A Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of murine IgA nephropathy.

IgA nephropathy (IgAN) is the most prevalent primary chronic glomerular disease for which no safe disease-specific therapies currently exist. IgAN is an autoimmune disease involving the production of autoantigenic, aberrantly O-glycosylated IgA1 and ensuing deposition of nephritogenic immune complexes in the kidney. A Proliferation Inducing Ligand (APRIL) has emerged as a key B-cell-modulating factor in this pathogenesis. Using a mouse anti-APRIL monoclonal antibody (4540), we confirm both the pathogenic role of APRIL in IgAN and the therapeutic efficacy of antibody-directed neutralization of APRIL in the grouped mouse ddY disease model. Treatment with 4540 directly translated to a reduction in relevant pathogenic mechanisms including suppressed serum IgA levels, reduced circulating immune complexes, significantly lower kidney deposits of IgA, IgG and C3, and suppression of proteinuria compared to mice receiving vehicle or isotype control antibodies. Furthermore, we translated these findings to the pharmacological characterization of VIS649, a highly potent, humanized IgG2κ antibody targeting and neutralizing human APRIL through unique epitope engagement, leading to inhibition of APRIL-mediated B-cell activities. VIS649 treatment of non-human primates showed dose-dependent reduction of serum IgA levels of up to 70%. A reduction of IgA+, IgM+, and IgG+ B cells was noted in the gut-associated mucosa of VIS649-treated animals. Population-based modeling predicted a favorable therapeutic dosing profile for subcutaneous administration of VIS649 in the clinical setting. Thus, our data highlight the potential therapeutic benefit of VIS649 for the treatment of IgAN.

A broadly neutralizing human monoclonal antibody is effective against H7N9.

Emerging strains of influenza represent a significant public health threat with potential pandemic consequences. Of particular concern are the recently emerged H7N9 strains which cause pneumonia with acute respiratory distress syndrome. Estimates are that nearly 80% of hospitalized patients with H7N9 have received intensive care unit support. VIS410, a human antibody, targets a unique conserved epitope on influenza A. We evaluated the efficacy of VIS410 for neutralization of group 2 influenza strains, including H3N2 and H7N9 strains in vitro and in vivo. VIS410, administered at 50 mg/kg, protected DBA mice infected with A/Anhui/2013 (H7N9), resulting in significant survival benefit upon single-dose (-24 h) or double-dose (-12 h, +48 h) administration (P < 0.001). A single dose of VIS410 at 50 mg/kg (-12 h) combined with oseltamivir at 50 mg/kg (-12 h, twice daily for 7 d) in C57BL/6 mice infected with A/Shanghai 2/2013 (H7N9) resulted in significant decreased lung viral load (P = 0.002) and decreased lung cytokine responses for nine of the 11 cytokines measured. Based on these results, we find that VIS410 may be effective either as monotherapy or combined with antivirals in treating H7N9 disease, as well as disease from other influenza strains.

The Hemagglutinin Stem-Binding Monoclonal Antibody VIS410 Controls Influenza Virus-Induced Acute Respiratory Distress Syndrome.

Most cases of severe influenza are associated with pulmonary complications, such as acute respiratory distress syndrome (ARDS), and no antiviral drugs of proven value for treating such complications are currently available. The use of monoclonal antibodies targeting the stem of the influenza virus surface hemagglutinin (HA) is a rapidly developing strategy for the control of viruses of multiple HA subtypes. However, the mechanisms of action of these antibodies are not fully understood, and their ability to mitigate severe complications of influenza has been poorly studied. We evaluated the effect of treatment with VIS410, a human monoclonal antibody targeting the HA stem region, on the development of ARDS in BALB/c mice after infection with influenza A(H7N9) viruses. Prophylactic administration of VIS410 resulted in the complete protection of mice against lethal A(H7N9) virus challenge. A single therapeutic dose of VIS410 given 24 h after virus inoculation resulted in dose-dependent protection of up to 100% of mice inoculated with neuraminidase inhibitor-susceptible or -resistant A(H7N9) viruses. Compared to the outcomes in mock-treated controls, a single administration of VIS410 improved viral clearance from the lungs, reduced virus spread in lungs in a dose-dependent manner, resulting in a lower lung injury score, reduced the extent of the alteration in lung vascular permeability and protein accumulation in bronchoalveolar lavage fluid, and improved lung physiologic function. Thus, antibodies targeting the HA stem can reduce the severity of ARDS and show promise as agents for controlling pulmonary complications in influenza.

Identification of a human monoclonal antibody to replace equine diphtheria antitoxin for treatment of diphtheria intoxication.

Diphtheria antitoxin (DAT) has been the cornerstone of the treatment of Corynebacterium diphtheriae infection for more than 100 years. Although the global incidence of diphtheria has declined steadily over the last quarter of the 20th century, the disease remains endemic in many parts of the world, and significant outbreaks still occur. DAT is an equine polyclonal antibody that is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody-secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid, as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in in vitro cytotoxicity assays with a 50% effective concentration of 0.65 ng/ml for the lead candidate hMAb, 315C4. In addition, 25 µg of 315C4 completely protected guinea pigs from intoxication in an in vivo lethality model, yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor-binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor. The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic.

Treatment with monoclonal antibodies against Clostridium difficile toxins.

BACKGROUND: New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection. METHODS: We performed a randomized, double-blind, placebo-controlled study of two neutralizing, fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1). The antibodies were administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight, in patients with symptomatic C. difficile infection who were receiving either metronidazole or vancomycin. The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo. RESULTS: Among the 200 patients who were enrolled (101 in the antibody group and 99 in the placebo group), the rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P<0.001). The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P=0.06); among patients with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively (P=0.006). The mean duration of the initial hospitalization for inpatients did not differ significantly between the antibody and placebo groups (9.5 and 9.4 days, respectively). At least one serious adverse event was reported by 18 patients in the antibody group and by 28 patients in the placebo group (P=0.09). CONCLUSIONS: The addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection. (ClinicalTrials.gov number, NCT00350298.)

Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Sibeprenlimab in Healthy Participants.

Sibeprenlimab blocks the cytokine "A Proliferation-Inducing Ligand" (APRIL), which may play a key role in immunoglobulin A nephropathy pathogenesis. A phase 1 study of subcutaneous (SC) sibeprenlimab evaluated preliminary safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy participants. This was an open-label, single-ascending-dose study. Twelve participants in each of 4 sequential dosing cohorts received 1 SC dose of sibeprenlimab (200 mg [1×1 mL injection], 400 mg [2×1 mL injections], 400 mg [1×2 mL injection], or 600 mg [1 mL+2 mL injections]) and underwent 16-week follow-up for adverse events, pharmacokinetics, and pharmacodynamics (serum APRIL, immunoglobulin [Ig] levels). Sibeprenlimab in single SC doses of 200-600 mg was slowly absorbed into the systemic circulation, with a median time to maximum serum concentration of approximately 6-10.5 days, and a mean elimination half-life of approximately 8-10 days. Serum APRIL, IgA, IgM, and, to a lesser extent, IgG decreased in a dose-dependent and reversible manner. Maximal reduction in serum IgA was approximately 60% at the 400- and 600-mg doses and 40% at 200 mg. Serum APRIL rapidly decreased to near the lower limit of quantification, and duration of suppression was dose-dependent, with near complete suppression until weeks 4-6 at the 400-mg dose and week 8 at the 600-mg dose. Adverse events occurred in 30/48 (62.5%) participants; none were serious or led to study discontinuation. Sibeprenlimab rapidly and sustainably reduced target APRIL and Ig biomarkers in a dose-dependent and reversible manner, with acceptable preliminary safety and pharmacokinetics.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VIS649 (Sibeprenlimab), an APRIL-Neutralizing IgG2 Monoclonal Antibody, in Healthy Volunteers.

Introduction: VIS649 (sibeprenlimab), a humanized IgG2 monoclonal antibody that inhibits APRIL, is being developed as a potential treatment for IgA nephropathy (IgAN). This phase 1, first-in-human, randomized, double-blind, single ascending dose study aimed to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of VIS649 in healthy adults. Methods: Participants were randomized to VIS649 (sequential i.v. dosing cohorts: 0.5, 2.0, 6.0, 12.0 mg/kg) or placebo; a further cohort received VIS649 6.0 mg/kg or placebo followed by a tetanus/diphtheria vaccine challenge. Results: A total of 51 participants were randomized, dosed, and analyzed for safety (7 for each VIS649 dose; 8 for placebo; 10 for VIS649 + vaccine; 5 for placebo + vaccine). There were no serious adverse events (AEs) or AEs leading to study discontinuation. VIS649 had nonlinear PK: half-life increased with dose and drug exposure increased in a greater than dose-proportional manner. Serum APRIL, IgA, galactose-deficient (Gd) IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner, with a dose-response in time to recovery. Tetanus and diphtheria serum IgG titers increased after recall vaccination. Conclusion: VIS649 was safe, well tolerated, and reversibly suppressed APRIL and various immunoglobulins, without loss of antigen-specific vaccination response. Further clinical development of VIS649 for IgAN is warranted. Trial registration: ClinicalTrials.gov: NCT03719443.

Identification and characterization of broadly neutralizing human monoclonal antibodies directed against the E2 envelope glycoprotein of hepatitis C virus.

Nearly all livers transplanted into hepatitis C virus (HCV)-positive patients become infected with HCV, and 10 to 25% of reinfected livers develop cirrhosis within 5 years. Neutralizing monoclonal antibody could be an effective therapy for the prevention of infection in a transplant setting. To pursue this treatment modality, we developed human monoclonal antibodies (HuMAbs) directed against the HCV E2 envelope glycoprotein and assessed the capacity of these HuMAbs to neutralize a broad panel of HCV genotypes. HuMAb antibodies were generated by immunizing transgenic mice containing human antibody genes (HuMAb mice; Medarex Inc.) with soluble E2 envelope glycoprotein derived from a genotype 1a virus (H77). Two HuMAbs, HCV1 and 95-2, were selected for further study based on initial cross-reactivity with soluble E2 glycoproteins derived from genotypes 1a and 1b, as well as neutralization of lentivirus pseudotyped with HCV 1a and 1b envelope glycoproteins. Additionally, HuMAbs HCV1 and 95-2 potently neutralized pseudoviruses from all genotypes tested (1a, 1b, 2b, 3a, and 4a). Epitope mapping with mammalian and bacterially expressed proteins, as well as synthetic peptides, revealed that HuMAbs HCV1 and 95-2 recognize a highly conserved linear epitope spanning amino acids 412 to 423 of the E2 glycoprotein. The capacity to recognize and neutralize a broad range of genotypes, the highly conserved E2 epitope, and the fully human nature of the antibodies make HuMAbs HCV1 and 95-2 excellent candidates for treatment of HCV-positive individuals undergoing liver transplantation.

Clinical and virological responses to a broad-spectrum human monoclonal antibody in an influenza virus challenge study.

Influenza A infections cause significant seasonal morbidity and mortality as well as periodic pandemic infections. Currently, no approved therapies exist for patients hospitalized with influenza. The efficacy of VIS410, a broadly neutralizing human immunoglobulin IgG1 monoclonal antibody engineered to bind to the stem region of group 1 and 2 influenza A hemagglutinins, was explored in experimental human influenza infection. Healthy volunteers were inoculated with influenza A/California/07/2009 (H1N1) and received a single dose of VIS410 or placebo 24 h later. Subjects were monitored for symptoms, viral shedding, and safety, including cytokine measurements. The primary efficacy endpoint was the area under the curve (AUC) of viral load (VL) in the VIS410 group versus placebo. VIS410 treatment was associated with a 76% reduction in median VL AUC as measured by qRT-PCR (p = 0.024). Similar VIS410 antiviral activity was observed by virus culture, with a 91% reduction in median VL AUC by TCID50 (p = 0.019) compared to placebo-treated volunteers. Influenza symptoms were generally mild or moderate, with a trend toward faster resolution in VIS410-treated subjects. Treatment with VIS410 was generally safe, with an increase in gastrointestinal events that were largely mitigated by pre-treatment with oral diphenhydramine (50 mg) in combination with 600 mg of ibuprofen. Transient elevation of specific cytokines (IL-8 and TNFα) were associated with gastrointestinal adverse events. Treatment with VIS410 did not interfere with the endogenous immune response to influenza A. These data indicate that VIS410 may provide therapeutic benefit in influenza A infection. TRIAL REGISTRATION: ClinicaTtrials.gov Identification NCT02468115; https://clinicaltrials.gov/ct2/show/NCT02468115?term=NCT02468115&rank=1).

Safety and efficacy of monoclonal antibody VIS410 in adults with uncomplicated influenza A infection: Results from a randomized, double-blind, phase-2, placebo-controlled study.

BACKGROUND: VIS410, a broadly neutralizing monoclonal antibody that binds the hemagglutinin stem of influenza A viruses, was safe and efficacious in a human H1N1 virus challenge study. This study evaluated the safety and tolerability of VIS410 in non-hospitalized adult patients with uncomplicated influenza A. METHODS: Patients 18 to 65 years of age with symptom onset within 72 h were randomized 1:1:1 to receive a single intravenous infusion of VIS410 4000 mg, 2000 mg, or placebo. Neuraminidase inhibitor therapy was prohibited. Treatment-emergent adverse events (TEAEs) were evaluated up to 100 days post-infusion. Influenza symptoms were assessed daily for 10 days using the FLU-PRO tool. Nasopharyngeal virus shedding was assessed by quantitative reverse-transcription PCR (qRT-PCR) and viral culture through Day 7. FINDINGS: Of the 150 patients randomized, 148 received study drug, and 138 were confirmed influenza A positive. Median age was 42 years; median time from symptom onset to treatment was 42 h; 93% had influenza A subtype H3N2. SAFETY: TEAEs, most commonly diarrhea of mild severity, were dose-related, occurring in 55%, 35%, and 24% of the 4000 mg, 2000 mg, and placebo patients, respectively. Two serious adverse events occurred, both in placebo patients. SYMPTOM ANALYSES: Baseline FLU-PRO symptom scores were balanced among groups. Mean scores were lower by Days 3 and 4 in the pooled VIS410 treatment group versus placebo (p < 0.023), with a tendency toward faster resolution by Kaplan-Meier analysis. VIROLOGY ANALYSES: VIS410 was associated with reduced median nasopharyngeal viral load TCID50 AUCDay7 (days × log10 TCID50/mL) (3.66 pooled VIS410 vs 4.78 placebo, p = 0.08) and in the subset of patients with baseline hemagglutination inhibition (HAI) titer ≤40 (overall, 74% of patients) was significantly reduced vs placebo (4.218 pooled VIS410 vs 6.152 placebo, p = 0.009). Kaplan-Meier estimated time to resolution of viral shedding was reduced (1.9 vs 3.6 days, p = 0.03) in VIS410 treated patients. There was a trend toward greater proportion of culture-negative patients by Day 3 (66.7% vs 51.1%, p = 0.11); when this analysis was limited to the subset of patients with positive baseline cultures, this difference became more pronounced (63.2% vs 42.5%, p = 0.053). No differences were observed in nasopharyngeal influenza qRT-PCR profiles, which represent both live and neutralized virus. INTERPRETATION: VIS410 was safe and well tolerated in adults with uncomplicated influenza A, with favorable effects on symptom resolution and virus replication. TRIAL REGISTRATION: Clinical Trials: NCT02989194. FUNDING: This project was funded in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under Contract No. HHSO100201500018C.