EP4028392A1 - Compositions et méthodes pour le traitement du virus respiratoire syncytial - Google Patents

Compositions et méthodes pour le traitement du virus respiratoire syncytial

Info

Publication number
EP4028392A1
EP4028392A1 EP20863252.1A EP20863252A EP4028392A1 EP 4028392 A1 EP4028392 A1 EP 4028392A1 EP 20863252 A EP20863252 A EP 20863252A EP 4028392 A1 EP4028392 A1 EP 4028392A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
conjugate
formula
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP20863252.1A
Other languages
German (de)
English (en)
Inventor
Allen Borchardt
Thomas P. Brady
Zhi-yong CHEN
Quyen-Quyen Thuy Do
Travis James HAUSSENER
Alain Noncovich
Leslie W. TARI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cidara Therapeutics Inc
Original Assignee
Cidara Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cidara Therapeutics Inc filed Critical Cidara Therapeutics Inc
Publication of EP4028392A1 publication Critical patent/EP4028392A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • each A 1 and each A 2 is independently described by formula (A-III) and U 3 is a substituent of the ring atom Ua.
  • Ua is CH.
  • Ua is N.
  • each A 1 and each A 2 is independently described by any one of formulas (A-IIIa)-(A-IIIf): or a pharmaceutically acceptable salt thereof.
  • each A 1 and each A 2 is independently described by formula (A-III) (e.g., any one of formulas (A-IIIa)-(A-IIIf) or any one of formulas (A-IIIb)-(A-IIIf)), wherein each U 3 is described by:
  • each A 1 and each A 2 is independently described by formula (A-IV) (e.g., any one of formulas (A-IVa)-(A-IVf)), wherein each U 3 is an optionally substituted C1-C6 alkyl (e.g., -(CH 2 )4, -(CH 2 )3CN, -(CH 2 )4F, -(CH 2 )4OH, -(CH 2 )2SO2Me, -(CH 2 )3SO2CH 2 Me, or -(CH 2 )3SO2Me).
  • C1-C6 alkyl e.g., -(CH 2 )4, -(CH 2 )3CN, -
  • the conjugate is described by formula (M-I) or (D-I).
  • the invention features a conjugate described by formula (D-I): wherein each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138); L in each A 1 -L-A 2 is a linker covalently attached (e.g., by way of a covalent bond or linker) to a sulfur atom of a hinge cysteine in E and to each of A 1 and A 2 ; n is 1 or 2 (e.g., when n is 2, the two Fc domain monomers dimerize to form and Fc domain); T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the squiggly line connected to the E indicates that each A 1 -L-A 2 is covalently attached to a sulfur atom
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • each A 1 may be independently selected from a structure described by any one of formulas (A-I)-(A-VI).
  • each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138);
  • L in each L-A 1 is a linker covalently attached to a sulfur atom in a hinge cysteine in E and to A 1 ;
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two squiggly lines connected to the two sulfur atoms indicate that each L-A 1 is covalently attached to a pair of sulfur atoms of two hinge cysteines in the two Es, or a pharmaceutically acceptable salt thereof.
  • the pair of sulfur atoms are (e.g., the sulfur atoms corresponding to) Cys10 and Cys13 in SEQ ID NO: 10 or SEQ ID NO: 11 or Cys 36 and Cys 38 in SEQ ID NO: 10 or SEQ ID NO: 11.
  • the pair of sulfur atoms include one sulfur atom of a cysteine from each E, i.e., L-A along with the sulfur atoms to which it is attached forms a bridge between two Fc domains (e.g., two Fc domains including the sequence of SEQ ID NO: 10 or SEQ ID NO: 11 ).
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E;
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 8 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 8 from another E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 8 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 8 from another E.
  • the nitrogen atom is the nitrogen of a surface exposed lysine, e.g., the nitrogen atom corresponding to (e.g., the nitrogen atom of) Lys35, Lys63, Lys77, Lys79, Lys106, Lys123, Lys129, Lys181, Lys203, Lys228, or Lys236 of SEQ ID NO: 10 or SEQ ID NO: 11.
  • the nitrogen atom is the nitrogen atom corresponding to (e.g., the nitrogen atom of) Lys65, Lys79, Lys108, Lys230, and/or Lys238 of SEQ ID NO: 10 or SEQ ID NO: 11.
  • the invention features a conjugate of Table 2.
  • Each conjugate of Table 2 corresponds to a conjugate of either formula (M-I) or formula (D-I), as indicated.
  • Conjugates of Table 2 include conjugates formed by the covalent reaction of an Int of Table 1 with a linker which is in turn conjugated to E (e.g., an Fc domain monomer, an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide).
  • L’ may include a triazole (formed by the click chemistry reaction between the Int and a linker conjugated to E) and a linker (e.g., a PEG2-PEG20 linker) which in turn is conjugated to an amino acid side chain of E.
  • n is 1 or 2.
  • each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1- 138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139- 141), an albumin protein-binding peptide, or an Fc-binding peptide.
  • each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), and the Fc domain monomers dimerize to form and Fc domain.
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • the disclosure also provides a population of any of the conjugates of Table 2 wherein the average value of T is 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20).
  • each E includes an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 82. In other embodiments, each E includes an Fc domain monomer having the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 82. In other embodiments, each E includes an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 85 or SEQ ID NO: 86. In other embodiments, each E includes an Fc domain monomer having the amino acid sequence of SEQ ID NO: 85 or SEQ ID NO: 86.
  • the conjugate is described by the formula (D-II-5): (D-II-5) wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1-20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (D-II-6): (D-II-6) or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (D-IV-20): (D-IV-20) or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (D-IV-21): (D-IV-21) or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (D-IV-22): (D-IV-22) wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1-20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (D-V-8): wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1-20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (D-V-21): wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1-20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (D-VI-5): wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1-20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • each M 1 is H (e.g., the corresponding phenyl ring is unsubstituted).
  • each M 1 is a C 1 -C 3 alkyl (e.g., -CH 3 ) and b is 1 or 2.
  • the conjugate is described by formula (D-VI-6): (D-VI-6) wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1-20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (D-VI-32): (D-VI-32) wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1-20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (D-VI-33): (D-VI-33) or a pharmaceutically acceptable salt thereof.
  • each M 1 is H (e.g., the corresponding phenyl ring is unsubstituted).
  • the conjugate is described by formula (D-VII-8): wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1-20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (D-VII-9): wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1-20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (D-VII-10): or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (D-VII-39): (D-VII-39) wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1-20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (D-VII-40): (D-VII-40) or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (D-VII-41): (D-VII-41) wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1-20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (D-VII-42): (D-VII-42) or a pharmaceutically acceptable salt thereof.
  • each K 1 is H (e.g., the corresponding phenyl is unsubstituted).
  • Linkers of the formula (D-L-I) may also include any of
  • each E independently includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc- binding peptide;
  • n is 1 or 2;
  • T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20);
  • L is a linker covalently attached to each of E and A 1 , or a pharmaceutically acceptable salt thereof.
  • conjugate is described by formula (M-II-1): (M-II-1) wherein R7 and R8 are each independently selected from OH, halogen, nitrile, nitro, optionally substituted amine, optionally substituted imine, optionally substituted C 1 -C 20 alkamino, optionally substituted sulfhydryl, optionally substituted carboxyl, optionally substituted cyano, optionally substituted C 1 -C 20 alkyl, optionally substituted C 3 -C 20 cycloalkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 3 -C 20 cycloalkenyl, optionally substituted C 2 -C 20 alkynyl, optionally substituted C 5 -C 20 aryl, optionally substituted C 2 -C 15 heteroaryl, and optionally substituted C 1 -C 20 alkoxy; or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (M-II-17): (M-II-17) wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (M-III): (M-III) or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (M-III-1): (M-III-1) or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (M-IV-9): (M-IV-9) or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (M-IV-10): (M-IV-10) or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (M-IV-11): (M-IV-11) wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (M-IV-23): (M-IV-23) or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (M-IV-24): wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • U 3 is an optionally substituted C1-C6 alkyl (e.g., -(CH 2 )4, -(CH 2 )3CN, -(CH 2 )4F, -(CH 2 )4OH, -(CH 2 )2SO2Me, -(CH 2 )3SO2CH 2 Me, or -(CH 2 )3SO2Me).
  • the conjugate is described by formula (M-V-1): or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (M-V-2): or a pharmaceutically acceptable salt thereof.
  • each M 1 is a C 1 -C 3 alkyl (e.g., -CH 3 ) and b is 1 or 2.
  • the conjugate is described by formula (M-VI-3): or a pharmaceutically acceptable salt thereof.
  • M 1 is a C 1 -C 3 alkyl (e.g., -CH 3 ) and b is 1 or 2.
  • each M 1 is H (e.g., the corresponding phenyl ring is unsubstituted).
  • each M 1 is a C 1 -C 3 alkyl (e.g., -CH 3 ) and b is 1 or 2.
  • L’ is a nitrogen atom.
  • each M 1 is H (e.g., the corresponding phenyl ring is unsubstituted).
  • each M 1 is a C 1 -C 3 alkyl (e.g., -CH 3 ) and b is 1 or 2.
  • the conjugate is described by formula (M-VI-6): wherein L’ is the remainder of L, and each y1 are independently an integer from 1-20 (e.g., each y1 are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • each M 1 is a C 1 -C 3 alkyl (e.g., -CH 3 ) and b is 1 or 2.
  • the conjugate is described by formula (M-VI-9): wherein L’ is the remainder of L, and each y1 are independently an integer from 1-20 (e.g., each y1 are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • each M 1 is H (e.g., the corresponding phenyl ring is unsubstituted).
  • L’ is a nitrogen atom.
  • each M 1 is H (e.g., the corresponding phenyl ring is unsubstituted).
  • each M 1 is a C 1 -C 3 alkyl (e.g., -CH 3 ) and b is 1 or 2.
  • the conjugate is described by formula (M-VI-29): wherein L’ is the remainder of L, and each y1 are independently an integer from 1-20 (e.g., each y1 are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (M-VII-24): wherein L’ is the remainder of L, and each y1 are independently an integer from 1-20 (e.g., each y1 are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (M-VII-25): or a pharmaceutically acceptable salt thereof.
  • the conjugate is described by formula (M-VII-29): wherein L’ is the remainder of L, and each y1 are independently an integer from 1-20 (e.g., each y1 are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • L’ is a nitrogen atom.
  • the conjugate is described by formula (M-VII-30): or a pharmaceutically acceptable salt thereof.
  • each K 1 is H (e.g., the corresponding phenyl is unsubstituted).
  • An antibody may include any form of immunoglobulin, heavy chain antibody, light chain antibody, LRR-based antibody, or other protein scaffold with antibody-like properties, as well as any other immunological binding moiety known in the art, including antibody fragments (e.g., a Fab, Fab', Fab’2, F(ab')2, Fd, Fv, Feb, scFv, or SMIP).
  • antibody fragments e.g., a Fab, Fab', Fab’2, F(ab')2, Fd, Fv, Feb, scFv, or SMIP.
  • the subunit structures and three-dimensional configurations of different classes of antibodies are known in the art.
  • An antibody fragment may include a binding moiety that includes a portion derived from or having significant homology to an antibody, such as the antigen- determining region of an antibody.
  • the antibody fragment includes an scFv, sdAb, dAb, Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, or SMIP.
  • the Fc-domain-containing composition e.g., an antibody or antibody fragment
  • confers binding specificity to a one or more targets e.g., an antigen such as an antigen associated with RSV.
  • targets e.g., an antigen such as an antigen associated with RSV.
  • RSV targeting antibodies are known in the art, for example, as described in Gilman et al. Sci. Immunol.1(6), (2006), which is incorporated herein by reference in its entirety.
  • E includes the amino acid sequence of SEQ ID NO: 8.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8.
  • E includes the amino acid sequence of SEQ ID NO: 9.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9.
  • E includes the amino acid sequence of SEQ ID NO: 22. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 22. In some embodiments of any of the aspects described herein, E (e.g., each E) includes the amino acid sequence of SEQ ID NO: 23. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23.
  • E includes the amino acid sequence of SEQ ID NO: 34. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 34. In some embodiments of any of the aspects described herein, E (e.g., each E) includes the amino acid sequence of SEQ ID NO: 35. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 35.
  • E includes the amino acid sequence of SEQ ID NO: 44. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments of any of the aspects described herein, E (e.g., each E) includes the amino acid sequence of SEQ ID NO: 46. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 46.
  • E includes the amino acid sequence of SEQ ID NO: 70. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments of any of the aspects described herein, E (e.g., each E) includes the amino acid sequence of SEQ ID NO: 71. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 77.
  • E e.g., each E
  • E includes the amino acid sequence of SEQ ID NO: 78.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 78.
  • E includes the amino acid sequence of SEQ ID NO: 79. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 79. In some embodiments of any of the aspects described herein, E (e.g., each E) includes the amino acid sequence of SEQ ID NO: 80. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 80.
  • E includes the amino acid sequence of SEQ ID NO: 81.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 81.
  • E includes the amino acid sequence of SEQ ID NO: 82.
  • E includes the amino acid sequence of SEQ ID NO: 84. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 84. In some embodiments of any of the aspects described herein, E (e.g., each E) includes the amino acid sequence of SEQ ID NO: 85. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 85.
  • E includes the amino acid sequence of SEQ ID NO: 86.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 86.
  • E includes the amino acid sequence of SEQ ID NO: 87.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 87.
  • E e.g., each E
  • E includes the amino acid sequence of SEQ ID NO: 88.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 88.
  • E includes the amino acid sequence of SEQ ID NO: 96.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 96.
  • E includes the amino acid sequence of SEQ ID NO: 97.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97.
  • E e.g., each E
  • E includes the amino acid sequence of SEQ ID NO: 98.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 98.
  • E includes the amino acid sequence of SEQ ID NO: 101. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 101. In some embodiments of any of the aspects described herein, E (e.g., each E) includes the amino acid sequence of SEQ ID NO: 102. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 102.
  • E includes the amino acid sequence of SEQ ID NO: 106.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 106.
  • E includes the amino acid sequence of SEQ ID NO: 107.
  • E includes the amino acid sequence of SEQ ID NO: 109. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 109. In some embodiments of any of the aspects described herein, E (e.g., each E) includes the amino acid sequence of SEQ ID NO: 110. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 110.
  • E includes the amino acid sequence of SEQ ID NO: 111. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 111. In some embodiments of any of the aspects described herein, E (e.g., each E) includes the amino acid sequence of SEQ ID NO: 112. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 112.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 114.
  • E e.g., each E
  • E includes the amino acid sequence of SEQ ID NO: 115.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 115.
  • E includes the amino acid sequence of SEQ ID NO: 116.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 116.
  • E includes the amino acid sequence of SEQ ID NO: 117.
  • E includes the amino acid sequence of SEQ ID NO: 119. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 119. In some embodiments of any of the aspects described herein, E (e.g., each E) includes the amino acid sequence of SEQ ID NO: 120. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 120.
  • E includes the amino acid sequence of SEQ ID NO: 121.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 121.
  • E includes the amino acid sequence of SEQ ID NO: 122.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 122.
  • E e.g., each E
  • E includes the amino acid sequence of SEQ ID NO: 123.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 123.
  • E includes the amino acid sequence of SEQ ID NO: 124.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 124.
  • E includes the amino acid sequence of SEQ ID NO: 125.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 125.
  • E e.g., each E
  • E includes the amino acid sequence of SEQ ID NO: 126.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 126.
  • E includes the amino acid sequence of SEQ ID NO: 127.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 127.
  • E includes the amino acid sequence of SEQ ID NO: 128.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 128.
  • E e.g., each E
  • E includes the amino acid sequence of SEQ ID NO: 129.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 129.
  • E includes the amino acid sequence of SEQ ID NO: 130. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 130. In some embodiments of any of the aspects described herein, E (e.g., each E) includes the amino acid sequence of SEQ ID NO: 131. In some embodiments, E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 131.
  • E includes the amino acid sequence of SEQ ID NO: 132.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 132.
  • E includes the amino acid sequence of SEQ ID NO: 133.
  • E includes the amino acid sequence of SEQ ID NO: 135.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 135.
  • E includes the amino acid sequence of SEQ ID NO: 136.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 136.
  • an amino acid “corresponding to” a particular amino acid residue should be understood to include any amino acid residue that one of skill in the art would understand to align to the particular residue (e.g., of the particular sequence).
  • any one of SEQ ID NOs: 1-138 may be mutated to include a YTE mutation.
  • the Fc domain monomer e.g., the Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138
  • LS double mutant corresponding to M428L/N434S
  • the Fc domain monomer (e.g., the Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-95) includes a triple mutation corresponding to L309D/Q311H/N434S (DHS).
  • DHS L309D/Q311H/N434S
  • an amino acid “corresponding to” a particular amino acid residue should be understood to include any amino acid residue that one of skill in the art would understand to align to the particular residue (e.g., of the particular sequence).
  • any one of SEQ ID NOs: 1-95 may be mutated to include a DHS mutation.
  • the Fc domain monomer (e.g., the Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138) is a fragment of the Fc domain monomer (e.g., a fragment of at least 25 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more), at least 50 (e.g., 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 or more), at least 75 (e.g., 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86
  • one or more nitrogen atoms of one or more surface exposed lysine residues of E or one or more sulfur atoms of one or more surface exposed cysteines in E is covalently conjugated to a linker (e.g., a PEG 2 -PEG 20 linker).
  • the linker conjugated to E may be functionalized such that it may react to form a covalent bond with the L of any A 1 -L or any A 2 -L-A 1 described herein.
  • the conjugate is conjugate 11, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the conjugate is conjugate 12, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the conjugate is conjugate 21, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the conjugate is conjugate 22, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the conjugate is conjugate 23, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0. In some embodiments the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0. In some embodiments, the conjugate is conjugate 24, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0. In some embodiments the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the conjugate is conjugate 25, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0. In some embodiments the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0. In some embodiments, the conjugate is conjugate 26, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0. In some embodiments the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the Fc domain monomer includes a region of any one of SEQ ID NOs: 1- 138, wherein the region includes positions 220, 252, 254, and 256.
  • the region includes at least 40 amino acid residues, at least 50 amino acid residues, at least 60 amino acid residues, at least 70 amino acids residues, at least 80 amino acids residues, at least 90 amino acid residues, at least 100 amino acid residues, at least 110 amino acid residues, at least 120 amino residues, at least 130 amino acid residues, at least 140 amino acid residues, at least 150 amino acid residues, at least 160 amino acid residues, at least 170 amino acid residues, at least 180 amino acid residues, at least 190 amino acid residues, or at least 200 amino acid residues.
  • the Fc domain monomer dimerizes (e.g., a homodimer or a heterodimer) to form an Fc domain.
  • the Fc domain is at least 40 kDa (e.g., at least 45 kDa, at least 50 kDa, at least 55 kDa, at least 60 kDa, at least 65 kDa, at least 70 kDa, at least 75 kDa, or at least 80 kDa) in mass.
  • viral infection is meant the pathogenic growth of a virus (e.g., RSV such as RSV A or RSV B) in a host organism (e.g., a human subject).
  • a viral infection can be any situation in which the presence of a viral population(s) is damaging to a host body.
  • a subject is “suffering” from a viral infection when an excessive amount of a viral population is present in or on the subject’s body, or when the presence of a viral population(s) is damaging the cells or other tissue of the subject.
  • a human Fc domain monomer e.g., an IgG heavy chain, such as IgG1
  • a human Fc domain monomer includes a region that extends from any of Asn201 or Glu216 (e.g., Asn201, Val 202, Asn203, His204, Lys 205, Pro206, Ser207, Asn208, Thr209, Lys210, Val211, Asp212, Lys 213, Lys214, Val215, or Glu216), to the carboxyl-terminus of the heavy chain, e.g., at Gly446 or Lys447.
  • C- terminal Lys447 of the Fc region may or may not be present, without affecting the structure or stability of the Fc region.
  • numbering of amino acid residues in the IgG or Fc domain monomer is according to the EU numbering system for antibodies, also called the Kabat EU index, as described, for example, in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.
  • the term “Fc domain” refers to a dimer of two Fc domain monomers that is capable of binding an Fc receptor.
  • Fc-binding peptides of the invention include Fc-binding peptides which have been engineered to include one or more (e.g., two, three, four, or five) solvent-exposed cysteine or lysine residues, which may provide a site for conjugation to a compound of the invention (e.g., conjugation to a RSV F protein inhibitor monomer or dimer, including by way of a linker). Most preferably, the Fc-binding peptide will contain a single solvent-exposed cysteine or lysine, thus enabling site-specific conjugation of a compound of the invention. Fc-binding peptides may include only naturally occurring amino acid residues, or may include one or more non-naturally occurring amino acid residues.
  • a non-naturally occurring amino acid residue e.g., the side chain of a non-naturally occurring amino acid residue
  • a compound of the invention e.g., a RSV F protein inhibitor monomer or dimer, including by way of a linker
  • Fc-binding peptides of the invention may be linear or cyclic.
  • Fc-binding peptides of the invention include any Fc-binding peptides known to one of skill in the art.
  • albumin protein refers to a polypeptide including an amino acid sequence corresponding to a naturally-occurring albumin protein (e.g., human serum albumin) or a variant thereof, such as an engineered variant of a naturally-occurring albumin protein.
  • Variants of albumin proteins include polymorphisms, fragments such as domains and sub-domains, and fusion proteins (e.g., an albumin protein having a C-terminal or N-terminal fusion, such as a polypeptide linker).
  • the albumin protein has the amino acid sequence of human serum albumin (HSA) or a variant or fragment thereof, most preferably a functional variant or fragment thereof.
  • albumin protein will contain a single solvent-exposed cysteine or lysine, thus enabling site-specific conjugation of a compound of the invention.
  • Albumin proteins may include only naturally occurring amino acid residues, or may include one or more non-naturally occurring amino acid residues. Where included, a non-naturally occurring amino acid residue (e.g., the side chain of a non- naturally occurring amino acid residue) may used as the point of attachment for a compound of the invention (e.g., a RSV F protein inhibitor monomer or dimer, including by way of a linker).
  • a molecule containing one or more azide groups may be used as a linker, in which the azide group may form a 1,2,3-triazole linkage with an alkyne in a component (e.g., an Fc domain or an albumin protein) in the conjugate.
  • a molecule containing one or more bis-sulfone groups may be used as a linker, in which the bis-sulfone group may form a linkage with an amine group a component (e.g., an Fc domain or an albumin protein) in the conjugate.
  • a molecule containing one or more sulfonic acid groups may be used as a linker, in which the sulfonic acid group may form a sulfonamide linkage with a component in the conjugate.
  • a molecule containing one or more isocyanate groups may be used as a linker, in which the isocyanate group may form a urea linkage with a component in the conjugate.
  • a molecule containing one or more haloalkyl groups may be used as a linker, in which the haloalkyl group may form a covalent linkage, e.g., C-N and C-O linkages, with a component in the conjugate.
  • the substituent will be classified as “noninterfering.” For example, the noninterfering substituent would leave the ability of the compound to provide antiviral efficacy based on an IC50 value of 10 mM or less in a viral plaque reduction assay. Thus, the substituent may alter the degree of inhibition based on plaque reduction or RSV F protein inhibition.
  • an effective amount of a conjugate is, for example, an amount sufficient to prevent, slow down, or reverse the progression of the viral infection as compared to the response obtained without administration of the conjugate.
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • E may be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different A 1 -L-A 2 moieties.
  • E is conjugated to a first A 1 -L-A 2 moiety, and a second A 1 -L-A 2 , moiety.
  • two dimers of RSV F protein inhibitors may be attached to an atom in the Fc domain monomer, Fc domain, Fc-binding peptide, albumin protein, or albumin protein-binding peptide.
  • a linker in a conjugate described herein e.g., L or L’
  • a linker in a conjugate described herein e.g., L or L’
  • Conjugates of monomers of RSV F protein inhibitors linked to an Fc domain or an albumin protein include an Fc domain monomer, Fc domain, Fc-binding peptide, albumin protein, or albumin protein-binding peptide covalently linked to one or more monomers of RSV F protein inhibitors.
  • Conjugates of an Fc domain monomer or albumin protein and one or more monomers of RSV F protein inhibitors may be formed by linking the Fc domain or albumin protein to each of the monomers of RSV F protein inhibitors through a linker, such as any of the linkers described herein.
  • the squiggly line connected to E indicates that one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) monomers of RSV F protein inhibitors may be attached to an Fc domain monomer, Fc domain, Fc-binding peptide, albumin protein, or albumin protein-binding peptide.
  • n is 1, one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) monomers of RSV F protein inhibitors may be attached to an Fc domain monomer or an albumin protein.
  • a linker in a conjugate having an Fc domain monomer, Fc domain, Fc-binding peptide, albumin protein, or albumin protein-binding peptide covalently linked to one or more monomers of the RSV F protein inhibitors described herein may be a divalent structure having two arms. One arm in a divalent linker may be attached to the monomer of the RSV F protein inhibitor and the other arm may be attached to the Fc domain monomer, Fc domain, Fc-binding peptide, albumin protein, or albumin protein-binding peptide.
  • the Fc domain monomer can also be of any immunoglobulin antibody isotype (e.g., IgG1, IgG2a, IgG2b, IgG3, or IgG4).
  • the Fc domain monomer can be of any immunoglobulin antibody allotype (e.g., IGHG1*01 (i.e., G1m(za)), IGHG1*07 (i.e., G1m(zax)), IGHG1*04 (i.e., G1m(zav)), IGHG1*03 (G1m(f)), IGHG1*08 (i.e., G1m(fa)), IGHG2*01, IGHG2*06, IGHG2*02, IGHG3*01, IGHG3*05, IGHG3*10, IGHG3*04, IGHG3*09, IGHG3*11, IGHG3*12, IGHG3*06, IGHG3*07,
  • the Fc domain may include a quadruple mutant corresponding to C220S/L309D/Q311H/N434S (CDHS) (e.g., an IgG1, such as a human or humanized IgG1 having a CDHS mutation, such as SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, and SEQ ID NO: 117).
  • CDHS C220S/L30
  • Exemplary Fc domains with enhanced binding to the FcRN and methods for making Fc domains having enhanced binding to the FcRN are known in the art, for example, as described in Maeda, A. et al., Identification of human IgG1 variant with enhanced FcRn binding and without increased binding to rheumatoid factor autoantibody, MABS, 2017, 9(5):844-853, which is incorporated herein in its entirety.
  • an amino acid “corresponding to” a particular amino acid residue e.g., of a particular SEQ ID NO.
  • any one of SEQ ID NOs: 1-138 may be mutated to include a YTE mutation, an LS mutation, and/or an N434H mutation by mutating the “corresponding residues” of the amino acid sequence.
  • the Fc-domain containing composition includes an Fc domain monomer.
  • the Fc domain monomer is a variant Fc domain (e.g., a variant of a parent Fc polypeptide).
  • the Fc domain monomer may include an amino acid substitution at position 220.
  • the Fc domain monomer may include amino acid substitutions at position 220 and positions 252, 254, and 256.
  • the Fc domain monomer may include amino acid substitutions at positions 309, 311, and 434.
  • the Fc domain monomer includes less than about 300 amino acid residues (e.g., less than about 300, less than about 295, less than about 290, less than about 285, less than about 280, less than about 275, less than about 270, less than about 265, less than about 260, less than about 255, less than about 250, less than about 245, less than about 240, less than about 235, less than about 230, less than about 225, or less than about 220 amino acid residues).
  • the Fc domain monomer is less than about 40 kDa (e.g., less than about 35 kDa, less than about 30 kDa, less than about 25 kDa).
  • the Fc domain monomer includes at least 200 amino acid residues (e.g., at least 210, at least 220, at least 230, at least 240, at least 250, at least 260, at least 270, at least 280, at least 290, or at least 300 amino residues). In some embodiments, the Fc domain monomer is at least 20 kDa (e.g., at least 25 kDa, at least 30 kDa, or at least 35 kDa). In some embodiments, the Fc domain monomer includes 200 to 400 amino acid residues (e.g., 200 to 250, 250 to 300, 300 to 350, 350 to 400, 200 to 300, 250 to 350, or 300 to 400 amino acid residues).
  • the Fc domain monomer is between 240 and 255 amino acid residues (e.g., 241 amino acid residues, 242 amino acid residues, 243 amino acid residues, 244 amino acid residues, 245 amino acid residues, 246 amino acid residues, 247 amino acid residues, 248 amino acid residues, 249 amino acid residues, 250 amino acid residues, 251 amino acid residues, 252 amino acid residues, 253 amino acid residues, or 254 amino acid residues). In even more particular embodiments, the Fc domain monomer is 246 amino acid residues in length.
  • the N-terminus of the Fc domain monomer is amino acid residue 202 (e.g., Val 202).
  • the C-terminus of the variant Fc domain monomer is any one of amino acid residues 437-447.
  • the C-terminus of the variant Fc domain monomer is amino acid residue 446 (e.g., Gly 446).
  • the C-terminus of the variant Fc domain monomer is amino acid residue 447 (e.g. Lys 447).
  • the Fc domain monomer dimerizes (e.g., a homodimer or a heterodimer) to form a Fc domain.
  • the Fc domain is at least 40 kDa (e.g., at least 45 kDa, at least 50 kDa, at least 55 kDa, at least 60 kDa, at least 65 kDa, at least 70 kDa, at least 75 kDa, or at least 80 kDa).
  • the protein sequence alignment of human IgG1 (UniProtKB: P01857; SEQ ID NO: 164), human IgG2 (UniProtKB: P01859; SEQ ID NO: 165), human IgG3 (UniProtKB: P01860; SEQ ID NO: 166), and human IgG4 (UniProtKB: P01861; SEQ ID NO: 167) is provided below (aligned with Clustal Omega Multiple Pairwise Alignment).
  • the alignment indicates cysteine residues (e.g., sulfur atoms of cysteine residues) that “correspond to” one another (in boxes and indicated by the • symbol).
  • the protein sequence alignment of human IgG1 (UniProtKB: P01857; SEQ ID NO: 164), human IgG2 (UniProtKB: P01859; SEQ ID NO: 165), human IgG3 (UniProtKB: P01860; SEQ ID NO: 166), and human IgG4 (UniProtKB: P01861; SEQ ID NO: 167) is provided below (aligned with Clustal Omega Multiple Pairwise Alignment).
  • the alignment indicates lysine residues (e.g., nitrogen atoms of lysine residues) that “correspond to” one another (in boxes and indicated by the * symbol).
  • Lys35 of SEQ ID NO: 10 corresponds to, for example, Lys129 of IgG1, Lys126 of IgG2, Lys176 of IgG3, Lys51 of SEQ ID NO: 1, Lys31 of SEQ ID NO: 2, Lys50 of SEQ ID NO: 3, or Lys30 of SEQ ID NO: 10.
  • Fc-gamma receptors bind the Fc portion of immunoglobulin G (IgG) and play important roles in immune activation and regulation.
  • FcgRs Fc-gamma receptors
  • ICs immune complexes
  • the human FcgR family contains several activating receptors (FcgRI, FcgRIIa, FcgRIIc, FcgRIIIa, and FcgRIIIb) and one inhibitory receptor (FcgRIIb).
  • FcgR signaling is mediated by intracellular domains that contain immune tyrosine activating motifs (ITAMs) for activating FcgRs and immune tyrosine inhibitory motifs (ITIM) for inhibitory receptor FcgRIIb.
  • ITAMs immune tyrosine activating motifs
  • ITIM immune tyrosine inhibitory motifs
  • FcgR binding by Fc domains results in ITAM phosphorylation by Src family kinases; this activates Syk family kinases and induces downstream signaling networks, which include PI3K and Ras pathways.
  • a conjugate having an Fc domain (SEQ ID NO: 73) decorated with one or more small molecule antiviral inhibitors ELF levels are surprisingly ⁇ 60% of plasma exposure levels as measured by AUC across the rest of the time course indicating nearly immediate partitioning of the conjugate from plasma to the ELF in the lung.
  • An albumin protein of the invention may be a naturally-occurring albumin or a variant thereof, such as an engineered variant of a naturally-occurring albumin protein.
  • Bovine serum albumin proteins also includes fragments of full-length bovine serum albumin or variants thereof, as defined herein.
  • the albumin protein may include the sequence of an albumin derived from one of serum albumin from dog (e.g., Swissprot accession number P49822-1), pig (e.g., Swissprot accession number P08835- 1), goat (e.g., Sigma product no.
  • horse e.g., Swissprot accession number P35747-1
  • rhesus monkey e.g., Swissprot accession number Q28522-1
  • mouse e.g., Swissprot accession number P07724-1
  • pigeon e.g., as defined by Khan et al. Int. J. Biol. Macromol.30(3-4),171-8 (2002)
  • rabbit e.g., Swissprot accession number P49065-1
  • rat e.g., Swissprot accession number P02770-1
  • sheep e.g., Swissprot accession number P14639-1
  • albumin proteins of the invention include variants of naturally-occurring albumin proteins.
  • An albumin protein may include a C-terminal or N-terminal polypeptide fusion of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 or more amino acid.
  • the C-terminal or N-terminal polypeptide fusion may include one or more solvent-exposed cysteine or lysine residues, which may be used for covalent conjugation of a compound of the invention (e.g., conjugation to a RSV F protein inhibitor monomer or dimer, including by way of a linker).
  • Albumin proteins of the invention include any albumin protein which has been engineered to include one or more solvent-exposed cysteine or lysine residues, which may provide a site for conjugation to a compound of the invention (e.g., conjugation to a RSV F protein inhibitor monomer or dimer, including by way of a linker). Most preferably, the albumin protein will contain a single solvent-exposed cysteine or lysine, thus enabling site-specific conjugation of a compound of the invention. Exemplary methods for the production of engineered variants of albumin proteins that include one or more conjugation-competent cysteine residues are provided in U.S. Patent Application No. 2017/0081389, which is incorporated herein by reference in its entirety.
  • the net result of the substitution, deletion, addition, or insertion events of (a), (b), (c) and/or (d) is that the number of conjugation competent cysteine residues of the polypeptide sequence is increased relative to the parent albumin sequence.
  • the net result of the substitution, deletion, addition, or insertion events of (a), (b), (c) and/or (d) is that the number of conjugation competent-cysteine residues of the polypeptide sequence is one, thus enabling site-specific conjugation.
  • Preferred albumin protein variants also include albumin proteins having a single solvent-exposed lysine residue, thus enabling site-specific conjugation of a linker to the lysine residue.
  • Such variants may be generated by engineering an albumin protein, including any of the methods previously described (e.g., insertion, deletion, substitution, or C-terminal or N-terminal fusion).
  • Albumin protein-binding peptides Conjugation of a biologically-active compound to an albumin protein-binding peptide can alter the pharmacodynamics of the biologically-active compound, including the alteration of tissue uptake, penetration, and diffusion.
  • conjugation of an albumin protein-binding peptide to a compound of the invention e.g., a RSV F protein inhibitor monomer or dimer, by way of a linker
  • Albumin protein-binding peptides of the invention include albumin protein-binding peptides which have been engineered to include one or more (e.g., two, three, four, or five) solvent-exposed cysteine or lysine residues, which may provide a site for conjugation to a compound of the invention (e.g., conjugation to a RSV F protein inhibitor monomer or dimer, including by way of a linker).
  • the albumin protein-binding peptide will contain a single solvent-exposed cysteine or lysine, thus enabling site-specific conjugation of a compound of the invention.
  • Albumin protein-binding peptide and conjugates including an albumin protein-binding peptide, preferably bind an albumin protein (e.g., human serum albumin) with an affinity characterized by a dissociation constant, Kd, that is less than about 100 mM, preferably less than about 100 nM, and most preferably do not substantially bind other plasma proteins.
  • an albumin protein e.g., human serum albumin
  • Kd dissociation constant
  • Specific examples of such compounds are linear or cyclic peptides, preferably between about 10 and 20 amino acid residues in length, optionally modified at the N-terminus or C-terminus or both.
  • Albumin protein-binding peptides include linear and cyclic peptides including the following general formulae, wherein Xaa is any amino acid: SEQ ID NO: 144 Xaa-Xaa-Cys-Xaa-Xaa-Xaa-Xaa-Cys-Xaa-Xaa-Phe-Cys-Xaa-Asp-Trp-Pro-Xaa-Xaa-Xaa-Ser-Cys SEQ ID NO: 145 Val-Cys-Tyr-Xaa-Xaa-Xaa-Ile-Cys-Phe SEQ ID NO: 146 Cys-Tyr-Xaa-Pro-Gly-Xaa-Cys SEQ ID NO: 147 Asp-Xaa-Cys-Leu-Pro-Xaa-Trp-Gly-Cys-Leu-Trp SEQ ID NO: 148 Trp-Cys-
  • albumin protein-binding peptides are provided in U.S. Patent Application No. 2005/0287153, which is incorporated herein by reference in its entirety.
  • Conjugation of albumin protein-binding peptides An albumin protein-binding peptide of the invention may be conjugated to (e.g., by way of a covalent bond) to any compound of the invention (e.g., by way of the linker portion of a RSV F protein inhibitor monomer or dimer).
  • the albumin protein-binding peptide may be conjugated to any compound of the invention by any method known to those of skill in the art for producing peptide-small molecule conjugates.
  • the linker when the linker has three arms, two of the arms may be attached to the first and second RSV F protein inhibitors and the third arm may be attached to the Fc domain monomer, and Fc domain, an Fc-binding peptide, an albumin protein, or an albumin protein-binding peptide. In some embodiments when the linker has two arms, one arm may be attached to an Fc domain or an albumin protein and the other arm may be attached to one of the two RSV F protein inhibitors. In other embodiments, a linker with two arms may be used to attach the two RSV F protein inhibitors on a conjugate containing an Fc domain or albumin protein covalently linked to one or more dimers of RSV F protein inhibitors.
  • optionally substituted includes substitution with a PEG.
  • a PEG has a repeating unit structure (-CH 2 CH 2 O-)n, wherein n is an integer from 2 to 100.
  • a polyethylene glycol may selected any one of PEG2 to PEG100 (e.g., PEG2, PEG3, PEG4, PEG5, PEG5-PEG10, PEG10-PEG20, PEG20-PEG30, PEG30-PEG40, PEG50-PEG60, PEG60-PEG70, PEG70-PEG80, PEG80-PEG90, PEG90-PEG100).
  • L C may have two points of attachment to the Fc domain (e.g., two G C2 ).
  • a polyethylene glycol linker may covalently join a RSV F protein inhibitor dimer and E (e.g., in a conjugate of any one of formulas (D-I)-(D-VII)).
  • a polyethylene glycol linker may selected any one of PEG2 to PEG100 (e.g., PEG2, PEG3, PEG4, PEG5, PEG5-PEG10, PEG10-PEG20, PEG20-PEG30, PEG30-PEG40, PEG50-PEG60, PEG60-PEG70, PEG70-PEG80, PEG80-PEG90, PEG90-PEG100).
  • L c includes a PEG linker, where L C is covalently attached to each of Q i and E.
  • Linkers in conjugates having an Fc domain or an albumin protein covalently linked to monomers of RSV F protein inhibitors In a conjugate containing an Fc domain monomer, and Fc domain, an Fc-binding peptide, an albumin protein, or an albumin protein-binding peptide covalently linked to one or more monomers of RSV F protein inhibitors as described herein, a linker in the conjugate (e.g., L, or L’) may be a divalent structure having two arms.
  • One arm in a divalent linker may be attached to the monomer of RSV F protein inhibitor and the other arm may be attached to the Fc domain monomer, and Fc domain, an Fc- binding peptide, an albumin protein, or an albumin protein-binding peptide.
  • the one or more monomers of RSV F protein inhibitors in the conjugates described herein may each be, independently, connected to an atom in the Fc domain monomer, and Fc domain, an Fc-binding peptide, an albumin protein, or an albumin protein-binding peptide.
  • a linker is described by formula (M-L-I): J 1 -(Q 1 )g-(T 1 )h-(Q 2 )i-(T 2 )j-(Q 3 )k-(T 3 )l-(Q 4 )m-(T 4 )n-(Q 5 )o-J 2 wherein J 1 is a bond attached to a RSV F protein inhibitor; J 2 is a bond attached to an Fc domain monomer, and Fc domain, an Fc-binding peptide, an albumin protein, or an albumin protein-binding peptide, or a functional group capable of reacting with a functional group conjugated to an Fc domain monomer, an Fc domain, an Fc-binding peptide, an albumin protein, or an albumin protein-binding peptide (e.g., maleimide and cysteine, amine and activated carboxylic acid, thiol and maleimide, activated sulfonic acid and amine,
  • optionally substituted includes substitution with a polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • a PEG has a repeating unit structure (-CH 2 CH 2 O-)n, wherein n is an integer from 2 to 100.
  • a polyethylene glycol may selected any one of PEG2 to PEG100 (e.g., PEG2, PEG3, PEG4, PEG5, PEG5- PEG 10 , PEG 10 -PEG 20 , PEG 20 -PEG 30 , PEG 30 -PEG 40 , PEG 50 -PEG 60 , PEG 60 -PEG 70 , PEG 70 -PEG 80 , PEG 80 - PEG90, PEG90-PEG100).
  • PEG2 to PEG100 e.g., PEG2, PEG3, PEG4, PEG5, PEG5- PEG 10 , PEG 10 -PEG 20 , PEG 20 -PEG 30 , PEG 30 -PEG 40 , PEG 50 -
  • a linker includes no more than 250 non-hydrogen atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1- 10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1- 85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1- 220, 1-230, 1-240, or 1-250 non-hydrogen atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non-hydrogen atom(s); 250,
  • two arms of a linker may contain two dicarboxylic acids, in which the first carboxylic acid may form a covalent linkage with the first RSV F protein inhibitor in the conjugate and the second carboxylic acid may form a covalent linkage with the second RSV F protein inhibitor in the conjugate, and the third arm of the linker may for a covalent linkage (e.g., a C-O bond) with an Fc domain monomer, and Fc domain, an Fc-binding peptide, an albumin protein, or an albumin protein-binding peptide in the conjugate.
  • a covalent linkage e.g., a C-O bond
  • the divalent linker may contain two carboxylic acids, in which the first carboxylic acid may form a covalent linkage with one component (e.g., a RSV F protein inhibitor) in the conjugate and the second carboxylic acid may form a covalent linkage (e.g., a C-S bond or a C-N bond) with another component (e.g., an Fc domain monomer, and Fc domain, an Fc-binding peptide, an albumin protein, or an albumin protein- binding peptide) in the conjugate.
  • dicarboxylic acid molecules may be used as linkers (e.g., a dicarboxylic acid linker).
  • the first carboxylic acid in a dicarboxylic acid molecule may form a covalent linkage with a hydroxyl or amine group of the first RSV F protein inhibitor and the second carboxylic acid may form a covalent linkage with a hydroxyl or amine group of the second RSV F protein inhibitor.
  • dicarboxylic acids molecules that may be used to form linkers include, but are not limited to,
  • n is an integer from 1 to 20 (e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • a linking group may including a moiety including a carboxylic acid moiety and an amino moiety, such as the ones described herein, may be further functionalized to contain one or more additional functional groups.
  • Such linking groups may be further functionalized, for example, to provide an attachment point to an Fc domain monomer, an Fc domain, an Fc-binding peptide, an albumin protein, or an albumin protein-binding peptide (e.g., by way of a linker, such as a PEG linker).
  • n is an integer from 1 to 20 (e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • a linking group may including a diamino moiety, such as the ones described herein, may be further functionalized to contain one or more additional functional groups.
  • Such diamino linking groups may be further functionalized, for example, to provide an attachment point to an Fc domain monomer, an Fc domain, an Fc-binding peptide, an albumin protein, or an albumin protein- binding peptide (e.g., by way of a linker, such as a PEG linker).
  • a linker e.g., an active ester, e.g., a nitrophenylester or N- hydroxysuccinimidyl ester, or derivatives thereof (e.g., a funtionalized PEG linker (e.g., azido-PEG2- PEG40-NHS ester)
  • a T of e.g., DAR
  • 0.5 and 10.0 e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2
  • the E-(PEG2-PEG40)-azide can react with an Int having a terminal alkyne linker (e.g., L, or L’, such as L C of D-L-I) through click conjugation.
  • an Int having a terminal alkyne linker e.g., L, or L’, such as L C of D-L-I
  • the copper-catalyzed reaction of the an azide (e.g., the Fc-(PEG2-PEG40)-azide) with the alkyne (e.g., the Int having a terminal alkyne linker (e.g., L or L’, such as L C of D-L-I) forming a 5-membered heteroatom ring.
  • the linker conjugated to E is a terminal alkyne and is conjugated to an Int having a terminal azide.
  • Exemplary preparations of preparations of E-(PEG2-PEG40)-azide are described in Examples 2, 3, and 12.
  • One of skill in the art would readily understand the final product from a click chemistry conjugation.
  • Exemplary linking strategies e.g., methods for linking a monomer or a dimer of a neuraminidase inhibitor to E, such as, by way of a linker are further depicted in FIGS.1-4. VI.
  • one or more antiviral agents may be administered in combination (e.g., administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions, or administered separately at different times) with a conjugate described herein (e.g., a conjugate of any one of formulas (1), (2), (D-I)-(D-VII), or (M-I)-(M-VII)).
  • the antiviral agent is an antiviral agent for the treatment of RSV.
  • the antiviral agent may be a viral replication inhibitor, a RSV F protein inhibitor, a polymerase inhibitor, or a fusion protein inhibitor.
  • the antiviral agent may target either the virus or the host subject.
  • the antiviral agent for the treatment of RSV used in combination with a conjugate described herein may be selected from Presatovir, MDT 637, JNJ 179, TMC353121, or Ziresovir.
  • a conjugate described herein e.g., a conjugate of any one of formulas (1), (2), (D-I)-(D-VII), or (M-I)-(M-VII)
  • Presatovir may be selected from Presatovir, MDT 637, JNJ 179, TMC353121, or Ziresovir.
  • derivatives of Presatovir, MDT 637, JNJ 179, TMC353121, or Ziresovir such as those found in the literature, have RSV F protein inhibitor activity and are useful as RSV F protein inhibitors in combination with the compounds herein (see, for example, Cockerill et al. J. Med.
  • any one of conjugates described herein e.g., a conjugate of any one of formulas (1), (2), (D-I)-(D-VII), or (M-I)-(M-VII)
  • an antiviral vaccine e.g., a composition that elicits an immune response in a subject directed against a virus.
  • the antiviral vaccine may be administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions) as the conjugates, or may be administered prior to or following the conjugates (e.g., within a period of 1 day, 2, days, 5, days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 6 months, or 12 months, or more).
  • the viral vaccine includes an immunogen that elicits an immune response in the subject against RSV A or RSV B.
  • the vaccine is administered as a nasal spray. VII.
  • Methods described herein include, e.g., methods of protecting against or treating a viral infection (e.g., an RSV infection) in a subject and methods of preventing, stabilizing, or inhibiting the growth of viral particles.
  • a method of treating a viral infection (e.g., an RSV infection) in a subject includes administering to the subject a conjugate described herein (e.g., a conjugate of any one of formulas (1), (2), (D-I)-(D-VII), or (M-I)-(M-VII)) or a pharmaceutical composition thereof.
  • the viral infection is cause by the respiratory synctitial virus (e.g., RSV A or RSV B).
  • the viral infection is caused by a resistant strain of virus.
  • a method of preventing, stabilizing, or inhibiting the growth of viral particles or preventing the replication and spread of the virus includes contacting the virus or a site susceptible to viral growth with a conjugate described herein (e.g., a conjugate of any one of formulas (1), (2), (D-I)-(D-VII), or (M-I)-(M-VII)) or a pharmaceutical composition thereof.
  • methods described herein also include methods of protecting against or treating viral infection in a subject by administering to the subject a conjugate described herein (e.g., a conjugate of any one of formulas (1), (2), (D-I)-(D-VII), or (M-I)-(M-VII)).
  • the method further includes administering to the subject an antiviral agent or an antiviral vaccine.
  • Methods described herein also include methods of preventing, stabilizing, or inhibiting the growth of viral particles or preventing the replication or spread of a virus, by contacting the virus or a site susceptible to viral growth with (1) a conjugate described herein (e.g., a conjugate of any one of formulas (1), (2), (D-I)- (D-VII), or (M-I)-(M-VII)) and (2) an antiviral agent or an antiviral vaccine.
  • a conjugate described herein e.g., a conjugate of any one of formulas (1), (2), (D-I)- (D-VII), or (M-I)-(M-VII)
  • the conjugate described herein or the antiviral agent or antiviral vaccine is administered first, followed by administering of the conjugate described herein and the antiviral agent or antiviral vaccine substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions). In some embodiments, the conjugate described herein and the antiviral agent or antiviral vaccine are administered first substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions), followed by administering of the conjugate described herein or the antiviral agent or antiviral vaccine alone.
  • a conjugate described herein e.g., a conjugate of any one of formulas (1), (2), (D-I)-(D-VII), or (M- I)-(M-VII)
  • an antiviral agent or antiviral vaccine when administered together (e.g., substantially simultaneously in the same or separate pharmaceutical compositions, or separately in the same treatment regimen), inhibition of viral replication of each of the conjugate and the antiviral agent or antiviral vaccine may be greater (e.g., occur at a lower concentration) than inhibition of viral replication of each of the conjugate and the antiviral agent or antiviral vaccine when each is used alone in a treatment regimen.
  • a conjugate described herein may be formulated in a pharmaceutical composition for use in the methods described herein.
  • a conjugate described herein may be formulated in a pharmaceutical composition alone.
  • a conjugate described herein may be formulated in combination with an antiviral agent or antiviral vaccine in a pharmaceutical composition.
  • the pharmaceutical composition includes a conjugate described herein (e.g., a conjugate described by any one of formulas (1), (2), (D-I)-(D-VII), or (M-I)-(M-VII)) and pharmaceutically acceptable carriers and excipients. Acceptable carriers and excipients in the pharmaceutical compositions are nontoxic to recipients at the dosages and concentrations employed.
  • excipients examples include, but are not limited to, antiadherents, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, sorbents, suspensing or dispersing agents, or sweeteners.
  • the conjugates herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the conjugates herein be prepared from inorganic or organic bases.
  • the conjugates are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for forming basic salts.
  • Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, n
  • alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • a conjugate herein or a pharmaceutical composition thereof used in the methods described herein will be formulated into suitable pharmaceutical compositions to permit facile delivery.
  • a conjugate e.g., a conjugate of any one of formulas (1), (2), (D- I)-(D-VII), or (M-I)-(M-VII)
  • a pharmaceutical composition thereof may be formulated to be administered intramuscularly, intravenously (e.g., as a sterile solution and in a solvent system suitable for intravenous use), intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally (e.g., a tablet, capsule, caplet, gelcap, or syrup), topically (e.g., as a cream, gel, lotion, or o
  • a conjugate herein or a pharmaceutical composition thereof may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols.
  • the compositions may be formulated according to conventional pharmaceutical practice.
  • a conjugate described herein may be formulated in a variety of ways that are known in the art.
  • a conjugate described herein can be formulated as pharmaceutical or veterinary compositions.
  • a conjugate described herein is formulated in ways consonant with these parameters.
  • a summary of such techniques is found in Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins (2012); and Encyclopedia of Pharmaceutical Technology, 4th Edition, J. Swarbrick and J. C. Boylan, Marcel Dekker, New York (2013), each of which is incorporated herein by reference.
  • Formulations may be prepared in a manner suitable for systemic administration or topical or local administration.
  • Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration.
  • the formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, and preservatives.
  • the conjugates can be administered also in liposomal compositions or as microemulsions.
  • Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration.
  • Oral administration is also suitable for conjugates herein. Suitable forms include syrups, capsules, and tablets, as is understood in the art.
  • compositions can be administered parenterally in the form of an injectable formulation.
  • Pharmaceutical compositions for injection can be formulated using a sterile solution or any pharmaceutically acceptable liquid as a vehicle.
  • Formulations may be prepared as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions.
  • Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco’s Modified Eagle Medium (DMEM), a-Modified Eagles Medium (a-MEM), F-12 medium).
  • Such injectable compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, such as sodium acetate and sorbitan monolaurate.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiad
  • Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • Dissolution or diffusion controlled release of a conjugate described herein e.g., a conjugate of any one of formulas (1), (2), (D-I)-(D-VII), or (M-I)-(M-VII)
  • a pharmaceutical composition thereof can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of the conjugate, or by incorporating the conjugate into an appropriate matrix.
  • a controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
  • shellac beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyce
  • an antiviral agent if an antiviral agent is also administered in addition to a conjugate described herein, the antiviral agent or a pharmaceutical composition thereof may also be administered in any of the routes of administration described herein.
  • the dosage of a conjugate described herein e.g., a conjugate of any one of formulas (1), (2), (D- I)-(D-VII), or (M-I)-(M-VII)
  • pharmaceutical compositions thereof depends on factors including the route of administration, the disease to be treated (e.g., the extent and/or condition of the viral infection), and physical characteristics, e.g., age, weight, general health, of the subject.
  • the amount of the conjugate or the pharmaceutical composition thereof contained within a single dose may be an amount that effectively prevents, delays, or treats the viral infection without inducing significant toxicity.
  • a pharmaceutical composition may include a dosage of a conjugate described herein ranging from 0.01 to 500 mg/kg (e.g., 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg/kg) and, in a more specific embodiment, about 0.1 to about 30 mg/kg and, in a more specific embodiment, about 1 to about 30 mg/kg.
  • a conjugate described herein e.g., a conjugate of any one of formulas (1), (2), (D-I)-(D-VII), or (M-I)-(M- VII)
  • an antiviral agent or antiviral vaccine are administered in combination (e.g., substantially simultaneously in the same or separate pharmaceutical compositions, or separately in the same treatment regimen)
  • the dosage needed of the conjugate described herein may be lower than the dosage needed of the conjugate if the conjugate was used alone in a treatment regimen.
  • a conjugate described herein e.g., a conjugate of any one of formulas (1), (2), (D-I)-(D-VII), or (M-I)-(M-VII)
  • a pharmaceutical composition thereof may be administered to a subject in need thereof, for example, one or more times (e.g., 1-10 times or more; 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times) daily, weekly, monthly, biannually, annually, or as medically necessary. Dosages may be provided in either a single or multiple dosage regimens. The timing between administrations may decrease as the medical condition improves or increase as the health of the patient declines.
  • the oligonucleotide templates were cloned into pcDNA3.1 (Life Technologies, Carlsbad, CA, USA) at the cloning sites BamHI and XhoI (New England Biolabs, Ipswich, MA, USA) and included signal sequences derived from the human Interleukin-2 or human albumin.
  • the pcDNA3.1 plasmids were transformed into Top10 E. coli cells (LifeTech). DNA was amplified, extracted, and purified using the PURELINK® HiPure Plasmid Filter Maxiprep Kit (LifeTech). The plasmid DNA is delivered, using the EXPIFECTAMINETM 293 Transfection Kit (LifeTech), into HEK- 293 cells per the manufacturer’s protocol.
  • FIGs.5-11 show non-reducing and reducing SDS-PAGE of an Fc domain formed from Fc domain monomers having the sequences of SEQ ID NOs: 1, 3, 5, 7, 9, 12, and 14, respectively.
  • Example 2
  • PEG4-azido Fc 0.050M PEG4-azidoNHS ester PBS buffer solution (1.803 mL, 90.13 mmol, 9.5 equivalents) was added to a solution of h-IgG1 Fc (SEQ ID NO: 4) (552.2 mg in 33.75mL of pH 7.4 PBS, MW ⁇ 58,200 Da, 9.487 mmol) and the mixture was shaken gently for 2 hours at ambient temperature. The solution was concentrated by using six centrifugal concentrators (30,000 MWCO, 15 mL) to a volume of ⁇ 1.5 mL. The crude mixture was diluted 1:10 in PBS pH 7.4, and concentrated again. This wash procedure was repeated for total of three times.
  • the concentrated Fc-PEG4-azide was diluted to 33.75 mL with pH 7.4 PBS 1x buffer and ready for Click conjugation.
  • the purified material was quantified using a NANODROPTM UV visible spectrophotomer (using a calculated extinction coefficient based on the amino acid sequence of h-IgG1 (SEQ ID NO: 4). Yield is quantitative after purification.
  • the nucleic acid construct encoding the Fc for any conjugate described herein may include a nucleic acid sequence encoding the amino acid sequence of an Fc including Lys447 (e.g., a C-terminal lysine residue) and/or an N-terminal murine IgG signal sequence.
  • the C-terminal lysine and, when present, the N-terminal murine IgG signal sequence of the Fc are proteolytically cleaved, resulting in an Fc having the amino acid sequence lacking Lys447 (e.g., lacking a C-terminal lysine residue) and, when present in the expression construct, the N-terminal murine IgG signal sequence.
  • the presence or absence of a C-terminal lysine does not alter the properties of the Fc or the corresponding conjugate.
  • azido-acetate Fc 0.05M azido-acetate NHS ester PBS buffer solution (4.723 mL, 236.1 mmol, 12.6 equivalents) was added to a solution of h-IgG1 Fc (552.2 mg in 47.92 mL of pH 7.4 PBS, MW ⁇ 53360 Da, 18.74 mmol) then the mixture was shaken rotated for 2 hours at ambient temperature. The solution was concentrated by using six centrifugal concentrators (30,000 MWCO, 15 mL) to a volume of ⁇ 1.5 mL. The crude mixture was diluted 1:10 in PBS pH 7.4, and concentrated again. This wash procedure was repeated for total of three times.
  • the crude mixture was diluted 1:10 in PBS pH 7.4, and concentrated again. This wash procedure was repeated for total of three times. The small molecule reagent was removed with this wash procedure.
  • the concentrated MSA-PEG4-azide was diluted to 75.0 mL with pH 7.4 PBS 1x buffer and ready for Click conjugation.
  • the purified material was quantified using a NANODROPTM UV visible spectrophotomer (using a calculated extinction coefficient based on the amino acid sequence of h-IgG1). Yield is quantitative after purification.
  • DAR 3.5 determined by MALDI. The DAR value can be adjusted by altering the equivalents of PEG4-azido NHS ester similar to h-IgG1 Fc (Example 2).
  • step-b product 104.6 mg, 0.226 mmol
  • DIPEA 65 mg, 0.5 mmol
  • BOP reagent 104.9 mg, 0.238 mmol
  • the resulting mixture was heated at 70°C for 10 minutes, then 3-Boc-aminomethylazetedine (63 mg, 0.27 mmol) was added.
  • the reaction was continued at 70 °C for 1 hour.
  • Example 6 Synthesis of Int-3 The major product from step-b of Example 5 (Int-2) (23.4 mg, 0.0297 mmol) was dissolved in MeOH (2 ml), and the solution was treated with 30% NaOH in water (0.5 ml) and 1ml of water. The resulting mixture was heated at 70 °C for 3 hours.
  • Example 7 Synthesis of Int-4 Step a. To a solution of starting material (231.5 mg, 0.5 mmol, described in Example 4, Int-1) in anhydrous DMF (1 ml) was added DIPEA (129.2 mg, 1 mmol) and BOP reagent (243.3 mg, 0.55 mmol). The resulting mixture was heated at 70 °C for 10 minutes, then (3R,4S)-(4-hydroxy-pyrrolidin-3-yl)- carbamic acid tert-butyl ester (132 mg, 0.65 mmol) was added. The reaction was continued at 70 °C for 1 hour.
  • Step b To a solution of the step-a product (104 mg, 0.162 mmol) in anhydrous DMF (1 ml) was added propargyl-PEG4-bromide (95.6 mg, 0.324 mmol) and potassium carbonate (44.8 mg, 0.324 mmol). The resulting mixture was heated at 100 °C for 5 hours. It was then purified by preparative HPLC (5% to 60% acetonitrile and water, using 0.1% TFA as modifier).
  • Step b To a solution of product from the previous step (0.8 g, 2.0 mmol) in anhydrous DMF was added sodium hydride (200 mg, 60% in oil, 5 mmol) and propargyl bromide (80 wt. % in toluene, 0.45 ml, 4 mmol) under the ice-water bath. The reaction was stirred for 4 hrs at room temperature under nitrogen atmosphere, then the mixture was concentrated and purified by column chromatography over silica silica eluted with 0% to 20% ethyl acetate and methanol. Yield of 0.7 g, 80%.
  • the nucleic acid construct encoding the Fc for any conjugate described herein may include a nucleic acid sequence encoding the amino acid sequence of an Fc including Lys447 (e.g., a C-terminal lysine residue) and/or an N-terminal murine IgG signal sequence (e.g., SEQ ID NO: 35).
  • Lys447 e.g., a C-terminal lysine residue
  • N-terminal murine IgG signal sequence e.g., SEQ ID NO: 35.
  • the C-terminal lysine and, when present, the N-terminal murine IgG signal sequence of the Fc are proteolytically cleaved, resulting in an Fc having the amino acid sequence lacking Lys447 (e.g., lacking a C-terminal lysine residue) and, when present in the expression construct, the N-terminal murine IgG signal sequence.
  • Example 11 Activity of pre-conjugation intermediates (Ints) and conjugates in an RSV Cytopathic Effects (CPE) assay
  • the activity of anti-RSV compounds and conjugates was determined using an in vitro cell-based assay following a standard protocol in the field. Briefly, ten four-fold serial dilutions of each test article (TA) starting at 10 ⁇ M were prepared in duplicate and incubated with RSV (Respiratory Syncytial Virus strain A 2 ) at a multiplicity of infection (MOI) of 0.01, for one hour. The RSV-TA mix was then added to HEp-2 cells seeded in 96-well plates and incubated for one hour.
  • TA test article
  • MOI multiplicity of infection
  • Example 12 RSV F protein binding assay Nunc MaxiSorp flat-bottom 96-well plates (12-565-136, Fisher Scientific) were coated with recombinant RSV F protein (11049-V08B, Sino Biological) at 1 ⁇ g/mL in Seracare KPL coating solution (50-674-4, Fisher Scientific) at room temp for 1 h (100 ⁇ L, 0.1 ⁇ g/well) on an orbital microplate shaker at 500 rpm (BT908, BT LabSystems). Plates were washed (5 x 300 ⁇ L) with wash buffer (PBS 0.05% Tween 20) and blocked with 5% non-fat dry milk (9999S, Cell Signaling Technology) in wash buffer for 1 h at room temp with shaking.
  • wash buffer PBS 0.05% Tween 20
  • the blocking agent was removed and wells incubated with 3-fold serial dilutions of RVC in sample diluent (2.5% non-fat milk in PBS 0.025% Tween 20) starting at 2 ⁇ M for 2 h with shaking at room temp. After 5 x 300 ⁇ L washes, the plates were incubated with HRP conjugated donkey anti-human IgG Fc F(ab’)2 (709-036-098, Jackson ImmunoResearch) secondary antibody diluted 1:1,000 in sample diluent for 1 h with shaking at room temp. Plates were then washed (8 x 300 ⁇ L) and developed with TMB substrate (BD555214, Fisher Scientific) for 3-5 minutes at room temp.
  • PEG4-azido Fc 0.050M PEG4-azidoNHS ester PBS buffer solution (0.593 mL, 29.6 mmol, 16 equivalents) was added to above solution of h-IgG1 Fc (SEQ ID NO: 48) and the mixture was shaken rotated for 2 hours at ambient temperature. The solution was concentrated by using four centrifugal concentrators (30,000 MWCO, 15 mL) to a volume of ⁇ 1.5 mL. The crude mixture was diluted 1:10 in PBS pH 7.4, and concentrated again. This wash procedure was repeated for total of three times. The concentrated Fc-PEG4-azide was diluted to 8.80 mL with pH 7.4 PBS buffer and ready for Click conjugation.
  • Example 14 Synthesis of Conjugate 6 A solution of azido functionalized Fc (75 mg, 7.5 mL, 1.406 umol, Example 13; SEQ ID NO: 35 functionalized with PEG4-azide) was added to a 40 mL centrifuge tube containing alkyne functionalized small molecule (12.2 mg, 13.49 umol, described in Example 8, Int-5).
  • the nucleic acid construct encoding the Fc for conjugate 6 included a nucleic acid encoding the amino acid sequence of SEQ ID NO: 35, which includes a C-terminal lysine residue and N-terminal murine IgG signal sequence.
  • the C-terminal lysine and the N-terminal murine IgG signal sequence of the Fc of conjugate 6 are proteolytically cleaved, resulting in an Fc having the sequence lacking Lys447 (e.g., lacking a C-terminal lysine residue) and the N-terminal murine IgG signal sequence.
  • Lys447 e.g., lacking a C-terminal lysine residue
  • the presence or absence of a C-terminal lysine does not alter the properties of the Fc or the corresponding conjugate.
  • the nucleic acid construct encoding the Fc for conjugate 3a included a nucleic acid encoding the amino acid sequence of SEQ ID NO: 35, which includes a C-terminal lysine residue and N-terminal murine IgG signal sequence.
  • the C-terminal lysine and the N-terminal murine IgG signal sequence of the Fc of conjugate 3a are proteolytically cleaved, resulting in an Fc having the sequence lacking Lys447 (e.g., lacking a C-terminal lysine residue) and the N-terminal murine IgG signal sequence.
  • Lys447 e.g., lacking a C-terminal lysine residue
  • the presence or absence of a C-terminal lysine does not alter the properties of the Fc or the corresponding conjugate.
  • Step b The intermediate from step a (4 g, 14.4 mmol), tosyl chloride (3.6 g, 18.7 mmol), and triethylamine (2.6g, 25.9 mmol) were stirred in DCM (50 mL) at room temperature for 12 hours. DI water was added and the mixture was extracted with DCM (3 x 30mL). The combined organic extracts were washed with brine and dried over sodium sulfate.
  • Step b Synthesis of tert-butyl 2'-oxo-1',2'-dihydro-1H-spiro[piperidine-4,3'-pyrrolo[2,3- c]pyridine]-1-carboxylate
  • methanol 10 ml
  • palladium on charcoal 0.2 g
  • Palladium was removed by filtration after the reaction was complete as indicated by LCMS.
  • saturated NaHCO 3 solution 5 ml
  • Boc anhydride (0.44 g, 2.1mmol
  • Step d Synthesis of 4-chloro-N-1-(4-fluorobutyl)benzene-1,2-diamine To a solution of the products from previous step (1.3 g, 5.3 mmol) in ethanol (30 ml) was added a saturated ammonium solution (12 ml). The resulting solution was heated to 60°C and Zin powder (3.3g, 5mmol) was added.
  • Step c HATU (92 mg, 0.24 mmol) was added to a stirring mixture of the intermediate described in step b. of this example (170 mg, 0.19 mmol), propargyl-peg4-carboxylic acid ( 63 mg, 0.24 mmol), and triethylamine (94 mg, 0.93 mmol) in DMF (3 mL).
  • Step b Oxalyl chloride was added to DCM (15 mL) cooled to -78°C (dry ice /acetone bath) under an atmosphere of nitrogen. DMSO (801 mg, 10.26 mmol in 5 m of DCM was added to the oxalyl chloride solution dropwise via syringe over a period of 5 minutes. The mixture was stirred at -78 °C for 10 minutes at which point the intermediate alcohol described in step a of this example (1.5g, 5.13 mmol, in 5 mL DCM) was added dropwise via syringe over a period of 5 minutes. The mixture was stirred at -78 °C for 30 minutes.
  • Step e The intermediate from step d (282 mg, 0.37 mmol) was dissolved in DMF (2 mL), then treated with propargyl-peg4-bromide (140 mg, 0.47 mmol), and N,N-diisopropylethylamine (188 mg, 1.5 mmol) and stirred at 80°C for 3 hours.
  • the boc-protected intermediate was stirred in TFA (3 mL) at room temperature for 30 minutes. The solvent was removed by the rotary evaporator and purified by reversed phase HPLC chromatography ISCO ACCQ semi prep (20-95% acetonitrile in DI water, 0.1% TFA, 30 minute gradient). The pure fractions were pooled and lyophilized to afford the desired product as an off white solid.
  • the nucleic acid construct encoding the Fc for conjugate 7 included a nucleic acid encoding the amino acid sequence of SEQ ID NO: 35, which includes a C-terminal lysine residue and N-terminal murine IgG signal sequence.
  • the C-terminal lysine and the N-terminal murine IgG signal sequence of the Fc of conjugate 7 are proteolytically cleaved, resulting in an Fc having the sequence lacking Lys447 (e.g., lacking a C-terminal lysine residue) and the N-terminal murine IgG signal sequence.
  • Lys447 e.g., lacking a C-terminal lysine residue
  • the presence or absence of a C-terminal lysine does not alter the properties of the Fc or the corresponding conjugate.
  • Example 26 The presence or absence of a C-terminal lysine does not alter the properties of the Fc or the corresponding conjugate.
  • the nucleic acid construct encoding the Fc for conjugate 8 included a nucleic acid encoding the amino acid sequence of SEQ ID NO: 35, which includes a C-terminal lysine residue and N-terminal murine IgG signal sequence.
  • the C-terminal lysine and the N-terminal murine IgG signal sequence of the Fc of conjugate 8 are proteolytically cleaved, resulting in an Fc having the sequence lacking Lys447 (e.g., lacking a C-terminal lysine residue) and the N-terminal murine IgG signal sequence.
  • the presence or absence of a C-terminal lysine does not alter the properties of the Fc or the corresponding conjugate.
  • Virus only (no drug) and cells only (no virus, no drug) controls were included on each plate.
  • the compound-virus mix was incubated for 1 h at 37 ⁇ C and 5% CO 2 . After 1 h, medium was removed from HEp-2cells by aspiration and wells washed once with 100 ⁇ L/well 1X PBS pH 7.4 (Fisher cat # MT21040CM).
  • Plates were washed 5x with 300 ⁇ L/well PBST and incubated with 100 ⁇ L/well HRP- conjugated goat anti-mouse IgG antibody (SouthernBiotech cat # 1030-05) diluted 1:1,000 in diluent for 1 h with shaking. Plates were washed 5x with 300 ⁇ L/well PBST and incubated with 100 ⁇ L/well TMB substrate (Fisher cat # BDB555214) for ⁇ 5 min. The reaction was stopped with 100 ⁇ L/well 1N H2SO4. Absorbance was read at 450 nm with an EnSpire multimode plate reader (PerkinElmer).
  • the mean A450 for the cells only control was subtracted from all A450 values, and the percent virus neutralisation calculated for each compound concentration, relative to the virus only control.
  • Half maximal effective concentration (EC50) was calculated with GraphPad Prism version 8 using nonlinear regression analysis of % neutralisation vs. log10 concentration plots.
  • the 50% cytotoxic concentration (CC50) at day 6 post infection was determined for assays run in parallel with the microneutralization assay. Briefly, the medium was removed by aspiration and the cells fixed/ stained for 1 h at room temperature with 60 ⁇ L/well crystal violet solution (0.1% crystal violet, 20% methanol, 3% paraformaldehyde). The stain was removed and wells washed 3x times with 100 ⁇ L/well 1X PBS pH 7.4.
  • Example 39 30-day comparative non-human primate PK study following IV administration of a conjugate including an Fc domain having a C220S/YTE quadruple mutation
  • a conjugate including an Fc domain having a C220S mutation and a YTE mutation was synthesized as described in Example 38.
  • mice were non-terminally bled (via femoral or cephalic veins) with blood collected in K 2 EDTA tubes to prevent coagulation. Collected blood was centrifuged (2,000 x g, for 10 minutes) and plasma withdrawn for analysis of test article concentrations over time. The plasma concentrations for the C220S/YTE Fc conjugate and the C220S conjugate at each time point were measured by sandwich ELISA. Briefly, test articles were captured on Fc-coated plates and then detected using a HRP-conjugated anti-human IgG-Fc antibody. Protein concentrations were calculated in GraphPad Prism using 4PL non-linear regression of the C220S/YTE Fc conjugate or C220S conjugate standard curves.
  • Example 40.14-day mouse PK study comparing plasma and epithelial lining fluid (ELF) concentrations of a conjugate including an Fc domain Female BALB/c mice from Charles River Laboratories were allowed to acclimate for 5 days prior to study commencement. Animals were housed 3-6 per cage with free access to food and water. All procedures were performed to NeoSome IACUC policies and guidelines. Mice were injected subcutaneously (SC) with 20 mg/kg of a conjugate having an Fc domain (SEQ ID NO: 73) decorated with one or more small molecule antiviral inhibitors (10 mL/kg dose volume). At selected time points, 3 mice were euthanized by CO2 inhalation.
  • SC subcutaneously
  • SEQ ID NO: 73 Fc domain
  • small molecule antiviral inhibitors 10 mL/kg dose volume
  • a bronchoalveolar lavage was performed by exposing the trachea, inserting a 23G tubing adaptor, and performing 2 x 0.5 mL flushes with sterile 1X PBS pH 7.4. The recovered fluid volume was recorded and retained. Once the BAL procedure was complete, the lungs were removed, weighed and stored at -80 ⁇ C. Aliquots of the plasma and BAL fluid (BALF) were decanted prior to -80 ⁇ C storage of the samples for use in a urea quantification assay.
  • BAL bronchoalveolar lavage
  • ELF volume and conjugate concentration in ELF was determined using urea as a dilution marker as described previously (Rennard et al., 1986 J Appl Physiol 60:532-538).
  • the curves comparing conjugate to ELF levels are shown in FIG. 14.
  • conjugate epithelial lining fluid (ELF) levels are ⁇ 60% of plasma exposure levels (AUCs) across the rest of the time course indicating nearly immediate partitioning of conjugate 45 from plasma to the ELF in the lung (FIG.14, Table 8).
  • Step c A solution of product from the previous step b (1.10 g, 2.54 mmol) dissolved in ethanol (3 mL), was treated with 40% aqueous methyl amine (3 mL) and heated in 70 °C oil bath for 1h, at which time LCMS show complete consumption of starting material. The reaction was concentrated by rotary evaporation, then stored under high vacuum overnight, and used as mixture of N-methyl-phthalimide and desired product in the next step without further purification. Step d.
  • step e A mixture of the product from step d, 5-chloro-2-fluoronitrobenzene (210 mg, 1.2 mmol), and K 2 CO 3 (496 mg, 3.6 mmol) in dry acetonitrile was heated at 70 °C for 2 hours.
  • the Boc protected intermediate was stirred in 4N HCl in dioxane (25 mL) at ambient temperature for 30 minutes. The solvent was removed on the rotary evaporator, azeotroped with toluene (3x, 10 mL), and dried under high vacuum to afford the product as a yellow oil. Yield 69%, 3 steps.
  • LC/MS [M+H] + 338.2.
  • Example 56 Synthesis of Int-36
  • the product of Example 49 (66 mg, 0.23 mmol), the intermediate from step c. of Example 55 (Synthesis of Int-43) (120 mg, 0.23 mmol), and cesium carbonate (75 mg, 0.23 mmol) were stirred together in DMF (2 mL) at ambient temperature for 12 hours.
  • Step c To crude 1-[(5-chloro-1- ⁇ 3-[(2- ⁇ 2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy ⁇ ethyl) sulfonyl]propyl ⁇ benzimidazol-2-yl)methyl]spiro[2-pyrrolino[2,3-c]pyridine-3,4'-piperidine]-2-one (25 mg, 0.040 mmol assuming 100% yield) in DMF (5 mL) was added Boc-Thr-OH (10 mg, 0.05 mmol) followed by Hünigs base (2 drops).
  • Example 61 Synthesis of Int-37 4N HCl in Dioxane (6 mL) was added to N-(1-((1R)-1-hydroxyethyl)(1S)-2- ⁇ 1-[(5-chloro-1- ⁇ 3-[(2- ⁇ 2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy ⁇ ethyl)sulfonyl]propyl ⁇ benzimidazol-2-yl)methyl]-2-oxospiro[2- pyrrolino[2,3-c]pyridine-3,4'-piperidine]-10-yl ⁇ -2-oxoethyl)(tert-butoxy)carboxamide (15 mg, 0.020 mmol, described in Example 59, Int-43) and the solution was stirred for 1h.
  • Example 62 Synthesis of Int-38 The title compound was prepared analogously to Example 61 (Int-37) from crude (tert-butoxy)-N-(2- ⁇ 1-[(5- chloro-1- ⁇ 3-[(2- ⁇ 2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy ⁇ ethyl) sulfonyl]propyl ⁇ benzimidazol-2- yl)methyl]-2-oxospiro[2-pyrrolino[2,3-c]pyridine-3,4'-piperidine]-10-yl ⁇ -2-oxoethyl)carboxamide (described in Example 60, Int-45).
  • Step b The product from step-a (1.4 g, 4.01 mmol) in anhydrous THF (8.5 mL) at 0 °C under Nitrogen was treated with BH3-THF (1M, 12 mL, 12.02 mmol). The reaction mixture was stirred at 0 °C for 1 hour then the ice bath was removed and stirred for another 30 minutes. It was quenched with methanol before the reaction completed.
  • Step c To a solution of the product from step-b (608.34 mg, 1.35 mmol) in anhydrous THF (5 mL) under nitrogen was added triethylamine (0.59 mL, 4.21 mmol). The resulting solution was cooled down to 10 °C then 6-methyl-2,4-dichloroquinazoline (280 mg, 1.31 mmol) was added slowly to keep the reaction temperature below 30 C.
  • Example 66 Synthesis of Int-31
  • the product from step-c of Example 65 (Int-30) (217.4 mg, 0.27 mmol), propagyl-PEG8-bromide (140.6 mg, .029 mmol), potassium carbonate (91.8 mg, 0.66 mmol) and NaI (3.98 mg, 0.027 mmol) in acetonitrile (4 mL) was heated 80 °C for 16 hours.
  • the reaction mixture was filtered then purified by RPLC (ACCQ, 0% to 40% acetonitrile and water, using 0.1%TFA as modifier). Yield 147.0 mg, 51.4%.
  • Step b The product from the previous step (370.4 mg, 1.82 mmol) was dissolved in DCM (5 mL) at 0 °C was added 2-chloro-1,1,1-trimethoxyethane (1.75 mL, 12.7 mmol) and concentrated aqueous HCl (0.23 mL, 2.73 mmol).
  • Step b To a solution of product from the previous step (0.52 g, 2.09 mmol) in MeOH:ethyl acetate:THF (1:1:1, 42 mL) at room temperature was charged with Raney Nickel as suspension in isopropanol (2.0 g, 34.08 mmol, previously rinsed with isopropanol) and hydrogen gas balloon. The resulting mixture was stirred for 16 hours then filtered through a pad of celite.
  • Step c The product from the previous step (534.4 mg, 2.44 mmol) was dissolved in DCM (12 mL) at 0 °C was added 2-chloro-1,1,1-trimethoxyethane (2.0 mL, 14.6 mmol) and concentrated aqueous HCl (0.3 mL, 3.66 mmol). The ice bath was removed and the reaction mixture was stirred at 0 °C until completion. The reaction mixture was poured into saturated NaHCO 3 aqueous then extracted with DCM.
  • Example 69 Synthesis of Int-48 Step a.
  • Step b The step-a product (1.1 g, 1.852 mmol) in DCM (7 ml) was treated with TFA (3 ml). The solution was stirred at room temperature for 6 hours. It was then concentrated and purified by RPLC (100 g, 5 to 100% acetonitrile and water). Yield 961 mg as TFA salt, 96.4%.
  • LCMS: [M + H] + 425.0. Step c.
  • Step d To a solution of the step-c product (271.7 mg, 0.253 mmol) in DCM (2 ml) was added TFA (0.5 ml), thioanisole (0.2 ml) and bromotrimethylsilane (0.2 ml). The reaction mixture was stirred at room temperature for 3 hours. It was then concentrated by rotary evaporation and purified by RPLC (100 g, 5 to 60% acetonitrile and water). Yield 152.8 mg, 84.6%.
  • Example 71 Synthesis of Int-50 To a solution of starting material (prepared as described in WO 201406411, 30 mg, 0.0627 mmol) and the product of Example 50 (1-[4-(prop-2-yn-1-yl)piperazin-1-yl]-3,6,9,12-tetraoxapentadecan-15-oic acid , 60 mg, 0.135 mmol) in anhydrous DMF (0.5 ml) was added DIPEA (65 mg, 0.5 mmol) and HATU (38 mg, 01 mmol).
  • step-a product (4.8 g, 13.5 mmol) in anhydrous DMF (15 ml) was added Cs2CO 3 (11 g, 33.75 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then treated with the step-b product in benzene (15 ml). After the reaction was stirred for 2 hours, it was extracted with water (100 ml) and Ethyl acetate (100 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (220g, 10 to 50% ethyl acetate in DCM). Yield 4.2 g, 70.2%.
  • Step d A flame-dried reaction flask was purged with nitrogen and charged with the step-c product (3.15 g, 7.41 mmol), sodium tert-butoxide (1.07 g, 11.1 mmol), Pd(II) acetate (499.1 mg, 2.223 mmol), tricyclohexyl phosphine (626.1 mg, 2.223 mmol) and dioxane (14 ml). The resulting mixture was heated at 100 °C under nitrogen for 2 hours. After cooling to room temperature, it was diluted with saturated solution of ammonium chloride (70 ml) and extracted with DCM (100 ml x 4).
  • Step f To a solution of propargyl-PEG4 acid (286.3 mg, 1.1 mmol) in anhydrous DMF (1.5 ml) was added HATU (456 mg, 1.2 mmol) and DIEA (426.7 mg, 3.3 mmol). After stirring for 5 minutes, the reaction mixture was added to a solution of the step-e product (397.9 mg, 1 mmol) in DMF (1 ml). The resulting mixture was stirred for 30 minutes, then directly purified by RPLC (5 to 70% acetonitrile and water, using 0.1% TFA as modifier).
  • Step g A solution of the step-f product (361.3 mg, 0.53 mmol) in acetonitrile (3 ml) was cooled in an ice- water bath and added with a pre-cooled solution of ceric ammonium nitrate(CAN) (350.9 mg, 0.64 mmol) in water (1 ml) and additional water (0.5 ml x 3), which is used to rinsed the CAN glassware. The resulting mixture was stirred at room temperature for 2 hours. It was cooled back in an ice-water bath and mixed with additional CAN (116.2 mg, 0.212 mmol). The reaction was continued at room temperature for two more hours.

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Abstract

Des compositions et des méthodes pour le traitement d'infections virales comprennent des conjugués contenant des inhibiteurs de la protéine F du virus VRS (par exemple, Presatovir, MDT 637, JNJ 179, TMC353121, Zirésovir ou un analogue de ceux-ci) liés à un monomère Fc, un domaine Fc et un peptide de liaison à Fc, une protéine d'albumine, ou un peptide de liaison à l'albumine. En particulier, les conjugués peuvent être utilisés dans le traitement d'infections virales (par exemple, des infections par le VRS).
EP20863252.1A 2019-09-09 2020-09-09 Compositions et méthodes pour le traitement du virus respiratoire syncytial Withdrawn EP4028392A1 (fr)

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TW202220698A (zh) 2020-08-06 2022-06-01 美商席達拉醫療有限公司 蛋白質－藥物結合物之合成方法
WO2023125806A1 (fr) * 2021-12-30 2023-07-06 苏州爱科百发生物医药技术有限公司 Conjugué pour la prévention et le traitement d'infections virales et son utilisation

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SI1196408T1 (en) * 1999-06-28 2005-02-28 Janssen Pharmaceutica N.V. Respiratory syncytial virus replication inhibitors
WO2004014316A2 (fr) * 2002-08-09 2004-02-19 Viropharma Incorporated Composes, compositions et techniques de traitement et de prevention de l'infection par des pneumovirus et de maladies associees
BRPI0615354A2 (pt) * 2005-08-19 2011-05-17 Endocyte Inc conjugado de liberação de fármaco de ligação de receptor, composição farmacêutica que o compreende, bem como seu uso
AU2011270798B2 (en) * 2010-06-24 2015-03-19 Gilead Sciences, Inc. Pyrazolo [1, 5 -a] pyrimidines as antiviral agents
US8871756B2 (en) * 2011-08-11 2014-10-28 Hoffmann-La Roche Inc. Compounds for the treatment and prophylaxis of Respiratory Syncytial Virus disease
HUE033476T2 (en) * 2012-10-16 2017-12-28 Janssen Sciences Ireland Uc Anti-RSV Antibodies
RU2016105970A (ru) * 2013-08-12 2017-09-19 Ф. Хоффманн-Ля Рош Аг Новые азаоксоиндолы для лечения и профилактики инфекции респираторного синцитиального вируса
CN105408330A (zh) * 2013-08-12 2016-03-16 豪夫迈·罗氏有限公司 新的用于治疗和预防呼吸道合胞病毒感染的氮杂-氧代-吲哚

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JP2022547538A (ja) 2022-11-14
WO2021050612A1 (fr) 2021-03-18
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AU2020345850A1 (en) 2022-04-28
CN114728937A (zh) 2022-07-08

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