JPWO2020198329A5 - - Google Patents

Description

EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be covered by the following claims.
The present invention provides, for example, the following items.
(Item 1)
One or more comprising an anti-HA antibody molecule and an endonuclease inhibitor, a polymerase basic protein 2 (PB2) inhibitor or both for use in the treatment or prevention of influenza virus infection or symptoms thereof in a human subject and an antiviral agent,
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
combinations, including
(Item 2)
A method of treating or preventing influenza virus infection or symptoms thereof in a human subject, said subject comprising an anti-HA antibody molecule and an endonuclease inhibitor, a polymerase basic protein 2 (PB2) inhibitor or both. administering a combination with one or more antiviral agents;
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
A method, including
(Item 3)
The use of item 1, wherein said one or more antiviral agents comprise an endonuclease inhibitor, optionally said endonuclease inhibitor comprises a cap-dependent endonuclease inhibitor or baloxavir marboxil. or the method of item 2 for.
(Item 4)
A combination for use according to items 1 or 3 or according to items 2 or 3, wherein said one or more antiviral agents comprise a PB2 inhibitor, optionally wherein said PB2 inhibitor comprises pimodivir. the method of.
(Item 5)
Item 1 or 3, wherein said one or more antiviral agents further comprises a neuraminidase inhibitor, optionally wherein said neuraminidase inhibitor comprises one, two or all of oseltamivir, peramivir or zanamivir 5. A combination for use according to any one of items 2-4 or a method according to any one of items 2-4.
(Item 6)
A combination for use according to any of items 1 or 3 to 5 or from items 2 to 5, wherein said anti-HA antibody molecule is administered prior to, concurrently with, or after said one or more antiviral agents. 6. The method according to any one of 5.
(Item 7)
said anti-HA antibody molecule is administered intravenously at a dose of between 1500 mg and 2500 mg or between 3500 mg and 4500 mg, optionally said anti-HA antibody molecule is administered at a dose of about 2000 mg or about 4000 mg; Optionally, a combination for use according to any one of items 1 or 3-6 or a method according to any one of items 2-6, wherein said anti-HA antibody molecule is administered in a single dose.
(Item 8)
wherein said one or more antiviral agents comprises baloxavir marboxil, wherein baloxavir marboxil is between 20 mg and 60 mg as a single dose for subjects having a body weight of less than 80 kg or having a body weight of 80 kg or more orally administered to a subject at a dose of between 60 mg and 100 mg, and optionally baloxavir marboxil at a dose of about 40 mg for a subject having a body weight of less than 80 kg or a body weight of 80 kg or greater A combination for use according to any one of items 1 or 3-7 or a method according to any one of items 2-7, administered at a dose of about 80 mg to a subject having
(Item 9)
said one or more antiviral agents comprises pimodivir, wherein pimodivir is administered orally twice daily at a dose of between 200 mg and 400 mg or between 500 mg and 700 mg, optionally 9. A combination for use according to any one of items 1 or 3 to 8 or a method according to any one of items 2 to 8, wherein pimodivir is administered at a dose of about 300 mg or about 600 mg.
(Item 10)
said one or more antiviral agents comprises oseltamivir, administered orally at a dose of between 50 mg and 100 mg of oseltamivir, optionally once every 12 hours or once daily, optionally The combination for use according to any of items 1 or 3-9 or the combination of items 2-9, wherein oseltamivir is administered at a dose of about 75 mg and optionally oseltamivir is administered for 5-10 days. Any method described.
(Item 11)
wherein said one or more antiviral agents comprises peramivir, optionally administered intravenously in a dose of between 400 mg and 800 mg as a single dose, optionally peramivir comprising about A combination for use according to any one of items 1 or 3 to 10 or a method according to any one of items 2 to 10, administered in a dose of 600 mg optionally with peramivir.
(Item 12)
said one or more antiviral agents comprises zanamivir, wherein zanamivir is administered by inhalation at a dose of between 5 mg and 15 mg, optionally once every 12 hours or once daily; A combination for use according to any of items 1 or 3 to 11 or items 2 to 11, optionally wherein zanamivir is administered in a dose of about 10 mg, and optionally zanamivir is administered for 5-10 days. The method according to any one of
(Item 13)
13. For use according to any of items 1 or 3-12, wherein said one or more antiviral agents are administered within 12, 24, 36, 48, 60 or 72 hours of onset of influenza symptoms. 13. A combination or method according to any of items 2-12.
(Item 14)
wherein said one or more antiviral agents are administered within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days of exposure to influenza virus or influenza infection A combination for use according to any one of items 1 or 3-13 or a method according to any one of items 2-13.
(Item 15)
wherein said one or more antiviral agents are administered within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days of an influenza pandemic; A combination for use according to any one of items 1 or 3 to 14 or a method according to any one of items 2 to 14.
(Item 16)
A combination for use according to any of items 1 or 3 to 15 or any of items 2 to 15, wherein said subject is infected with influenza virus A or is at risk of becoming infected with it. The method described in .
(Item 17)
Said subject is infected or at risk of being infected with a Group 1 influenza virus, optionally said Group 1 influenza virus is H1, H2, H5, H6, H8, H9, H11, A combination for use according to any one of items 1 or 3 to 16 or a method according to any one of items 2 to 16 comprising H12, H13 or H16 influenza virus or a combination thereof.
(Item 18)
Said subject is infected with, or is at risk of being infected with, a Group 2 influenza virus, optionally said Group 2 influenza virus is H3, H4, H7, H10, H14 or H15 influenza virus or A combination for use according to any one of items 1 or 3 to 17 or a method according to any one of items 2 to 17, including combinations thereof.
(Item 19)
Said subject is infected with or at risk of being infected with H1N1, H1N2, H2N2, H3N2, H5N1, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2 or H10N7 influenza viruses or combinations thereof; for use according to any of items 1 or 3 to 18, wherein said subject is infected with or at risk of being infected with H1N1 or H3N2 influenza virus or a combination thereof, depending on or the method of any of items 2-18.
(Item 20)
said subject is infected with or at risk of being infected with an influenza virus that is resistant to one, two, three or all of oseltamivir, peramivir, zanamivir or baloxavir marboxil; A combination for use according to any of items 1 or 3-19 or a method according to any of items 2-19.
(Item 21)
The combination for use according to any of items 1 or 3-20 or the combination of items 2-20, wherein said subject is infected with, or is at risk of becoming infected with, a secondary bacterial infection. Any method described.
(Item 22)
for use according to any of items 1 or 3 to 21 or the combination of items 2 to 21, wherein said combination provides enhanced synergistic and/or additive antiviral activity in vitro or in vivo Any method described.
(Item 23)
1. An anti-HA antibody molecule for use in the treatment or prevention of influenza virus infection or symptoms thereof in a human subject, comprising:
The antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
including
The subject is infected with, or at risk of being infected with, an influenza virus that is resistant to an antiviral agent selected from an endonuclease inhibitor, a neuraminidase inhibitor, a PB2 inhibitor, or a combination thereof. anti-HA antibody molecule.
(Item 24)
1. A method of treating or preventing influenza virus infection or symptoms thereof in a human subject, comprising administering to said subject an anti-HA antibody molecule,
The antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
including
The subject is infected with, or at risk of being infected with, an influenza virus that is resistant to an antiviral agent selected from an endonuclease inhibitor, a neuraminidase inhibitor, a PB2 inhibitor, or a combination thereof. there is a way.
(Item 25)
Obtaining knowledge that an influenza virus resistant to said antiviral agent is present in said subject and/or influenza resistant to said antiviral agent in a sample obtained from said subject An antibody molecule for use according to item 23 or a method according to item 24, further comprising determining the presence of a virus.
(Item 26)
An antibody molecule for use according to items 23 or 25 or according to items 24 or 25, wherein said antibody molecule is administered or used in response to a determination of the presence of an influenza virus that is resistant to said antiviral agent. the method of.
(Item 27)
Any of items 23 or 25-26, further comprising evaluating or selecting a subject infected with, or at risk of being infected with, an influenza virus that is resistant to said antiviral agent 27. An antibody molecule for use as described or a method according to any of items 24-26.
(Item 28)
said subject is or has been undergoing treatment comprising said antiviral agent, and optionally upon determination of the presence of an influenza virus that is resistant to said antiviral agent, said antiviral agent an antibody molecule for use according to any of items 23 or 25 to 27 or items 24 to 27, wherein said antibody molecule is administered or used after the agent is discontinued and/or after cessation of said antiviral agent The method according to any one of
(Item 29)
Antibody molecule for use according to any of items 23 or 25-28 or any of items 24-28, wherein said antibody molecule is administered or used as a single agent or in combination with a second antiviral agent The method described in Crab.
(Item 30)
said anti-HA antibody molecule is administered or used intravenously at a dose of between 1500 mg and 2500 mg or between 3500 mg and 4500 mg, optionally said antibody molecule is administered at a dose of about 2000 mg or about 4000 mg; An antibody molecule for use according to any one of items 23 or 25 to 29 or a method according to any one of items 24 to 29, optionally wherein said antibody molecule is administered as a single dose.
(Item 31)
31. Any of items 23 or 25-30, wherein the antiviral agent comprises an endonuclease inhibitor, optionally wherein the endonuclease inhibitor comprises a cap-dependent endonuclease inhibitor or baloxavir marboxil. 31. An antibody molecule for use or a method according to any of items 24-30.
(Item 32)
For use according to any of items 23 or 25-31, wherein said antiviral agent comprises a neuraminidase inhibitor, optionally said neuraminidase inhibitor comprises oseltamivir, peramivir, zanamivir or combinations thereof. or the method of any of items 24-31.
(Item 33)
An antibody molecule for use according to any of items 23 or 25-32 or items 24-32, wherein said antiviral agent comprises a PB2 inhibitor, optionally said PB2 inhibitor comprises pimodivir The method according to any one of
(Item 34)
The influenza virus is H1N1, H1N2, H2N2, H3N2, H5N1, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2 or H10N7 influenza virus or a combination thereof, and optionally the influenza virus is H1N1 or H3N2 An antibody molecule for use according to any of items 23 or 25-33 or a method according to any of items 24-33 which is an influenza virus or a combination thereof.
(Item 35)
said influenza virus has a mutation at position 38 of said polymerase acidic protein (PA), optionally said mutation comprises a substitution, optionally said substitution comprises an I38T or I38F substitution; an antibody molecule for use according to any of items 23 or 25-34 or a method according to any of items 24-34, comprising:
(Item 36)
A method of evaluating a human subject, comprising:
The subject is infected with, or at risk of being infected with, an influenza virus that is resistant to an antiviral agent selected from an endonuclease inhibitor, a neuraminidase inhibitor, a PB2 inhibitor, or a combination thereof. and
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
selecting said subject for therapy comprising an anti-HA antibody molecule comprising
A method, including
(Item 37)
A method of evaluating therapy comprising:
The human subject is infected with, or at risk of being infected with, an influenza virus that is resistant to an antiviral agent selected from an endonuclease inhibitor, a neuraminidase inhibitor, a PB2 inhibitor, or a combination thereof. and
selecting a therapy comprising an anti-HA antibody molecule to treat or prevent influenza in said subject
including
The antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
A method, including
(Item 38)
1. An anti-HA antibody molecule for use in treating or preventing influenza virus infection or symptoms thereof in a human subject, comprising:
administered in response to a change in the level of 1, 2, 3, 4, 5, 6 or more cytokines in said subject,
as needed,
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
An anti-HA antibody molecule comprising:
(Item 39)
A method of treating or preventing influenza virus infection or symptoms thereof in a human subject, comprising altering the level of 1, 2, 3, 4, 5, 6 or more cytokines in said subject administering to said subject an anti-HA antibody molecule in response to
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
A method, including
(Item 40)
an antibody molecule for use according to item 38, wherein a change in said level of said one or more cytokines indicates that said subject is responsive or partially responsive to said antibody molecule; or 40. The method of item 39.
(Item 41)
41. For use according to item 38 or 40, wherein said administration of said antibody molecule is continued or the dosage of said antibody molecule is maintained in response to a change in the level of said one or more cytokines. An antibody molecule or a method according to items 39 or 40.
(Item 42)
1. An anti-HA antibody molecule for use in treating or preventing influenza virus infection or symptoms thereof in a human subject, comprising:
administration of said anti-HA antibody molecule is modified in response to a change in the level of 1, 2, 3, 4, 5, 6 or more cytokines in said subject;
as needed,
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
An anti-HA antibody molecule comprising:
(Item 43)
A method of treating or preventing influenza virus infection or symptoms thereof in a human subject, comprising altering the level of 1, 2, 3, 4, 5, 6 or more cytokines in said subject modifying administration of the anti-HA antibody molecule to said subject according to
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
A method, including
(Item 44)
A change in the level of said one or more cytokines indicates that said subject will experience, have experienced, or is likely to experience an adverse event; comprises a gastrointestinal adverse event, optionally wherein said gastrointestinal adverse event comprises diarrhea, nausea, vomiting and/or abdominal pain. Method.
(Item 45)
Antibody molecule for use according to items 42 or 44 or according to items 43 or 44, wherein in response to a change in the level of said one or more cytokines said administration of said antibody molecule is reduced or discontinued. Method.
(Item 46)
antibody molecule for use according to any of items 38, 40-42 or 44-45 or items 39-41 or 39-41 or 46. The method of any of 43-45.
(Item 47)
further comprising determining that the level of said one or more cytokines is altered, optionally wherein the level of said one or more cytokines is determined periodically; Any of items 38, 40-42 or 44-46, wherein the level of one or more cytokines is determined every week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks An antibody molecule for the use as described or a method according to any of items 39-41 or 43-46.
(Item 48)
Antibody molecule for use according to any of items 38, 40-42 or 44-47, wherein the level of said one or more cytokines is increased, decreased, or increased and then decreased, or item The method of any of 39-41 or 43-47.
(Item 49)
the level of said one or more cytokines is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% compared to pre-administration levels of said anti-HA antibody molecule; 90% or 100% or at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 fold increase or decrease for use according to any of items 38, 40-42 or 44-48 An antibody molecule or a method according to any of items 39-41 or 43-48.
(Item 50)
levels of said one or more cytokines are increased within about 24 hours after administration of said anti-HA antibody molecule; Increased within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22 or 23 hours after administration and, optionally, the level of said one or more cytokines is increased within about 1 hour after administration of said anti-HA antibody molecule. 50. An antibody molecule for the use as described or a method according to any of items 39-41 or 43-49.
(Item 51)
the level of said one or more cytokines is further reduced within about 36 hours, and optionally the level of said one or more cytokines is about 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 hours; 51. Use according to item 50, wherein the levels of multiple cytokines return to about the same level or within about ±25%, ±20%, ±15%, ±10% or ±5%) before administration of said anti-HA molecule. or the method of item 50.
(Item 52)
said one or more cytokines is 1, 2, 3, 4, 5 or all of IL-6, IL-8, IL-10, IFN-γ, TNF-α or IL-33 and optionally wherein said one or more cytokines comprises one, two or all of IL-8, IFN-γ or TNF-α, items 38, 40-42 or 44-51 or a method according to any of items 39-41 or 43-51.
(Item 53)
53. For use according to item 52, wherein said one or more cytokines comprise IL-8 and optionally said one or more cytokines further comprise IFN-γ, TNF-α or both. or the method of item 52.
(Item 54)
item 38, further comprising administering a therapeutic agent or modality to treat or prevent an adverse event in said subject, wherein optionally said therapeutic agent or modality reduces the severity of said adverse event; An antibody molecule for use according to any of items 40-42 or 44-53 or a method according to any of items 39-41 or 43-53.
(Item 55)
The therapeutic agent or modality is administered prior to, concurrently with, or subsequent to the administration of the anti-HA antibody molecule, and optionally the therapeutic agent or modality is administered prior to the administration of the anti-HA antibody molecule. an antibody molecule for use according to item 54 or a method according to item 54.
(Item 56)
wherein said therapeutic agent or modality is:
(a) diphenhydramine,
(b) ibuprofen,
(c) aspirin,
(d) montelukast, or
(e) Ranitidine
56. An antibody molecule for use according to items 54 or 55 or a method according to items 54 or 55 comprising one, two, three, four or all of.
(Item 57)
A method of evaluating an influenza therapy comprising an anti-HA antibody molecule comprising:
obtaining the knowledge that levels of one or more cytokines are elevated in a human subject after administration of said anti-HA antibody molecule;
elevated levels of one or more cytokines indicates that said anti-HA antibody molecule is effective in treating or preventing influenza infection or symptoms thereof;
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
A method, including
(Item 58)
A method of evaluating an influenza therapy comprising an anti-HA antibody molecule comprising:
obtaining the knowledge that levels of one or more cytokines are elevated in a human subject following administration of said anti-HA antibody molecule;
elevated levels of one or more cytokines indicate that said anti-HA antibody molecule is capable of causing an adverse event in said subject;
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
A method, including
(Item 59)
A method of evaluating a human subject, comprising:
Obtaining knowledge that levels of one or more cytokines are elevated in said subject following administration of an anti-HA antibody molecule; and
selecting said subject as suitable for continued administration of said anti-HA antibody molecule
including
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
A method, including
(Item 60)
A method of evaluating an influenza therapy comprising an anti-HA antibody molecule comprising:
obtaining the knowledge that levels of one or more cytokines are elevated in a human subject following administration of said anti-HA antibody molecule; and
selecting said anti-HA antibody molecule as suitable for treating or preventing influenza infection or a symptom thereof in said subject
including
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
A method, including
(Item 61)
A method of evaluating a human subject, comprising:
Obtaining knowledge that levels of one or more cytokines are elevated in a subject following administration of an anti-HA antibody molecule; and
selecting said subject as unsuitable for continued administration of said anti-HA antibody molecule
including
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
A method, including
(Item 62)
A method of evaluating an influenza therapy comprising an anti-HA antibody molecule comprising:
obtaining the knowledge that levels of one or more cytokines are elevated in a human subject following administration of said anti-HA antibody molecule; and
selecting said anti-HA antibody molecule as not suitable for treating or preventing influenza infection or symptoms thereof in said subject
including
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
A method, including
(Item 63)
An anti-HA antibody molecule for use in treating or preventing influenza virus infection or a symptom thereof in a subject, comprising
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
including
The subject is
(a) requiring hospitalization, requiring intensive care unit (ICU) care as necessary; and
(b) is or is more likely to be receiving oxygen therapy, positive pressure ventilation and/or therapy to treat or prevent bacterial pneumonia; and/or is or is more likely to be intubated Tall, anti-HA antibody molecules.
(Item 64)
1. A method of treating or preventing influenza virus infection or symptoms thereof in a subject, comprising administering to said subject an anti-HA antibody molecule,
The antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70);
(b) a CDR1 comprising the sequence QSITFDYKNYLA (SEQ ID NO: 145); the sequence WGSYLES A light chain immunoglobulin variable region segment comprising a CDR2 comprising (SEQ ID NO: 72); and a CDR3 comprising the sequence QQHYRTTPPS (SEQ ID NO: 73).
including
Said subject has the following characteristics:
(i) requiring hospitalization, requiring intensive care unit (ICU) care as necessary; and
(ii) is or is more likely to be receiving oxygen therapy, positive pressure ventilation and/or therapy to treat or prevent bacterial pneumonia; and/or is or is more likely to be intubated high way.
(Item 65)
wherein said subject has the following characteristics:
(a) is at least about 60 years old, such as at least about 65, 70, 75 or 80 years old;
(b) received or not received a second antiviral therapy within about 1, 2 or 3 days prior to administration of said anti-HA antibody molecule; including oseltamivir;
(c) has influenza onset at least about 24, 36, 48, 60, 72 or 96 hours or within about 24, 36, 48, 60, 72, 96 or 120 hours prior to administration of said anti-HA antibody molecule; ;
(d) has or has not received an influenza vaccine within about 1, 2, 3, 4, 5 or 6 months prior to administration of said anti-HA antibody molecule;
(e) identified as being infected with influenza A virus within about 12, 24, 36 or 48 hours prior to administration of said anti-HA antibody molecule;
(f) infected with, or at risk of being infected with, an H1, H3 or H7 influenza virus; optionally said H1 influenza virus comprises an H1N1 virus and said H3 influenza virus is H3N2 virus, or said H7 influenza virus comprises H7N9 virus;
(g) has an Ordinal Scale Score greater than about 2.0, 2.1, 2.2, 2.25, 2.3, 2.4 or 2.5, wherein said Ordinal Scale Score is based on one or more parameters selected from ICU stay with ventilation, ICU stay without mechanical ventilation, non-ICU admission or discharge;
(h) 1, 2, 3, 4 meeting a specified threshold within about 24, 36, 48, 60, 72, 84, 96, 108 or 120 hours after administration of said anti-HA antibody molecule or have a clinical response as determined by 5 vital signs;
(i) within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after administration of said anti-HA antibody molecule, at least about 10%, 20% , 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) have a reduced symptom score as determined by FluPRO;
(j) within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after administration of said anti-HA antibody molecule, at least about 2, 3, 4 , 5, 6, 7, 8, 9 or 10-fold increased symptom scores as determined by visual analogue scores (VAS);
(k) viral titer as determined by TCID50 within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after administration of said anti-HA antibody molecule is negative for value; or
(l) no treatment-emergent adverse events (TEAEs) or 1 or fewer treatment-emergent adverse events (TEAEs)
64. An antibody molecule for use according to item 63 or a method according to item 64, having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or all of
(Item 66)
said subject has characteristics (i) and (ii), optionally 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 of said characteristics (a)-(l); , 11 or all.
(Item 67)
said subject has characteristics (i) and (ii), optionally 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 of said characteristics (a)-(l); , 11 or all, wherein said anti-HA antibody molecule is administered according to any of items 63 or 65-66 or any of items 64-66. the method of.
(Item 68)
said antibody molecule comprises a heavy chain immunoglobulin variable region segment comprising SEQ ID NO: 25, a light chain immunoglobulin variable region segment comprising SEQ ID NO: 52, or both;
Item 1, wherein optionally said antibody molecule comprises a tetramer of two heavy chain immunoglobulin variable region segments each comprising SEQ ID NO:25 and two light chain immunoglobulin variable region segments each comprising SEQ ID NO:52. or a combination for use according to any of items 3 to 22, an antibody molecule for use according to any of items 23, 25 to 35, 38, 40 to 42, 44 to 56, 63 or 65 to 67 or the method of any of items 2-22, 24-37, 39-41, 43-62 or 64-67.
(Item 69)
a combination for use according to any of items 1 or 3 to 22, wherein said antibody molecule comprises a full length antibody and/or comprises two heavy chain variable regions and two light chain variable regions; item 23; an antibody molecule for use according to any of 25 to 35, 38, 40 to 42, 44 to 56, 63 or 65 to 68 or items 2 to 22, 24 to 37, 39 to 41, 43 to 62 or 64 68. The method of any one of 68.
(Item 70)
A combination for use according to any of items 1 or 3 to 22, items 23, 25 to 35, 38, 40 to 42, 44 to 56, 63 or 65, wherein said antibody molecule comprises a humanized antibody molecule 69 or a method according to any of items 2-22, 24-37, 39-41, 43-62 or 64-69.
(Item 71)
Combination for use according to any of items 1 or 3-22, items 23, 25-35, 38, 40-42, 44-56, 63 or 65-70, wherein said antibody molecule is an IgG antibody or a method according to any of items 2-22, 24-37, 39-41, 43-62 or 64-70.
(Item 72)
Combination for use according to any of items 1 or 3 to 22, wherein said antibody molecule is a single chain antibody (scFv), F(ab') ₂ fragment, Fab fragment or Fd fragment, items 23, 25 35, 38, 40 to 42, 44 to 56, 63 or 65 to 71 for use according to any of items 2 to 22, 24 to 37, 39 to 41, 43 to 62 or 64 to 71. The method according to any of 71.

Claims (24)

One or more comprising an anti-HA antibody molecule and an endonuclease inhibitor, a polymerase basic protein 2 (PB2) inhibitor or both for use in the treatment or prevention of influenza virus infection or symptoms thereof in a human subject and an antiviral agent ,
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A combination comprising a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO:73). An anti-HA antibody molecule and one or both of an endonuclease inhibitor, a polymerase basic protein 2 (PB2) inhibitor, or both in the manufacture of a medicament for treating or preventing influenza virus infection or symptoms thereof in a human subject Use of a combination with multiple antiviral agents, comprising:
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A use comprising a light chain immunoglobulin variable region segment comprising a CDR3 comprising PS (SEQ ID NO:73). (i) said one or more antiviral agents comprise an endonuclease inhibitor, optionally wherein said endonuclease inhibitor comprises a cap-dependent endonuclease inhibitor or baloxavir marboxil;
(ii) said one or more antiviral agents comprise a PB2 inhibitor, optionally said PB2 inhibitor comprises pimodivir;
(iii) said one or more antiviral agents further comprise a neuraminidase inhibitor, optionally said neuraminidase inhibitor comprising one, two or all of oseltamivir, peramivir or zanamivir;
(iv) said anti-HA antibody molecule is administered before, concurrently with, or after said one or more antiviral agents;
(v) said anti-HA antibody molecule is administered intravenously at a dose of between 1500 mg and 2500 mg or between 3500 mg and 4500 mg; optionally said anti-HA antibody molecule is administered at a dose of about 2000 mg or about 4000 mg; and optionally said anti-HA antibody molecule is administered in a single dose.
(vi) said one or more antiviral agents comprises baloxavir marboxil, wherein baloxavir marboxil is between 20 mg and 60 mg, or 80 kg or more, as a single dose for a subject having a body weight of less than 80 kg; baloxavir marboxil administered orally at a dose of between 60 mg and 100 mg to subjects weighing less than 80 kg, or at a dose of about 40 mg for subjects weighing less than 80 kg, or administered at a dose of about 80 mg to a subject with a higher body weight,
(vii) said one or more antiviral agents comprises pimodivir, wherein pimodivir is administered orally twice daily at a dose of between 200 mg and 400 mg or between 500 mg and 700 mg, as needed; pimodivir is administered at a dose of about 300 mg or about 600 mg, depending on
(viii) said one or more antiviral agents comprises oseltamivir, administered orally at a dose of between 50 mg and 100 mg of oseltamivir, optionally once every 12 hours or once daily; Optionally, oseltamivir is administered at a dose of about 75 mg, and optionally oseltamivir is administered for 5-10 days.
(ix) said one or more antiviral agents comprises peramivir, optionally administered intravenously at a dose between 400 mg and 800 mg as a single dose; is administered at a dose of about 600 mg, optionally with peramivir
(x) said one or more antiviral agents comprises zanamivir, wherein zanamivir is administered by inhalation at a dose of between 5 mg and 15 mg once every 12 hours or once daily as needed; , optionally zanamivir is administered at a dose of about 10 mg, optionally zanamivir is administered for 5-10 days,
(xi) the one or more antiviral agents are administered within 12, 24, 36, 48, 60 or 72 hours of onset of influenza symptoms;
(xii) the one or more antiviral agents is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after exposure to or infection with influenza virus administered within
(xiii) said one or more antiviral agents were administered within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days of an influenza pandemic; Ru
(xiv) said subject is infected with, or at risk of becoming infected with, influenza virus A;
(xv) said subject is infected with, or at risk of becoming infected with, a Group 1 influenza virus, and optionally said Group 1 influenza virus is H1, H2, H5, H6, H8, H9 , H11, H12, H13 or H16 influenza viruses or combinations thereof;
(xvi) said subject is infected with, or is at risk of being infected with, a Group 2 influenza virus, and optionally said Group 2 influenza virus is H3, H4, H7, H10, H14 or H15; containing influenza virus or combinations thereof;
(xvii) said subject is infected with or at risk of being infected with H1N1, H1N2, H2N2, H3N2, H5N1, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2 or H10N7 influenza viruses or combinations thereof; and optionally said subject is infected with or at risk of being infected with an H1N1 or H3N2 influenza virus or a combination thereof;
(xviii) said subject is infected with or at risk of being infected with an influenza virus that is resistant to one, two, three or all of oseltamivir, peramivir, zanamivir or baloxavir marboxil ing,
(xix) said subject has or is at risk of contracting a secondary bacterial infection and/or
(xx) said combination provides enhanced synergistic and/or additive antiviral activity in vitro or in vivo;
A combination for use according to claim 1 or a use according to claim 2. 1. A composition for use in treating or preventing influenza virus infection or symptoms thereof in a human subject, comprising an anti-HA antibody molecule,
The antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO: 73);
The subject is infected with, or at risk of being infected with, an influenza virus that is resistant to an antiviral agent selected from an endonuclease inhibitor, a neuraminidase inhibitor, a PB2 inhibitor, or a combination thereof. composition . Use of an anti-HA antibody molecule in the manufacture of a medicament for treating or preventing influenza virus infection or symptoms thereof in a human subject,
The antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); and sequence DSRLRSLLYFEEWLSQGY - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO: 73);
The subject is infected with, or at risk of being infected with, an influenza virus that is resistant to an antiviral agent selected from an endonuclease inhibitor, a neuraminidase inhibitor, a PB2 inhibitor, or a combination thereof. are used . (i) said use obtains the knowledge that an influenza virus resistant to said antiviral agent is present in said subject; further comprising determining the presence of an influenza virus that is resistant to
(ii) said antibody molecule is administered or used in response to a determination of the presence of an influenza virus that is resistant to said antiviral agent;
(iii) said use further comprises evaluating or selecting a subject infected with or at risk of being infected with an influenza virus that is resistant to said antiviral agent;
(iv) said subject is or has undergone treatment comprising said antiviral agent, optionally upon determination of the presence of an influenza virus that is resistant to said antiviral agent; the antiviral agent is discontinued and/or the antibody molecule is administered or used after discontinuation of the antiviral agent;
(v) said antibody molecule is administered or used as a single agent or in combination with a second antiviral agent;
(vi) said anti-HA antibody molecule is administered or used intravenously at a dose of between 1500 mg and 2500 mg or between 3500 mg and 4500 mg; optionally said antibody molecule is administered or used at a dose of about 2000 mg or about 4000 mg; and optionally the antibody molecule is administered as a single dose.
(vii) said antiviral agent comprises an endonuclease inhibitor, optionally wherein said endonuclease inhibitor comprises a cap-dependent endonuclease inhibitor or baloxavir marboxil;
(viii) said antiviral agent comprises a neuraminidase inhibitor, optionally said neuraminidase inhibitor comprises oseltamivir, peramivir, zanamivir or a combination thereof;
(ix) said antiviral agent comprises a PB2 inhibitor, optionally said PB2 inhibitor comprises pimodivir;
(x) said influenza virus is H1N1, H1N2, H2N2, H3N2, H5N1, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2 or H10N7 influenza virus or a combination thereof, and optionally said influenza virus is is an H1N1 or H3N2 influenza virus or a combination thereof; and/or
(xi) said influenza virus has a mutation at position 38 of said polymerase acidic protein (PA), optionally said mutation comprises a substitution, optionally said substitution comprises I38T or containing an I38F substitution;
A composition for use according to claim 4 or a use according to claim 5 . 1. A method of obtaining knowledge that a human subject is infected with, or at risk of being infected with, an influenza virus as an indicator for evaluating the human subject, comprising:
Said subject is infected with or at risk of being infected with said influenza virus that is resistant to an antiviral agent selected from an endonuclease inhibitor, a neuraminidase inhibitor, a PB2 inhibitor, or a combination thereof. obtaining knowledge that the
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- 12 shows said subject selected for therapy with an anti-HA antibody molecule comprising a light chain immunoglobulin variable region segment comprising a CDR3 comprising PS (SEQ ID NO: 73) ;
Method. A method of obtaining knowledge that a human subject is infected with, or at risk of becoming infected with, an influenza virus as an indicator for evaluating therapy, comprising:
said human subject is infected with, or at risk of being infected with, said influenza virus that is resistant to an antiviral agent selected from an endonuclease inhibitor, a neuraminidase inhibitor, a PB2 inhibitor, or a combination thereof; including obtaining knowledge of being exposed,
said knowledge indicates said therapy selected to treat or prevent influenza in said subject, comprising an anti-HA antibody molecule;
The antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); and sequence DSRLRSLLYFEEWLSQGY - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A method comprising a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO:73). 1. A composition for use in treating or preventing influenza virus infection or symptoms thereof in a human subject , comprising an anti-HA antibody molecule,
administered in response to a change in the level of 1, 2, 3, 4, 5, 6 or more cytokines in said subject,
Optionally, the antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A composition comprising a light chain immunoglobulin variable region segment comprising a CDR3 comprising PS (SEQ ID NO:73). Use of an anti-HA antibody molecule in the manufacture of a medicament for treating or preventing influenza virus infection or symptoms thereof in a human subject,
said anti-HA antibody molecule is administered in response to a change in the level of 1, 2, 3, 4, 5, 6 or more cytokines in said subject;
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A use comprising a light chain immunoglobulin variable region segment comprising a CDR3 comprising PS (SEQ ID NO:73). (i) a change in said level of said one or more cytokines indicates that said subject is responsive or partially responsive to said antibody molecule, and/or
(ii) the administration of the antibody molecule is continued or the dosage of the antibody molecule is maintained in response to changes in the level of the one or more cytokines;
A composition for use according to claim 9 or a use according to claim 10 . 1. A composition for use in treating or preventing influenza virus infection or symptoms thereof in a human subject, comprising an anti-HA antibody molecule,
administration of said anti-HA antibody molecule is modified in response to a change in the level of 1, 2, 3, 4, 5, 6 or more cytokines in said subject;
Optionally, the antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A composition comprising a light chain immunoglobulin variable region segment comprising a CDR3 comprising PS (SEQ ID NO:73). Use of an anti-HA antibody molecule in the manufacture of a medicament for treating or preventing influenza virus infection or symptoms thereof in a human subject,
administration of said anti-HA antibody molecule is modified in response to a change in levels of 1, 2, 3, 4, 5, 6 or more cytokines in said subject;
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); and sequence DSRLRSLLYFEEWLSQGY - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A use comprising a light chain immunoglobulin variable region segment comprising a CDR3 comprising PS (SEQ ID NO:73). (i) a change in the level of said one or more cytokines indicates that said subject will experience, have experienced, or is likely to experience an adverse event; said adverse events comprise gastrointestinal adverse events, optionally wherein said gastrointestinal adverse events comprise diarrhea, nausea, vomiting and/or abdominal pain;
(ii) in response to a change in the level of said one or more cytokines, said administration of said antibody molecule is reduced or discontinued;
(iii) said use further comprises obtaining knowledge that the level of said one or more cytokines is altered;
(iv) said use further comprises determining that the level of said one or more cytokines is altered, optionally wherein said level of said one or more cytokines is periodically determined; optionally, the level of said one or more cytokines is determined every week, every two weeks, every three weeks, every four weeks, every six weeks or every eight weeks;
(v) the levels of said one or more cytokines are increased, decreased, or increased and then decreased;
(vi) the level of said one or more cytokines is at least 10%, 20%, 30%, 40%, 50%, 60%, 70% compared to pre-administration levels of said anti-HA antibody molecule; 80%, 90% or 100% or at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 fold increase or decrease;
(vii) the levels of said one or more cytokines are increased within about 24 hours after administration of said anti-HA antibody molecule; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22 or 23 hours after administration of the antibody molecule optionally, the level of said one or more cytokines is increased within about 1 hour after administration of said anti-HA antibody molecule, optionally said one or more cytokines is further reduced within about 36 hours, and optionally the level of said one or more cytokines is about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, further reduced within 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 hours, optionally wherein the level of said one or more cytokines is return to about the same level or within about ±25%, ±20%, ±15%, ±10% or ±5%) before administration of said anti-HA molecule;
(viii) said one or more cytokines is 1, 2, 3, 4, 5 of IL-6, IL-8, IL-10, IFN-γ, TNF-α or IL-33 optionally, said one or more cytokines comprise one, two or all of IL-8, IFN-γ or TNF-α, optionally said one the species or cytokines comprises IL-8, optionally wherein said one or more cytokines further comprise IFN-γ, TNF-α or both, and/or
(ix) said use further comprises administering a therapeutic agent or modality to treat or prevent an adverse event in said subject, optionally wherein said therapeutic agent or modality determines the severity of said adverse event; reduce,
Optionally, said therapeutic agent or modality is administered prior to, concurrently with, or subsequent to administration of said anti-HA antibody molecule, and optionally said therapeutic agent or modality is administered following administration of said anti-HA antibody molecule. and/or
wherein said therapeutic agent or modality is:
(a) diphenhydramine,
(b) ibuprofen,
(c) aspirin,
(d) montelukast, or
(e) Ranitidine
including one, two, three, four or all of
A composition for use according to claim 12 or a use according to claim 13 . A method of obtaining levels of one or more cytokines as an indicator for evaluating influenza therapy comprising anti-HA antibody molecules, comprising:
obtaining the knowledge that said levels of one or more cytokines are elevated in a human subject after administration of said anti-HA antibody molecule;
elevated levels of one or more cytokines indicates that said anti-HA antibody molecule is effective in treating or preventing influenza infection or symptoms thereof;
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A method comprising a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO:73). A method of obtaining levels of one or more cytokines as an indicator for evaluating influenza therapy comprising anti-HA antibody molecules, comprising:
obtaining the knowledge that said levels of one or more cytokines are elevated in a human subject following administration of said anti-HA antibody molecule;
elevated levels of one or more cytokines indicate that said anti-HA antibody molecule is capable of causing an adverse event in said subject;
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A method comprising a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO:73). A method of obtaining levels of one or more cytokines as an indicator for evaluating a human subject, comprising :
obtaining the knowledge that said levels of one or more cytokines are elevated in said subject after administration of an anti-HA antibody molecule ;
said knowledge indicates said subject is selected as suitable for continued administration of said anti-HA antibody molecule ;
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A method comprising a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO:73). A method of obtaining levels of one or more cytokines as an indicator for evaluating influenza therapy comprising anti-HA antibody molecules, comprising:
obtaining the knowledge that said levels of one or more cytokines are elevated in a human subject following administration of said anti-HA antibody molecule ;
indicating said anti-HA antibody molecule selected as said knowledge being suitable for treating or preventing influenza infection or a symptom thereof in said subject;
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A method comprising a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO:73). A method of obtaining levels of one or more cytokines as an indicator for evaluating a human subject, comprising :
obtaining the knowledge that said levels of one or more cytokines are elevated in a subject after administration of an anti-HA antibody molecule ;
said knowledge indicates said subject is selected as unsuitable for continued administration of said anti-HA antibody molecule;
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A method comprising a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO:73). A method of obtaining levels of one or more cytokines as an indicator for evaluating influenza therapy comprising anti-HA antibody molecules, comprising:
obtaining the knowledge that said levels of one or more cytokines are elevated in a human subject following administration of said anti-HA antibody molecule ;
said knowledge indicates that said anti-HA antibody molecule is selected as unsuitable for treating or preventing influenza infection or symptoms thereof in said subject;
Optionally, said antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- A method comprising a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO:73). 1. A composition for use in treating or preventing influenza virus infection or a symptom thereof in a subject, comprising an anti-HA antibody molecule ,
the antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); and sequence DSRLRSLLYFEEWLSQGY - a heavy chain immunoglobulin variable region segment comprising a CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO: 73);
The subject is
(a) requiring hospitalization, requiring intensive care unit (ICU) care as needed; and (b) oxygen therapy, positive pressure ventilation and/or therapy to treat or prevent bacterial pneumonia. and/or is or is likely to be intubated. Use of an anti-HA antibody molecule in the manufacture of a medicament for treating or preventing influenza virus infection or symptoms thereof in a subject,
The antibody molecule is
(a) a CDR1 comprising the sequence SYAMH (SEQ ID NO:68); the sequence VVSYDGNYKYYYADS - CDR2 containing VQG (SEQ ID NO: 69); - a heavy chain immunoglobulin variable region segment comprising CDR3 comprising FNP (SEQ ID NO: 70); and (b) the sequence QSITFDYKNYL - CDR1 with A (SEQ ID NO: 145); CDR2 with sequence WGSYLES (SEQ ID NO: 72); and sequence QQHYRTP- a light chain immunoglobulin variable region segment comprising CDR3 comprising PS (SEQ ID NO: 73);
Said subject has the following characteristics:
(i) requiring hospitalization, requiring intensive care unit (ICU) care as needed; and (ii) oxygen therapy, positive pressure ventilation and/or therapy to treat or prevent bacterial pneumonia. are, or are likely to be, intubated; and / or are or are likely to be intubated. wherein said subject has the following characteristics:
(a) is at least about 60 years old, such as at least about 65, 70, 75 or 80 years old;
(b) received or not received a second antiviral therapy within about 1, 2 or 3 days prior to administration of said anti-HA antibody molecule; including oseltamivir;
(c) has influenza onset at least about 24, 36, 48, 60, 72 or 96 hours or within about 24, 36, 48, 60, 72, 96 or 120 hours prior to administration of said anti-HA antibody molecule; ;
(d) has or has not received an influenza vaccine within about 1, 2, 3, 4, 5 or 6 months prior to administration of said anti-HA antibody molecule;
(e) identified as being infected with influenza A virus within about 12, 24, 36 or 48 hours prior to administration of said anti-HA antibody molecule;
(f) infected with, or at risk of being infected with, an H1, H3 or H7 influenza virus; optionally said H1 influenza virus comprises an H1N1 virus and said H3 influenza virus is H3N2 virus, or said H7 influenza virus comprises H7N9 virus;
(g) has an Ordinal Scale Score greater than about 2.0, 2.1, 2.2, 2.25, 2.3, 2.4 or 2.5, wherein said Ordinal Scale Score is based on one or more parameters selected from ICU stay with ventilation, ICU stay without mechanical ventilation, non-ICU admission or discharge;
(h) 1, 2, 3, 4 meeting a specified threshold within about 24, 36, 48, 60, 72, 84, 96, 108 or 120 hours after administration of said anti-HA antibody molecule or have a clinical response as determined by 5 vital signs;
(i) within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after administration of said anti-HA antibody molecule, at least about 10%, 20% , 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) have a reduced symptom score as determined by FluPRO;
(j) within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after administration of said anti-HA antibody molecule, at least about 2, 3, 4 , 5, 6, 7, 8, 9 or 10-fold increased symptom scores as determined by visual analogue scores (VAS);
(k) viral titer as determined by TCID50 within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after administration of said anti-HA antibody molecule or (l) no treatment emergent adverse events (TEAEs) or 1, 2, 3 out of 1 or fewer treatment emergent adverse events (TEAEs). 23. A composition for use according to claim 21 or a use according to claim 22 having 4, 5, 6, 7, 8, 9, 10, 11 or all. (i) said use is characterized in that said subject has characteristics (i) and (ii), optionally 1, 2, 3, 4, 5, 6, of said characteristics (a)-(l); further comprising knowing or determining having 7, 8, 9, 10, 11 or all
(ii) said subject has characteristics (i) and (ii), optionally 1, 2, 3, 4, 5, 6, 7, 8, of said characteristics (a)-(l); the anti-HA antibody molecule is administered in response to a determination to have 9, 10, 11 or all;
(iii) said antibody molecule comprises a heavy chain immunoglobulin variable region segment comprising SEQ ID NO:25, a light chain immunoglobulin variable region segment comprising SEQ ID NO:52 or both;
optionally, said antibody molecule comprises a tetramer of two heavy chain immunoglobulin variable region segments each comprising SEQ ID NO: 25 and two light chain immunoglobulin variable region segments each comprising SEQ ID NO: 52;
(iv) said antibody molecule comprises a full-length antibody and/or comprises two heavy chain variable regions and two light chain variable regions,
(v) said antibody molecule comprises a humanized antibody molecule;
(vi) said antibody molecule is an IgG antibody, and/or
(vii) said antibody molecule is a single chain antibody (scFv), F(ab') ₂ fragment, Fab fragment or Fd fragment;
A composition for use according to claim 21 or 23 or a use according to claim 22 or 23 .