Design of a Phase 3, Global, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study of Nipocalimab in Pregnancies at Risk for Severe Hemolytic Disease of the Fetus and Newborn.

Objective:  Nipocalimab is a neonatal fragment crystallizable (Fc) receptor (FcRn)-blocking monoclonal antibody that inhibits placental immunoglobulin G (IgG) transfer and lowers circulating maternal IgG levels. In an open-label, single-arm, phase 2 study, nipocalimab demonstrated evidence of safety and efficacy that support further investigation in a pivotal phase 3 trial of recurrent hemolytic disease of the fetus and newborn (HDFN). The phase 3 AZALEA study aims to evaluate the efficacy and safety of nipocalimab in a larger population at risk for severe HDFN, defined as HDFN associated with poor fetal outcomes or neonatal death.

Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn.

Background: In early-onset severe hemolytic disease of the fetus and newborn (HDFN), transplacental transfer of maternal antierythrocyte IgG alloantibodies causes fetal anemia that leads to the use of high-risk intrauterine transfusions in order to avoid fetal hydrops and fetal death. Nipocalimab, an anti-neonatal Fc receptor blocker, inhibits transplacental IgG transfer and lowers maternal IgG levels.

Methods: In an international, open-label, single-group, phase 2 study, we assessed treatment with intravenous nipocalimab (30 or 45 mg per kilogram of body weight per week) administered from 14 to 35 weeks' gestation in participants with pregnancies at high risk for recurrent early-onset severe HDFN.

Pharmacokinetics and Pharmacodynamics of Nipocalimab, a Neonatal Fc Receptor Blocker, in Healthy Japanese Volunteers.

Background And Objectives: Nipocalimab is a high-affinity, fully human, effectorless immunoglobulin G1 monoclonal antibody targeting the neonatal Fc receptor and is currently under evaluation for the treatment of rare and prevalent immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases. This phase I, randomized, double-blind, placebo-controlled, single-dose escalation study in healthy Japanese volunteers (N = 24) assessed the safety, pharmacokinetics, and effect on the serum immunoglobulin G level of single doses of nipocalimab.

Methods: Volunteers were grouped into three cohorts and received intravenous nipocalimab at 10, 30, or 60 mg/kg or placebo.

Pharmacokinetics and pharmacodynamics across infusion rates of intravenously administered nipocalimab: results of a phase 1, placebo-controlled study.

Introduction: Nipocalimab is a high-affinity, fully human, aglycosylated, effectorless, immunoglobulin G (IgG) 1 monoclonal antibody that targets the neonatal Fc receptor (FcRn), decreases systemic IgG including autoantibodies, and is under development in several IgG autoantibody- and alloantibody-mediated diseases, including generalized myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, maternal-fetal medicine, and multiple other therapeutic areas. An initial phase 1 study with single and multiple ascending doses of nipocalimab infused intravenously (IV) over 2 h demonstrated dose-dependent serum pharmacokinetics and IgG reductions, with an adverse event (AE) profile comparable to placebo.

Methods: The current investigation evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of nipocalimab across various IV infusion rates in a randomized, double-blind, placebo-controlled, sequential-dose study.

Live birth prevalence of hemolytic disease of the fetus and newborn in the United States from 1996 to 2010.

Background: Hemolytic disease of the fetus and newborn (HDFN) is mediated by maternal alloantibodies, a consequence of immune sensitization during pregnancy with maternal-fetal incompatibility with ABO, Rhesus factor (Rh), and/or other red blood cell antigens. RhD, Kell, and other non-ABO alloantibodies are the primary cause of moderate to severe HDFN, whereas ABO HDFN is typically mild. HDFN live birth prevalence owing to Rh alloimmunization among newborns in the United States was last estimated to be 106 per 100,000 births in 1986.

Molecular profiling of rheumatoid arthritis patients reveals an association between innate and adaptive cell populations and response to anti-tumor necrosis factor.

Background: The goal of this study is to use comprehensive molecular profiling to characterize clinical response to anti-TNF therapy in a real-world setting and identify reproducible markers differentiating good responders and non-responders in rheumatoid arthritis (RA).

Methods: Whole-blood mRNA, plasma proteins, and glycopeptides were measured in two cohorts of biologic-naïve RA patients (n = 40 and n = 36) from the Corrona CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) registry at baseline and after 3 months of anti-TNF treatment. Response to treatment was categorized by EULAR criteria.

M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex vivo placental perfusion model.

Background: The transfer of pathogenic immunoglobulin G antibodies from mother to fetus is a critical step in the pathophysiology of alloimmune and autoimmune diseases of the fetus and neonate. Immunoglobulin G transfer across the human placenta to the fetus is mediated by the neonatal Fc receptor, and blockade of the neonatal Fc receptor may provide a therapeutic strategy to prevent or minimize pathological events associated with immune-mediated diseases of pregnancy. M281 is a fully human, aglycosylated monoclonal immunoglobulin G1 antineonatal Fc receptor antibody that has been shown to block the neonatal Fc receptor with high affinity in nonclinical studies and in a phase 1 study in healthy volunteers.

Circulating Markers of Inflammation Persist in Children and Adults With Giant Aneurysms After Kawasaki Disease.

Background: The sequelae of Kawasaki disease (KD) vary widely with the greatest risk for future cardiovascular events among those who develop giant coronary artery aneurysms (CAA). We sought to define the molecular signature associated with different outcomes in pediatric and adult KD patients.

Methods: Molecular profiling was conducted using mass spectrometry-based shotgun proteomics, transcriptomics, and glycomics methods on 8 pediatric KD patients at the acute, subacute, and convalescent time points.

M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study.

M281 is a fully human, anti-neonatal Fc receptor (FcRn) antibody that inhibits FcRn-mediated immunoglobulin G (IgG) recycling to decrease pathogenic IgG while preserving IgG production. A randomized, double-blind, placebo-controlled, first-in-human study with 50 normal healthy volunteers was designed to probe safety and the physiological maximum for reduction of IgG. Intravenous infusion of single ascending doses up to 60 mg/kg induced dose-dependent serum IgG reductions, which were similar across all IgG subclasses.

A Quantitative Microtiter Assay for Sialylated Glycoform Analyses Using Lectin Complexes.

Fidelity of glycan structures is a key requirement for biotherapeutics, with carbohydrates playing an important role for therapeutic efficacy. Comprehensive glycan profiling techniques such as liquid chromatography (LC) and mass spectrometry (MS), while providing detailed description of glycan structures, require glycan cleavage, labeling, and paradigms to deconvolute the considerable data sets they generate. On the other hand, lectins as probes on microarrays have recently been used in orthogonal approaches for in situ glycoprofiling but require analyte labeling to take advantage of the capabilities of automated microarray readers and data analysis they afford.

STAT3 Signaling Is Required for Optimal Regression of Large Established Tumors in Mice Treated with Anti-OX40 and TGFβ Receptor Blockade.

In preclinical tumor models, αOX40 therapy is often successful at treating small tumors, but is less effective once the tumors become large. For a tumor immunotherapy to be successful to cure large tumors, it will most likely require not only an agonist to boost effector T-cell function but also inhibitors of T-cell suppression. In this study, we show that combining αOX40 antibodies with an inhibitor of the TGFβ receptor (SM16) synergizes to elicit complete regression of large established MCA205 and CT26 tumors.

The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis.

Effective tumor immunotherapy may require not only activation of anti-tumor effector cells, but also abrogation of tumor-mediated immunosuppression. The cytokine TGF-β, is frequently elevated in the tumor microenvironment and is a potent immunosuppressive agent and promoter of tumor metastasis. OX40 (CD134) is a member of the TNF-α receptor superfamily and ligation by agonistic antibody (anti-OX40) enhances effector function, expansion, and survival of activated T cells.

Tgf-beta type I receptor (Alk5) kinase inhibitors in oncology.

The TGFβ type I receptor kinase (ALK5) is an attractive target for intervention in TGFβ signaling due to its druggability as well as its centrality and specificity in the pathway. A number of potent, selective ALK5 inhibitors have been discovered which interact with the ATP-binding site of ALK5. Crystallographic studies of these molecules bound to ALK5 have provided an understanding of potency and selectivity achieved by these inhibitors.

An orally active small molecule TGF-beta receptor I antagonist inhibits the growth of metastatic murine breast cancer.

Background: Transforming growth factor beta (TGF-beta) plays a complex role in breast carcinogenesis. Initially functioning as a tumor suppressor, this cytokine later contributes to the progression of malignant cells by enhancing their invasive and metastatic potential as well as suppressing antitumor immunity. The purpose of this study was to investigate the efficacy of SM16, a novel small molecule ALK5 kinase inhibitor, to treat a highly metastatic, TGF-beta-producing murine mammary carcinoma (4T1).

Transforming growth factor-beta receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers.

Purpose: Adoptive cellular immunotherapy is a promising approach to eradicate established tumors. However, a significant hurdle in the success of cellular immunotherapy involves recently identified mechanisms of immune suppression on cytotoxic T cells at the effector phase. Transforming growth factor-beta (TGF-beta) is one of the most important of these immunosuppressive factors because it affects both T-cell and macrophage functions.

Small molecular inhibitor of transforming growth factor-beta protects against development of radiation-induced lung injury.

Purpose: To determine whether an anti-transforming growth factor-beta (TGF-beta) type 1 receptor inhibitor (SM16) can prevent radiation-induced lung injury.

Methods And Materials: One fraction of 28 Gy or sham radiotherapy (RT) was administered to the right hemithorax of Sprague-Dawley rats. SM16 was administered in the rat chow (0.

SM16, an orally active TGF-beta type I receptor inhibitor prevents myofibroblast induction and vascular fibrosis in the rat carotid injury model.

Objective: TGF-beta plays a significant role in vascular injury-induced stenosis. This study evaluates the efficacy of a novel, small molecule inhibitor of ALK5/ALK4 kinase, in the rat carotid injury model of vascular fibrosis.

Methods And Results: The small molecule, SM16, was shown to bind with high affinity to ALK5 kinase ATP binding site using a competitive binding assay and biacore analysis.

A novel small-molecule inhibitor of transforming growth factor beta type I receptor kinase (SM16) inhibits murine mesothelioma tumor growth in vivo and prevents tumor recurrence after surgical resection.

Malignant mesothelioma is an aggressive and lethal pleural cancer that overexpresses transforming growth factor beta (TGFbeta). We investigated the efficacy of a novel small-molecule TGFbeta type I receptor (ALK5) kinase inhibitor, SM16, in the AB12 syngeneic model of malignant mesothelioma. SM16 inhibited TGFbeta signaling seen as decreased phosphorylated Smad2/3 levels in cultured AB12 cells (IC(50), approximately 200 nmol/L).

Intracellular TGF-beta receptor blockade abrogates Smad-dependent fibroblast activation in vitro and in vivo.

Fibrosis, the hallmark of scleroderma, is characterized by excessive synthesis of collagen and extracellular matrix proteins and accumulation of myofibroblasts. Transforming growth factor-beta (TGF-beta), a potent inducer of collagen synthesis, cytokine production, and myofibroblast transdifferentiation, is implicated in fibrosis. Profibrotic TGF-beta responses are induced primarily via the type I activin-like receptor kinase 5 (ALK5) TGF-beta receptor coupled to Smad signal transducers.

Soluble type II transforming growth factor-beta receptor inhibits established murine malignant mesothelioma tumor growth by augmenting host antitumor immunity.

Purpose: Transforming growth factor (TGF)-beta blockade has been proposed as an anticancer therapy; however, understanding which tumor patients might benefit most from such therapy is crucial. An ideal target of such inhibitory therapy might be malignant mesothelioma (MM), a highly lethal, treatment-resistant malignancy of mesothelial cells of the pleura and peritoneum that produces large amounts of TGF-beta. The purpose of this study was to explore the possible therapeutic utility of TGF-beta blockade on MM.

Transforming the TGFbeta pathway: convergence of distinct lead generation strategies on a novel kinase pharmacophore for TbetaRI (ALK5).

The pathological activation of the transforming growth factor beta (TGFbeta) pathway plays a critical role in the progression of fibrotic diseases and also enhances tumor invasiveness and metastasis. Due to its central role in TGFbeta signaling, the TGFbeta type I receptor (TbetaRI) is emerging as an exciting target for blockade of the TGFbeta pathway. In this review we will discuss how three independent drug discovery strategies, ie, target-hopping, high-throughput screening and virtual screening, have converged in the identification of inhibitors of TalphaRI kinase.

Successful shape-based virtual screening: the discovery of a potent inhibitor of the type I TGFbeta receptor kinase (TbetaRI).

We describe the discovery, using shape-based virtual screening, of a potent, ATP site-directed inhibitor of the TbetaRI kinase, an important and novel drug target for fibrosis and cancer. The first detailed report of a TbetaRI kinase small molecule co-complex confirms the predicted binding interactions of our small molecule inhibitor, which stabilizes the inactive kinase conformation. Our results validate shape-based screening as a powerful tool to discover useful leads against a new drug target.

A dual role for Sonic hedgehog in regulating adhesion and differentiation of neuroepithelial cells.

In vertebrates, the nervous system arises from a flat sheet of epithelial cells, the neural plate, that gradually transforms into a hollow neural tube. This process, called neurulation, involves sequential changes in cellular interactions that are precisely coordinated both spatially and temporally by the combined actions of morphogens. To gain further insight into the molecular events regulating cell adhesion during neurulation, we investigated whether the adhesive and migratory capacities of neuroepithelial cells might be modulated by Sonic hedgehog (Shh), a signaling molecule involved in the control of cell differentiation in the ventral neural tube.

Postnatal recapitulation of embryonic hedgehog pathway in response to skeletal muscle ischemia.

Background: Hedgehog (Hh) proteins are morphogens regulating epithelial-mesenchymal signaling during several crucial processes of embryonic development, including muscle patterning. Sonic (Shh), Indian (Ihh), and Desert (Dhh) hedgehog constitute the repertoire of Hh genes in humans. The activities of all 3 are transduced via the Patched (Ptc1) receptor.