebo-controlled phase I studies. Healthy and atopic dermatitis subjects were enrolled in the single-dose study, and healthy subjects in the multiple-dose study.

Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial.

Background: Tezepelumab (AMG 157/MEDI9929), a first-in-class monoclonal antibody, targets thymic stromal lymphopoietin, a cytokine that is implicated in the pathogenesis of atopic dermatitis (AD).

Objective: We sought to evaluate the efficacy and safety of tezepelumab in adults with moderate to severe AD.

Methods: In this phase 2a study (NCT02525094), 113 patients were randomized 1:1 to subcutaneous tezepelumab 280 mg or placebo every 2 weeks, plus class 3 topical corticosteroids (TCS).

Tezepelumab in Adults with Uncontrolled Asthma.

Background: In some patients with moderate-to-severe asthma, particularly those with noneosinophilic inflammation, the disease remains uncontrolled. This trial evaluated the efficacy and safety of tezepelumab (AMG 157/MEDI9929), a human monoclonal antibody specific for the epithelial-cell-derived cytokine thymic stromal lymphopoietin (TSLP), in patients whose asthma remained uncontrolled despite treatment with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids.

Methods: In this phase 2, randomized, double-blind, placebo-controlled trial, we compared subcutaneous tezepelumab at three dose levels with placebo over a 52-week treatment period.

A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels.

Signaling through the BCR can drive B cell activation and contribute to B cell differentiation into Ab-secreting plasma cells. The positive BCR signal is counterbalanced by a number of membrane-localized inhibitory receptors that limit B cell activation and plasma cell differentiation. Deficiencies in these negative signaling pathways may cause autoantibody generation and autoimmune disease in both animal models and human patients.

Effects of an anti-TSLP antibody on allergen-induced asthmatic responses.

Background: Thymic stromal lymphopoietin (TSLP) is an epithelial-cell-derived cytokine that may be important in initiating allergic inflammation. AMG 157 is a human anti-TSLP monoclonal immunoglobulin G2λ that binds human TSLP and prevents receptor interaction.

Methods: In this double-blind, placebo-controlled study, we randomly assigned 31 patients with mild allergic asthma to receive three monthly doses of AMG 157 (700 mg) or placebo intravenously.