A Novel Investigational Fc-Modified Humanized Monoclonal Antibody, Motavizumab-YTE, Has an Extended Half-Life in Healthy Adults

Abstract

The study objective was to evaluate the pharmacokinetics (PK), antidrug antibody (ADA), and safety of motavizumab-YTE (motavizumab with amino acid substitutions M252Y/S254T/T256E [YTE]), an Fc-modified anti-respiratory syncytial virus (RSV) monoclonal antibody. Healthy adults (n ‫؍‬ 31) were randomized to receive a single intravenous (i.v.) dose of motavizumab-YTE or motavizumab (0.3, 3, 15, or 30 mg/kg) and followed for 240 days. Clearance of motavizumab-YTE was significantly lower (71% to 86%) and the half-life (t 1/2 ) was 2-to 4-fold longer than with motavizumab. However, similar peak concentrations and volume-of-distribution values, indicative of similar distribution properties, were seen at all dose levels. The sustained serum concentrations of motavizumab-YTE were fully functional, as shown by RSV neutralizing activity that persisted for 240 days with motavizumab-YTE versus 90 days postdose for motavizumab. Safety and incidence of ADA were comparable between groups. In this first study of an Fc-modified monoclonal antibody in humans, motavizumab-YTE was well tolerated and exhibited an extended half-life of up to 100 days. (This study has been registered at ClinicalTrials.gov under registration no. NCT00578682.) R espiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and young children (1). No vaccine is currently approved for the prevention of RSV illness; however, palivizumab (MedImmune, Gaithersburg, MD) is available as prophylaxis against serious RSV disease in high-risk children. These high-risk children include infants born prematurely, children with chronic lung disease of prematurity (bronchopulmonary dysplasia), and children with congenital heart disease (2). RSV prophylaxis with palivizumab requires monthly intramuscular administration throughout the RSV season to maintain adequate serum concentrations. This monthly administration is necessary as immunoglobulin G (IgG) monoclonal antibodies (MAbs) are subject to proteolytic degradation and elimination, resulting in a serum half-life of approximately 20 days (3). An antibody with an extended half-life would reduce the required dosing frequency during the RSV season.A growing body of evidence identifies the major histocompatibility complex class I-related neonatal Fc receptor (FcRn) as a critical receptor in maintaining IgG homeostasis and extending the serum half-life of IgG and albumin in humans (4, 5). FcRn was originally identified in the transport of maternal antibodies across the placenta and the fetal small intestines in rats (6). In adult tissues, FcRn localized on vascular endothelium is a key component in the antibody salvage pathway whereby serum IgG undergoes endocytosis and is sequestered in lysosomes (7).A distinguishing characteristic of the IgG-FcRn pathway is obligate pH dependence. IgG-FcRn binding is driven by acidic pH (6.0) in the lysosome, whereas disassociation occurs at the neutral pH (7.4) of the extracellular environment (3). Acidification (pH 6.0 to 6.5) in the lysosomes enable...

Extending human IgG half-life using structure-guided design

“…It has been previously shown that incorporation of YTE on motavizumab resulted in a 2–3.7-fold increase in half-life in cynomolgus monkeys and a half-life of up to 100 days in humans. 18 We anticipate that incorporation of the Fc variants described in this manuscript will result in comparable or even improved half-life in humans (as compared to YTE), while maintaining the desired effector functions of the antibody such as ADCC and CDC. Antibodies with intact effector function and significantly enhanced half-life would enable less frequent administration of antibody-based therapeutics for chronic indications.…”

“…Further, its half-life extending variant that includes the YTE mutation has also been studied in mice, monkeys and humans. Motavizumab has a half-life of 19–34 days 18 in humans and actoxumab has a half-life of 26 ± 8.4 days 34 in humans. Two different approaches were employed: recombinant (His) 6 -tagged FcRn capture on NiNTA biosensors with IgG as the analyte, and IgG captured on anti-CH1 biosensors with recombinant FcRn as the analyte.…”

“…11,13 The prototypical example of an FcRn affinity-enhancing Fc mutant is the M252Y/S254T/T256E (YTE) mutation which, when incorporated into motavizumab IgG1, is able to extend serum half-life in humans by more than four-fold. 18 In these studies, the Fc was primarily optimized for FcRn binding. However, the Fc of IgG binds to various other receptors, such as FcγRI, FcγRIIa, FcγRIIb, FcγRIII, C1q and TRIM21, and these interactions mediate various effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent intracellular neutralization (ADIN).…”

Combined glyco- and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody

“…Moreover, for the first time in healthy humans an Fc-engineered anti-RSV (motavizumab-YTE) recently demonstrated a significant increase in serum halflife of up to 100 days, validating the usefulness of increasing FcRn binding and fully confirming the results previously obtained in animal models. 26 For the past 20 years, the Fc/FcRn interaction has been extensively studied by directed mutagenesis and crystallography using the respective human, murine and rat proteins. 27,28 The FcRn binding site is structurally conserved among species and comprises three distinct zones in the CH2 and CH3 domains that are localized in the CH2/CH3 interdomain region.…”

Chimeric Pneumoviridae fusion proteins as immunogens to induce cross‐neutralizing antibody responses

“…Motavizumab [a more potent derivative of palivizumab (Robbie et al , 2013)] was produced in HEK293 cells transfected with plasmid DNA encoding the antibody heavy and light chains and purified using Protein A‐Sepharose. The Fab fragment was generated by papain digestion (mass ratio 100:1) for 4 h at 37°C, followed by passage over Protein A‐Sepharose to remove the Fc fragment.…”