Antibodies useful in passive influenza immunization, and compositions, combinations and methods for use thereof
Inventors
Estelles, Angeles • Kauvar, Lawrence M. • VIGIL, Adam • Wittekind, Michael
Assignees
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Publication Number
US-10639370-B2
Publication Date
2020-05-05
Expiration Date
Abstract
Antibodies, compositions and methods are provided for treatment and prophylaxis of influenza virus. Antibodies and antigen-binding fragments are provided that bind near the HA0 maturation cleavage site consensus sequence of influenza hemagglutinin A. Antibody compositions, combinations and methods for effective passive immunization across influenza A and B strains are also provided.
Core Innovation
The patent describes intranasal or inhalation pulmonary pharmaceutical compositions that include influenza virus neutralizing human monoclonal antibodies and antibody cocktails. The compositions combine antibodies targeting influenza B Yamagata and influenza B Victoria clades with antibodies targeting influenza A, including influenza A Group 1 and/or influenza A Group 2.
A central aspect is delivery by intranasal or inhalation administration for antibody delivery. The disclosure states that intranasal delivery of neutralizing antibodies provides improved efficacy versus systemic routes and supports synergy when intranasal delivery is combined with IP/IV dosing.
The patent further highlights isolated human monoclonal antibodies and antigen-binding fragments that exhibit very tight binding affinity and can bind to and/or inhibit influenza virus by recognizing a conserved hemagglutinin region, including the HA0 maturation cleavage-site consensus region. It also describes compatibility and formulation-relevant properties, including matching pI and IgG subtype/backbone, reduced antibody aggregation or competition binding, and stability thresholds described in terms of melting temperature Tm1 in PBS.
The compositions are presented with formulation concepts for pulmonary delivery and with additional combination possibilities including other antivirals or immune modulators. The problem being solved is the need for effective influenza virus neutralizing antibodies and antibody cocktails with broad strain coverage and improved in vivo efficacy, particularly in pulmonary delivery contexts.
Claims Coverage
The independent claims cover isolated human antibodies or antigen-binding fragments that specifically bind influenza B Yamagata and influenza B Victoria clades. One independent claim additionally specifies very tight binding affinity thresholds and defined HCDR/LCDR regions, while other claims define particular HCVR/LCVR or HC/LC sequence pairs. Dependent coverage further specifies a pharmaceutically acceptable carrier, a Tm1 stability constraint in PBS, the inclusion of influenza A-binding antibodies with specificity spanning both Group 1 and Group 2, and recombinant antibody or fragment status.
Tight binding influenza B dual-clade antibody with defined HCDR and LCDR SEQ ID NOs
An isolated human antibody, or antigen-binding fragment thereof, that exhibits a binding affinity of 10 nM or tighter, or 3 nM or tighter, to one or more strains of each of influenza B Yamagata and influenza B Victoria clades, the antibody or fragment comprising HCDR1/HCDR2/HCDR3 having SEQ ID NO: 241/242/243 and LCDR1/LCDR2/LCDR3 having SEQ ID NO: 244/245/246, and having the property of binding to and/or inhibiting influenza virus.
Dual-clade influenza B antibody defined by HCVR/LCVR sequence pair SEQ ID NOs 249/250
An isolated human antibody or antigen-binding fragment thereof that specifically binds to one or more strains of each of both influenza B Yamagata and influenza B Victoria clades and comprises a heavy chain variable region/light chain variable region sequence pair having SEQ ID NOs 249/250, and having the property of binding to and/or inhibiting influenza virus.
Dual-clade influenza B antibody defined by HC/LC sequence pair SEQ ID NOs 247/248
An isolated human antibody or antigen-binding fragment thereof that specifically binds to one or more strains of each of influenza B Yamagata and influenza B Victoria clades and comprises an HC/LC sequence pair having SEQ ID NOs 247/248, and having the property of binding to and/or inhibiting influenza virus.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition that includes the antibody, or an antigen-binding fragment, together with a pharmaceutically acceptable carrier.
Stability constraint by Tm1 in PBS
A pharmaceutical composition containing an antibody, or antigen-binding fragment, whose melting temperature measured in PBS is at least 55°C (Tm1).
Influenza A addition with defined specificity across Group 1 and Group 2
A pharmaceutical composition further includes one or more human antibodies or antigen-binding fragments that bind specifically to at least one strain of influenza A, wherein an antibody or antigen-binding fragment specific to influenza A also has specificity to one or more strains from both Group 1 and Group 2.
Recombinant antibody or recombinant antigen-binding fragment
The antibody or antigen-binding fragment is a recombinant antibody or a recombinant antigen-binding fragment.
Overall, the claims center on isolated human antibodies or antigen-binding fragments that specifically bind one or more strains from both influenza B Yamagata and influenza B Victoria clades and have the property of binding to and/or inhibiting influenza virus. Claim coverage further adds defined sequence regions or sequence pairs, with dependent claims adding composition, stability, influenza A combination, and recombinant status.
Stated Advantages
Intranasal delivery of neutralizing antibodies provides improved efficacy versus systemic routes.
Intranasal delivery combined with IP/IV dosing supports synergy.
The compositions provide broad strain coverage across influenza B clades.
The antibodies exhibit very tight binding affinity and can bind to and/or inhibit influenza virus.
Improved efficacy versus systemic routes for neutralizing antibodies delivered to the airway.
Ability to target influenza B strains across both influenza B Yamagata and influenza B Victoria clades, and in supported embodiments additional influenza A targeting.
Stability characterization is supported by inclusion of a quantitative melting-temperature threshold in PBS.
Documented Applications
Intranasal or inhalation pulmonary pharmaceutical compositions for influenza virus neutralizing human monoclonal antibodies and antibody cocktails.
Combination with other antivirals, including oseltamivir and zanamivir, or immune modulators.
Influenza passive immunization using recombinant human antibodies and antigen-binding fragments, including airway delivery concepts of neutralizing antibodies.
Use of antibody cocktails or mixtures that combine influenza B antibodies with additional antibodies targeting influenza A, and formulation as pharmaceutical compositions with a pharmaceutically acceptable carrier.
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