A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

Abstract

Influenza B can cause significant morbidity and mortality. MHAB5553A, a human monoclonal immunoglobulin G1 (IgG1) antibody that binds to a highly conserved region of the hemagglutinin protein of influenza B virus, is being examined as a novel therapeutic for the treatment of influenza B patients with severe disease. This phase 1, randomized, double-blind, placebo-controlled, single-ascendingdose study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of MHAB5553A. Twenty-six healthy male and female volunteers of Ͼ18 years of age were randomized into five cohorts receiving a single intravenous (i.v.) dose of 120, 1,200, 3,600, 8,400, or 10,800 mg MHAB5553A or placebo (four active:one placebo, except for the 120-mg cohort [4:2]). Subjects were followed for 120 days after dosing. No subject discontinued the study, no dose-limiting adverse events or serious adverse events were reported, and a maximum tolerated dose (MTD) was not defined. The most commonly reported adverse events were cold symptoms and headache; most were mild and occurred at a similar rate across all cohorts. MHAB5553A showed no relevant time-or dose-related changes in laboratory values or vital signs compared to the placebo. The observed serum PK was linear and generally dose proportional, and the observed nasal PK was nonlinear and generally non-dose proportional. MHAB5553A is generally well tolerated in healthy volunteers up to at least a single i.v. dose of 10,800 mg and demonstrated linear serum PK consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (This study has been registered at ClinicalTrials.gov under registration no. NCT02528903.)

Airway Delivery of Anti-influenza Monoclonal Antibodies Results in Enhanced Antiviral Activities and Enables Broad-Coverage Combination Therapies

“…If not, then it may be beneficial to treat patients with bnAbs simultaneously via both the airway and systemic routes. Additionally, airway delivery of bnAbs might be productively combined with currently marketed small molecule anti-influenza therapies, such as neuraminidase or polymerse inhibitors(66), which have very different mechanisms of action.Recent clinical trials testing HA stalk-binding antibody therapies for treating influenza employ systemic administration of a single bnAb(50)(51)(52)(53). In in vivo IAV challenge trials in humans, efficacy of a systemically-administered bnAb requires doses on the order of 40-50 mg/kg or ~3 grams for an average sized 70 kg adult patient (53).…”

Influenza virus glycoprotein-reactive human monoclonal antibodies

“…Based on the broad-spectrum of this mAb against IBVs, Lim et al tested 46B8 (MHAB5553A) in a clinical trial, and subjects were followed up for 120 days after injection of a certain dose. No adverse events were reported, and most of the adverse reactions were mild colds and headaches, demonstrating its good tolerance and pharmacokinetic profiles, thus offering the possibility for the development of therapeutic drugs in patients with severe IBVs [47].…”

Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1

“…Disappointingly, neither strategy was as successful as predicted, but they did improve the DM1-related molecular phenotypes ( Stepniak-Konieczna et al, 2020 ). It’s worth noting that a newly selected ASO called ISIS-DMPKRx (ISIS 598769) gapmer-type candidate has been evaluated in a Phase 1/2a clinical trial for the treatment of DM1 ( Lim et al, 2017 ), for it can bind to a specific 3′-UTR gene sequence outside the CUG repeat and degrade toxic RNA (NCT023412011). Though it presented great safety and tolerance, IONIS proposed an inefficient effect on the functional and biological endpoints set in the trial since no sufficient drug could reach the muscles.…”