Safety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults

Abstract

Prevention of respiratory syncytial virus (RSV) illness in infants is a major public health priority, but there is no approved vaccine. Palivizumab is a monoclonal antibody that provides RSV prophylaxis but requires 5 monthly injections and is approved only for infants who experience the greatest morbidity and mortality from RSV. Thus, there remains a significant unmet medical need for prevention of RSV disease in healthy infants. MEDI8897 is a recombinant human RSV monoclonal antibody with a modified Fc region that extends its half-life and is being developed as RSV prophylaxis for all infants. In this phase 1, first-in-human, placebo-controlled study, 136 healthy adults were randomized to receive a single dose of MEDI8897 (n = 102) or placebo (n = 34) in 1 of 5 cohorts (300, 1,000, or 3,000 mg intravenously or 100 or 300 mg intramuscularly [i.m.]) and were monitored for 360 days. The mean half-life of MEDI8897 was 85 to 117 days across dose groups, and bioavailability after 300-mg i.m. dose administration was 77%. Time to maximum concentration following i.m. dosing was 5 to 9 days. Antidrug antibody (ADA) responses were detected in a similar proportion of placebo (15.2%) and MEDI8897 (13.7%) recipients. The safety profile of MEDI8897 was similar to that of the placebo. These results support clinical studies of the i.m. administration of a single dose of MEDI8897 in the target population of infants to provide protection for the duration of the RSV season. (This study has been registered at ClinicalTrials.gov under identifier NCT02114268.)

Infants Infected with Respiratory Syncytial Virus Generate Potent Neutralizing Antibodies that Lack Somatic Hypermutation

“…These differences in the dominant epitopes targeted by infant and adult responses provide a unique opportunity for prevention strategies that seek to combine passive and active immunization. For example, vaccines could be designed to preferentially elicit site III antibodies, which would not compete for binding with second-generation prophylactic antibodies that target antigenic site Ø, such as MEDI8897 (Griffin et al, 2017; Zhu et al, 2017). In addition, antibodies elicited by a site-III-specific vaccine would not block access to the apex of the preF trimer on infectious virions, allowing the development of neutralizing antibodies directed against antigenic sites in this region to occur during RSV infection.…”

“…Antigenic site V, located between sites Ø and III, was recently identified and shown to be the target of additional preF-specific antibodies that are potently neutralizing (Gilman et al, 2016; Mousa et al, 2017). A preF-specific antibody that targets site Ø and contains Fc modifications to extend serum half-life (MEDI8897) is currently in late-phase clinical trials (Griffin et al, 2017; Zhu et al, 2017). …”

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

“…It is possible that dengue enhancement would also be mediated by cross-reactive antibodies elicited by vacci-nation against ZIKV (Andrade and Harris, 2018; George et al, 2017; Stettler et al, 2016). Because of this uncertainty, passive antibody administration for protection against ZIKV may represent a safe and practical alternative to vaccination during pregnancy and for infants and travelers, since antibodies can be engineered to prevent enhancement and have greatly extended half-lives by incorporating known Fc mutations (Gautam et al, 2018; Griffin et al, 2017; Ko et al, 2014; Robbie et al, 2013; Zalevsky et al, 2010) (https://www.clinicaltrials.gov identifier NCT02878330). Our observations indicate that a combination of two antibodies targeting the EDIII lateral ridge is not sufficient for complete protection of high-dose ZIKV challenge, and combinations of additional antibodies are likely required.…”

Immunological Features of Respiratory Syncytial Virus-Caused Pneumonia—Implications for Vaccine Design

“…Due to these previous results with monoclonal antibodies, currently, molecular strategies are focused on improving the neutralizing capacity but also on reducing the observed adverse effects. Promising results with derivatives of motavizumab have been reported [89,90]. These monoclonal antibodies contain a modified Fc region, are well tolerated and show up to 100 days of half-life in human subjects [89].…”

“…These monoclonal antibodies contain a modified Fc region, are well tolerated and show up to 100 days of half-life in human subjects [89]. Such an extended half-life together with higher levels of hRSV neutralizing antibodies as compared to palivizumab has also been reported with an anti-hRSV prefusion F monoclonal antibody, known as Medi8897 [90]. A phase II clinical trial in healthy preterm infants is currently in progress [91].…”