title: Evaluation of a fully human monoclonal antibody against multiple influenza A viral strains in mice and a pandemic H1N1 strain in nonhuman primates.
abstract: Influenza virus is a global health concern due to its unpredictable pandemic potential. Frequent mutations of surface molecules, hemagglutinin (HA) and neuraminidase (NA), contribute to low efficacy of the annual flu vaccine and therapeutic resistance to standard antiviral agents. The populations at high risk of influenza virus infection, such as the elderly and infants, generally mount low immune responses to vaccines, and develop severe disease after infection. Novel therapeutics with high effectiveness and mutation resistance are needed. Previously, we described the generation of a fully human influenza virus matrix protein 2 (M2) specific monoclonal antibody (mAb), Z3G1, which recognized the majority of M2 variants from natural viral isolates, including highly pathogenic avian strains. Passive immunotherapy with Z3G1 significantly protected mice from the infection when administered either prophylactically or 1-2days post infection. In the present study, we showed that Z3G1 significantly protected mice from lethal infection when treatment was initiated 3days post infection. In addition, therapeutic administration of Z3G1 reduced lung viral titers in mice infected with different viral strains, including amantadine and oseltamivir-resistant strains. Furthermore, prophylactic and therapeutic administration of Z3G1 sustained O2 saturation and reduced lung pathology in monkeys infected with a pandemic H1N1 strain. Finally, de-fucosylated Z3G1 with an IgG1/IgG3 chimeric Fc region was generated (AccretaMab® Z3G1), and showed increased ADCC and CDC in vitro. Our data suggest that the anti-M2 mAb Z3G1 has great potential as a novel anti-flu therapeutic agent.
authors.affiliation: Research Division, Kyowa Hakko Kirin, California, Inc., La Jolla, CA, USA. Electronic address: asong@kyowa-kirin-ca.com.
authors.forename: Aihua
authors.initials: A
authors.lastname: Song
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co. Ltd., Tokyo, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Myojo
authors.affiliation: Research Division, Kyowa Hakko Kirin, California, Inc., La Jolla, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Laudenslager
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co. Ltd., Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Harada
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co. Ltd., Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Miura
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co. Ltd., Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co. Ltd., Tokyo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Kuni-Kamochi
authors.affiliation: Research Division, Kyowa Hakko Kirin, California, Inc., La Jolla, CA, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Soloff
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co. Ltd., Tokyo, Japan.
authors.forename: Kinya
authors.initials: K
authors.lastname: Ohgami
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co. Ltd., Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kanda
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000914:Antibodies, Viral / Q000008:administration & dosage* / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000502:physiology; D009980:Influenza A virus / Q000187:drug effects* / Q000502:physiology; D007251:Influenza, Human / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D008251:Macaca; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014763:Viral Matrix Proteins / Q000276:immunology; D000086082:Viroporin Proteins
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
keywords: Antibody; Influenza A; Matrix protein 2; Therapeutic; Virus infection