Compositions and methods for treating viral infections

Abstract

Compositions and methods for treating viral infections include conjugates comprising a viral neuraminidase inhibitor (e.g., zanamivir, peramivir, or an analog thereof) linked to an Fc monomer, an Fc domain, an Fc binding peptide, an albumin protein, or an albumin binding peptide. In particular, the conjugates are useful in the treatment of viral infections (e.g., influenza virus infections).

Description

[0001] This application is a divisional application of the invention patent with an application date of September 8, 2020, application number 202080077368.1, and invention name “Compositions and methods for treating viral infections”. Background Art

[0002] The demand for novel antiviral treatments for influenza is significant and particularly crucial in the medical field. Influenza virus (the causative agent of influenza) or influenza causes three to five million cases of severe illness each year and approximately 500,000 deaths worldwide. Although most people recover completely from influenza in about one to two weeks, others develop life-threatening complications such as pneumonia. Therefore, influenza can be fatal, especially for young people, the elderly or chronic patients. People with weak or compromised immune systems, such as those with advanced HIV infection or transplant patients (whose immune systems are medically suppressed to prevent transplant rejection), are at greater risk of complications associated with influenza. Pregnant women and young children are also at high risk of complications.

[0003] The development of antiviral treatments for influenza has been an ongoing challenge. Several influenza antiviral agents have been approved for clinical use, and when used in vaccines, these agents play an important role in modulating disease severity and controlling epidemics. However, resistant strains have emerged against the most commonly used inhibitors.

[0004] Flu antivirals primarily target proteins presented on the surface of influenza virus particles. The envelope of the influenza virus contains two immunodominant glycoproteins, hemagglutinin and neuraminidase, which play a key role in viral infection and spread. Hemagglutinin enables the virus to attach to host cells via its interaction with surface sialic acid, thereby beginning to enter. Neuraminidase is an exoglycosidase that cleaves sialic acid (terminal neuraminidase residues) in the glycan structure on the surface of infected host cells, thereby releasing progeny viruses and allowing the virus to spread from the host cell to uninfected surrounding cells. The inhibition of neuraminidase therefore serves as a pharmacological target for antiviral drugs. Viral neuraminidase inhibitors for reducing viral spread have been identified, including oseltamivir (Tamiflu) and seletamivir (Seltamivir). TM ), zanamivir (Relenza TM ) and peramivir (Rapivab TM ).

[0005] However, influenza in transplant recipients is still characterized by prolonged viral shielding, increasing the likelihood of developing drug-resistant strains. New, more effective therapies for the treatment of influenza are needed. Summary of the Invention

[0006] The present disclosure relates to conjugates, compositions and methods for inhibiting viral growth, and methods for treating viral infections. Specifically, the conjugate contains a monomer or dimer of a portion (e.g., zanamivir, peramivir or its analogue) that inhibits influenza virus neuraminidase, which is conjugated to an Fc monomer, an Fc domain, an Fc binding peptide, albumin or an albumin binding peptide. The neuraminidase inhibitor (e.g., zanamivir, peramivir or its analogue) in the conjugate targets the neuraminidase on the surface of the virion. The Fc monomer or Fc domain in the conjugate binds to FcγR (e.g., FcRn, FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa and FcγRIIIb) on immune cells (e.g., neutrophils) to activate phagocytosis and effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), thereby causing immune cells to engulf and destroy virions and further enhance the antiviral activity of the conjugate. The albumin or albumin binding peptide can extend the half-life of the conjugate, for example by binding the albumin to the recycling neonatal Fc receptor. The composition can be used in methods of inhibiting viral growth and methods of treating viral infections such as those caused by influenza virus A, influenza virus B, and influenza virus C.

[0007] In a first aspect, the present invention provides a conjugate described by any one of the following: formula (DI), (MI), (1) or (2)

[0008]

[0009] wherein each A1 and each A2 are independently selected from any one of formulas (AI)-(A-XII):

[0010]

[0011] wherein R1 is selected from -OH, -NH2, -NHC(=NH)NH2 and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5 is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0012]

[0013] R6 is selected from

[0014] R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; R8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl and C2-C15 heteroaryl;

[0015] n is 1 or 2;

[0016] Each E comprises an Fc domain monomer, albumin, an albumin-binding peptide, or an Fc-binding peptide;

[0017] L is a linker covalently attached to E and to each A1 or each Y of each A1 and A2;

[0018] T is an integer from 1 to 20, and

[0019] Each wavy line in formula (DI), (MI), (1), or (2) indicates that L is covalently attached to each E;

[0020] or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, n is 1 and each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 139-141), an albumin binding peptide, or an Fc binding peptide;

[0022] In some embodiments, n is 2 and each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), wherein the Fc domain monomers dimerize to form an Fc domain;

[0023] L is a linker covalently attached to each E and to each Y or each A1 and / or A2;

[0024] 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 each wavy line in Formula (DI), (MI), (1), or (2) indicates that L is covalently attached (e.g., by means of a covalent bond or a linker) to each E; or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L or each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L or A1-L-A2 structures described herein).

[0025] In preferred embodiments of any aspect described herein, n is 2 and each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138). In a conjugate having two Fc domain monomers (e.g., a conjugate of Formula (1), Formula (2), Formula (DI) (wherein n is 2), or Formula (MI) (wherein n is 2), the Fc domain monomers dimerize to form an Fc domain.

[0026] In another aspect, the present invention provides a conjugate described by the following formula (DI)

[0027]

[0028] wherein each E comprises 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 A1-L-A2 is a linker covalently attached to the sulfur atom of the hinge cysteine ​​in E and attached to each of A1 and A2; n is 1 or 2 (e.g., when n is 2, two Fc domain monomers dimerize to form an 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 wavy line connected to E indicates that each A1-L-A2 is covalently attached (e.g., by means of a covalent bond or a linker) to the sulfur atom of the hinge cysteine ​​in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any one of the A1-L-A2 structures described herein).

[0029] In another aspect, the present invention provides a conjugate described by the following formula (DI)

[0030]

[0031] wherein each E comprises 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 A1-L-A2 is a linker covalently attached to a nitrogen atom of a surface-exposed lysine in E and to each of A1 and A2; n is 1 or 2 (e.g., when n is 2, two Fc domain monomers dimerize to form an 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 wavy line connected to E indicates that each A1-L-A2 is covalently attached (e.g., by a covalent bond or a linker) to a nitrogen atom of a surface-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein). In some embodiments, each of A1 and A2 can be independently selected from any of Formula (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1 and A2 can be independently selected from Formula (AI).

[0032] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0033]

[0034] wherein each E comprises 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-A1 is a linker that is covalently attached to the sulfur atom of the hinge cysteine ​​in E and attached to A1; n is 1 or 2 (e.g., when n is 2, two Fc domain monomers dimerize to form an 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 wavy line connected to E indicates that each L-A1 is covalently attached (e.g., by means of a covalent bond or a linker) to the sulfur atom of the hinge cysteine ​​in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any structure described by Formula (AI)-(A-XII). In some embodiments, each A1 can be independently selected from any of Formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each A1 can be independently selected from Formula (AI).

[0035] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0036]

[0037] wherein each E comprises an Fc domain monomer (e.g., an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138); L in each L-A1 is a linker covalently attached to a nitrogen atom of a surface-exposed lysine in E and to A1; n is 1 or 2 (e.g., when n is 2, two Fc domain monomers dimerize to form an 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 wavy line connected to E indicates that each L-A1 is covalently attached (e.g., by a covalent bond or a linker) to a nitrogen atom of a surface-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any structure described by Formula (AI)-(A-XII). In some embodiments, each A1 can be independently selected from any of Formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each A1 can be independently selected from Formula (AI).

[0038] In one aspect, the present disclosure provides a conjugate described by: Formula (1)

[0039]

[0040] wherein each A1 and each A2 are independently selected from any one of formulas (AI)-(A-XII);

[0041] Each E comprises 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 A1-L-A2 is a linker covalently attached to the sulfur atom of the hinge cysteine ​​in each E and to each of A1 and A2; 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 wavy lines connected to two E indicate that each A1-L-A2 is covalently attached (e.g., by means of a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein). In some embodiments, each of A1 and A2 can be independently selected from any of Formula (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1, A2 can be independently selected from Formula (AI).

[0042] In another aspect, the present disclosure provides a conjugate described by the following formula (1)

[0043]

[0044] wherein each A1 and each A2 is independently selected from any one of Formulae (AI)-(AV); each E comprises 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 A1-L-A2 is a linker covalently attached to the sulfur atom of the hinge cysteines in each E and to each of A1 and A2; 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 wavy lines connected to two E indicate that each A1-L-A2 is covalently attached (e.g., by a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any one of the A1-L-A2 structures described herein).

[0045] In another aspect, the present disclosure provides a conjugate described by the following formula (1)

[0046]

[0047] wherein each A1 and each A2 are independently selected from any one of formulas (A-VI) to (A-IX);

[0048] Each E comprises 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 A1-L-A2 is a linker covalently attached to the sulfur atom of the hinge cysteine ​​in each E and to each of A1 and A2; 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 wavy lines connected to two E indicate that each A1-L-A2 is covalently attached (e.g., by means of a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any one of the A1-L-A2 structures described herein).

[0049] In another aspect, the present invention provides a conjugate described by the following formula (2)

[0050]

[0051] wherein each A1 is independently selected from any one of Formulas (AI)-(A-XII); each E comprises 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-A1 is a linker covalently attached to the sulfur atoms in the hinge cysteines in E and to A1; 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 two wavy lines connected to two sulfur atoms indicate that each L-A1 is covalently attached (e.g., by means of a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of Formulas (AI)-(A-XII). In some embodiments, each of A1 and A2 can be independently selected from any one of Formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1 and A2 can be independently selected from Formula (AI).

[0052] In another aspect, the present invention provides a conjugate described by the following formula (2)

[0053]

[0054] wherein each A1 is independently selected from any one of Formulae (AI)-(AV); each E comprises 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-A1 is a linker covalently attached to the sulfur atoms in the hinge cysteines in E and to A1; 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 two wavy lines connected to two sulfur atoms indicate that each L-A1 is covalently attached (e.g., by means of a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (eg, T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of Formulae (AI)-(AV).

[0055] In another aspect, the present invention provides a conjugate described by the following formula (2)

[0056]

[0057] wherein each A1 is independently selected from any one of Formulas (A-VI)-(A-IX); each E comprises 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-A1 is a linker covalently attached to the sulfur atoms in the hinge cysteines in E and to A1; 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 two wavy lines connected to two sulfur atoms indicate that each L-A1 is covalently attached (e.g., by means of a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (eg, T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of Formulae (A-VI) to (A-IX).

[0058] In some embodiments of any of the preceding embodiments, each E comprises an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138.

[0059] In some embodiments, at least one of the pair of sulfur atoms is a sulfur atom corresponding to (e.g., a sulfur atom of) a hinge cysteine ​​of SEQ ID NO: 10 or SEQ ID NO: 11 (i.e., Cys10, Cys13, Cys16, or Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 and Cys13 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys10 and Cys16 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys30 and Cys18 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and Cys36 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and Cys38 in SEQ ID NO: 10 or SEQ ID NO: 11, and / or Cys36 and Cys38 in SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., sulfur atoms thereof).

[0060] In some embodiments, when T is 2, the sulfur atom pair is Cys10 and Cys13 in SEQ ID NO: 10 or SEQ ID NO: 11 or Cys36 and Cys38 in SEQ ID NO: 10 or SEQ ID NO: 11 (eg, the sulfur atoms corresponding thereto).

[0061] In some embodiments, the sulfur atom pair comprises one sulfur atom from the cysteine ​​of each E, i.e., LA together with the sulfur atom to which it is attached forms a bridge between two Fc domains (e.g., two Fc domains comprising the sequence of SEQ ID NO: 10 or SEQ ID NO: 11). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0062] In some embodiments, when T is 2, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, when T is 2, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, when T is 2, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0063] In some embodiments, when T is 2, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, when T is 2, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0064] In some embodiments, when T is 2, the sulfur atom pair is a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0065] In some embodiments, when T is 3, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, when T is 3, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.In some embodiments, when T is 3, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, when T is 3, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys18 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0066] In some embodiments, when T is 3, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and a sulfur atom corresponding to Cys16 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E. The sulfur atom of Cys18 (eg, the sulfur atom thereof) of SEQ ID NO: 11 and the sulfur atom corresponding to Cys18 (eg, the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0067] In some embodiments, the conjugate has the following structure:

[0068]

[0069] wherein a, b, c and d are each independently 0 or 1 and wherein when a, b, c or d is 0, the two sulfur atoms form a disulfide bond.

[0070] In some embodiments, a is 1 and b, c, and d are 0. In some embodiments, a and b are 1 and c and d are 0. In some embodiments, a and c are 1 and b and d are 0. In some embodiments, a and d are 1 and b and d are 0. In some embodiments, a, b, and c are 1 and d is 0. In some embodiments, a, b, and d are 1 and c is 0. In some embodiments, a, c, and d are 1 and b is 0. In some embodiments, b and c are 1 and a and d are 0. In some embodiments, b and d are 1 and a and c are 0. In some embodiments, b, c, and d are 1 and a is 0. In some embodiments, c and d are 1 and a and b are 0. In some embodiments, a, b, c, and d are 1.

[0071] In some embodiments, each E comprises the sequence

[0072] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:4).

[0073] In some embodiments, each E comprises the sequence

[0074] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:33).

[0075] In some embodiments, at least one of the sulfur atom pair is a sulfur atom corresponding to (e.g., the sulfur atoms thereof) the hinge cysteines (i.e., Cys10 and / or Cys13) of SEQ ID NO: 4 or SEQ ID NO: 33. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to (e.g., the sulfur atoms thereof) Cys10 and Cys13 of SEQ ID NO: 4 or SEQ ID NO: 33.

[0076] In some embodiments, the sulfur atom pair comprises one sulfur atom from the cysteine ​​of each E, i.e., LA together with the sulfur atom to which it is attached forms a bridge between two Fc domains (e.g., two Fc domains comprising the sequence of SEQ ID NO: 4 or SEQ ID NO: 33). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 4 or SEQ ID NO: 33 from another E. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 4 or SEQ ID NO: 33 from another E. In some embodiments, when T is 2, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 4 or SEQ ID NO: 33 from another E, and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 4 or SEQ ID NO: 33 from another E.

[0077] In some embodiments, the conjugate has the following structure:

[0078]

[0079] wherein a and b are each independently 0 or 1 and wherein when a or b is 0, the two sulfur atoms form a disulfide bond. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0080] In some embodiments, at least one of the sulfur atom pair is a sulfur atom corresponding to (e.g., the sulfur atoms thereof) the hinge cysteines (i.e., Cys10 and / or Cys13) of SEQ ID NO: 8. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to (e.g., the sulfur atoms thereof) Cys10 and Cys13 in SEQ ID NO: 8.

[0081] In some embodiments, the sulfur atom pair comprises one sulfur atom from the cysteine ​​of each E, i.e., LA together with the sulfur atom to which it is attached forms a bridge between two Fc domains (e.g., two Fc domains comprising the sequence of SEQ ID NO: 8). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 8 from another E. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 8 from another E. In some embodiments, when T is 2, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys10 (e.g., a sulfur atom thereof) of SEQ ID NO: 8 from another E, and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys13 (e.g., a sulfur atom thereof) of SEQ ID NO: 8 from another E.

[0082] In some embodiments, the conjugate has the following structure:

[0083]

[0084] wherein a and b are each independently 0 or 1 and wherein when a or b is 0, the two sulfur atoms form a disulfide bond. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0085] In some embodiments, the conjugate has the following structure:

[0086]

[0087] wherein a and b are each independently 0 or 1 and wherein when a or b is 0, the two sulfur atoms form a disulfide bond. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0088] In some embodiments, the conjugate has the following structure:

[0089]

[0090] wherein a and b are each independently 0 or 1 and wherein when a or b is 0, the two sulfur atoms form a disulfide bond. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0091] In some embodiments, the conjugate has the following structure:

[0092]

[0093] wherein a and b are each independently 0 or 1 and wherein when a or b is 0, the sulfur atom is a thiol. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0094] In some embodiments of the previous three aspects, the nitrogen atom is a surface-exposed lysine nitrogen, such as a nitrogen atom corresponding to Lys35, Lys63, Lys77, Lys79, Lys106, Lys123, Lys129, Lys181, Lys203, Lys228, or Lys236 (e.g., a nitrogen atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11. In some embodiments, the nitrogen atom is a nitrogen atom corresponding to Lys65, Lys79, Lys108, Lys230, and / or Lys238 (e.g., a nitrogen atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11.

[0095] In some embodiments, the conjugate has the following structure:

[0096]

[0097] wherein a, b, c, d, and e are each independently 0 or 1 and wherein when a, b, c, d, or e is 0, the two nitrogen atoms are NH2. In some embodiments, a is 1 and b, c, d, and e are 0. In some embodiments, b is 1 and a, c, d, and e are 0. In some embodiments, c is 1 and a, b, d, and e are 0. In some embodiments, d is 1 and a, b, c, and e are 0. In some embodiments, e is 1 and a, b, c, and d are 0. In some embodiments, a and b are 1 and c, d, and e are 0. In some embodiments, a and c are 1 and b, d, and e are 0. In some embodiments, a and d are 1 and b, c, and e are 0. In some embodiments, a and e are 1 and b, c, and d are 0. In some embodiments, b and c are 1 and a, d, and e are 0. In some embodiments, b and d are 1 and a, c, and e are 0. In some embodiments, b and e are 1 and a, c, and d are 0. In some embodiments, c and d are 1 and a, b, and e are 0. In some embodiments, c and e are 1 and a, b, and d are 0. In some embodiments, d and e are 1 and a, b, and c are 0. In some embodiments, a, b, and c are 1 and d and e are 0. In some embodiments, a, b, and d are 1 and c and e are 0. In some embodiments, a, b, and e are 1 and c and d are 0. In some embodiments, a, c, and d are 1 and b and e are 0. In some embodiments, a, c, and d are 1 and b and e are 0. In some embodiments, a, c, and e are 1 and b and d are 0. In some embodiments, a, d, and e are 1 and b and c are 0. In some embodiments, b, c, and d are 1 and a and e are 0. In some embodiments, b, d, and e are 1 and a and c are 0. In some embodiments, c, d, and e are 1 and a and b are 0.

[0098] In some embodiments of any of the conjugates described herein, the conjugate forms a homodimer including an Fc domain. In some embodiments of the conjugates described herein, E homodimerizes with another E to form an Fc domain.

[0099] In another aspect, the present invention provides a conjugate described by: (DI)

[0100]

[0101] wherein E comprises an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 139-141), an albumin-binding peptide, or an Fc-binding peptide; L in each A1-L-A2 is a linker that is independently covalently attached to a sulfur atom of a surface-exposed cysteine ​​or a nitrogen atom of a surface-exposed lysine in E and is attached to each of A1 and A2; n is 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 wavy line connected to E indicates that each A1-L-A2 is independently covalently attached to a sulfur atom of a solvent-exposed cysteine ​​or a nitrogen atom of a solvent-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein). In some embodiments, each of A1, A2 can be independently selected from any of Formula (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1, A2 can be independently selected from Formula (AI).

[0102] In the above preferred embodiment, x is 2.

[0103] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0104]

[0105] wherein E comprises an albumin (e.g., an albumin having a sequence of any one of SEQ ID NOs: 139-141), an albumin-binding peptide, or an Fc-binding peptide; L in each L-A1 is a linker that is independently covalently attached to a sulfur atom of a surface-exposed cysteine ​​or a nitrogen atom of a surface-exposed lysine in E and is attached to A1; n is 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 wavy line connected to E indicates that each L-A1 is independently covalently attached to a sulfur atom of a solvent-exposed cysteine ​​or a nitrogen atom of a solvent-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any structure described by formula (AI)-(A-XII). In some embodiments, each A1 can be independently selected from any one of formula (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each A1 can be independently selected from formula (AI). In the preferred embodiment above, x is 2.

[0106] In some embodiments, each E comprises an albumin having the sequence of any one of SEQ ID NOs: 139-141.

[0107] In some embodiments, T is 1 and L-A1 is covalently attached to the sulfur atom corresponding to Cys34 of SEQ ID NO:139.

[0108] The intermediates of Table 1a can be conjugated to an Fc domain or Fc domain monomer (e.g., via a linker) by any suitable method known to those skilled in the art, including any method described or exemplified herein. In some embodiments, the conjugate (e.g., a conjugate described by any of Formulas (1), (2), (DI)-(D-XI), or (MI)-(M-XI)) includes E, wherein E is an Fc domain monomer or Fc domain (e.g., an Fc domain monomer or Fc domain, each Fc domain monomer independently having a sequence of any one of SEQ ID NOs: 1-138). In preferred embodiments, 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 are covalently conjugated to a linker (e.g., PEG2-PEG 20Linker). The linker conjugated to E can be functionalized so that it can react to form a covalent bond with any of the Int described herein (e.g., Int of Table 1a). In a preferred embodiment, E is conjugated to an azide-functionalized linker and Int (e.g., Int of Table 1a) is functionalized with an alkynyl group. The linker-azido of E and the linker-alkyne of Int are conjugated (e.g., by click chemistry) to form a conjugate of the invention, such as the conjugate described by formula (5). In yet other embodiments, E is conjugated to an alkynyl-functionalized linker and Int (e.g., Int of Table 1a) is functionalized with an azide group. The linker-alkyne of E and the linker-azido of Int are conjugated (e.g., by click chemistry; see, e.g., Figure 103 ) to form a conjugate of the invention, such as a conjugate described by any of formulas (1), (2), (DI)-(D-XI), or (MI)-(M-XI).

[0109] Table 1a: Intermediates

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124] In another aspect, the present invention provides conjugates of Table 1b. As shown, each conjugate of Table 1b corresponds to a conjugate of formula (MI) or formula (DI). The conjugates of Table 1b include conjugates formed by the covalent reaction of Int of Table 1a with a linker, which in turn is conjugated to E (e.g., an Fc domain monomer, albumin, an albumin-binding peptide, or an Fc-binding peptide). In some embodiments, the reactive portion of Int (e.g., an alkyne or an azide) reacts with a corresponding reactive group (e.g., an alkyne or an azide) of a linker (represented by L') covalently attached to E, such that Int of Table 1a is covalently attached to E. As shown in Table 1b, L' corresponds to the remainder of L as defined in (MI) or (DI) (e.g., L' is a linker that covalently joins Int and E). For example, L' may include a triazole (formed by a click chemistry reaction between Int and a linker conjugated to E) and a linker (e.g., PEG2-PEG 20 linker), which in turn is conjugated to the amino acid side chains of E (see, e.g., Figure 103 ).

[0125] In some embodiments of the conjugates of Table 1b, n is 1 or 2. When n is 1, each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 139-141), an albumin-binding peptide, or an Fc-binding peptide. When n is 2, each E comprises 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 an Fc domain.

[0126] In some embodiments of any of the conjugates of Table 1b, 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 present disclosure also provides a population of any of the conjugates of Table 2, wherein the average value of T is from 1 to 20 (e.g., the average value of T is from 1 to 2, from 1 to 3, from 1 to 4, from 1 to 5, from 5 to 10, from 10 to 15, from 15 to 20, from 1.5 to 3.5, from 2.5 to 4.5, from 3.5 to 5.5, from 4.5 to 6.5, from 5.5 to 7.5, from 6.5 to 8.5, from 7.5 to 9.5, or from 8.5 to 10.5). In some embodiments, the average value of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, the average T is between 1 and 10 (e.g., 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10). In certain embodiments, the average T is 1 to 5 (e.g., 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5). In some embodiments, the average T is between 5 and 10 (e.g., 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10). In some embodiments, the average T is between 2.5 and 7.5 (e.g., 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, or 7.5).

[0127] The wavy lines in the conjugates of Table 1b indicate that each L'-Int is covalently attached to an amino acid side chain in E (eg, a nitrogen atom of a surface-exposed lysine or a sulfur atom of a surface-exposed cysteine ​​in E), or a pharmaceutically acceptable salt thereof.

[0128] Table 1b: Conjugates corresponding to the intermediates in Table 1a

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151] In some embodiments, each E comprises an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138. In other embodiments, each E comprises an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64. In other embodiments, each E comprises an Fc domain monomer having an amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64. In other embodiments, each E comprises an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 67 or SEQ ID NO: 68. In other embodiments, each E comprises an Fc domain monomer having an amino acid sequence of SEQ ID NO: 67 or SEQ ID NO: 68. In other embodiments, each E comprises an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 72 or SEQ ID NO: 73. In other embodiments, each E comprises an Fc domain monomer having an amino acid sequence of SEQ ID NO: 72 or SEQ ID NO: 73. In other embodiments, each E comprises an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 76 or SEQ ID NO: 77. In other embodiments, each E comprises an Fc domain monomer having an amino acid sequence of SEQ ID NO: 76 or SEQ ID NO: 77. In other embodiments, each E comprises 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 comprises an Fc domain monomer having an amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 82. In other embodiments, each E comprises 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 comprises an Fc domain monomer having an amino acid sequence of SEQ ID NO: 85 or SEQ ID NO: 86.

[0152] In another aspect, the present invention provides a conjugate comprising (i) a first moiety A1; (ii) a second moiety A2; (iii) an Fc domain monomer or an Fc domain; and (iv) a linker covalently attached to A1 and A2 and attached to the Fc domain monomer or the Fc domain; wherein each A1 and each A2 is independently selected from any one of Formulas (AI)-(A-XII). In some embodiments, each of A1 and A2 can be independently selected from any one of Formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1 and A2 can be independently selected from Formula (AI). In preferred embodiments above, x is 2.

[0153] In another aspect, the present invention provides a conjugate comprising (i) a first portion Int; (ii) an Fc domain monomer or an Fc domain; and (iv) a linker covalently attached to Int and to the Fc domain monomer or the Fc domain; wherein each Int is independently selected from any one of the intermediates of Table 1a.

[0154] In another aspect, the present invention provides a conjugate comprising (i) a first moiety A1; (ii) a second moiety A2; (iii) albumin, an albumin-binding peptide, or an Fc-binding peptide; and (iv) a linker covalently attached to A1 and A2 and to the albumin, the albumin-binding peptide, or the Fc-binding peptide; wherein each A1 and each A2 is independently selected from any one of Formulas (AI)-(A-XII). In some embodiments, each of A1 and A2 can be independently selected from any one of Formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1 and A2 can be independently selected from Formula (AI). In preferred embodiments above, x is 2.

[0155] In another aspect, the present invention provides a conjugate described by the following formula (DI)

[0156]

[0157] wherein each A1 and each A2 is independently selected from any one of Formulae (AI)-(A-XII); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 139-141), an albumin-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); and L is a linker covalently attached to each of E, A1, and A2, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein). In some embodiments, each of A1 and A2 can be independently selected from any of Formula (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1 and A2 can be independently selected from Formula (AI).

[0158] In another aspect, the present invention provides a conjugate described by the following formula (DI)

[0159]

[0160] wherein each A1 and each A2 is independently selected from any one of Formulae (AI)-(AV); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 139-141), an albumin-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); and L is a linker covalently attached to each of E, A1, and A2, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any one of the A1-L-A2 structures described herein).

[0161] In another aspect, the present invention provides a conjugate described by the following formula (DI)

[0162]

[0163] wherein each A1 and each A2 is independently selected from any one of Formulas (A-VI)-(A-IX); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 139-141), an albumin-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); and L is a linker covalently attached to each of E, A1, and A2, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any one of the A1-L-A2 structures described herein).

[0164] In some embodiments, the conjugate is described by: Formula (D-II)

[0165]

[0166] or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the conjugate is described by: Formula (D-II-1)

[0168]

[0169] or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the conjugate is described by: Formula (D-II-2)

[0171]

[0172] or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the conjugate is described by: Formula (D-II-3)

[0174]

[0175] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0176] In some embodiments, the conjugate has a structure selected from the group consisting of:

[0177]

[0178]

[0179] In some embodiments, the conjugate is described by: Formula (D-II-4)

[0180]

[0181] or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, the conjugate is described by: Formula (D-II-5)

[0183]

[0184]

[0185] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0186] In some embodiments, the conjugate has a structure selected from the group consisting of:

[0187]

[0188] or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the conjugate has a structure selected from the group consisting of:

[0190]

[0191] or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the conjugate is described by: Formula (D-II-6)

[0193]

[0194] wherein R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; or a pharmaceutically acceptable salt thereof. In some embodiments, R7 is selected from C1-C20 alkyl (e.g., methyl, ethyl, propyl, or butyl).

[0195] In some embodiments, the conjugate is described by: Formula (D-II-7)

[0196]

[0197] or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the conjugate is described by: Formula (D-II-8)

[0199]

[0200] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0201] In some embodiments, the conjugate has the structure

[0202]

[0203]

[0204] or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the conjugate has the structure

[0206]

[0207] or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the conjugate has the structure

[0209]

[0210]

[0211] or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the conjugate has the structure

[0213]

[0214]

[0215] or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the conjugate is described by: Formula (D-II-9)

[0217]

[0218] or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the conjugate is described by: Formula (D-II-10)

[0220]

[0221] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0222] In some embodiments, the conjugate has the structure

[0223]

[0224] or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the conjugate has the following structure:

[0226]

[0227] or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the conjugate is described by: Formula (D-III)

[0229]

[0230] or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the conjugate is described by: Formula (D-III-1)

[0232]

[0233] or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the conjugate is described by: Formula (D-III-2)

[0235]

[0236] or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, the conjugate is described by: Formula (D-III-3)

[0238]

[0239] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0240] In some embodiments, the conjugate is described by: Formula (D-III-4)

[0241]

[0242] or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, the conjugate is described by: Formula (D-III-5)

[0244]

[0245] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0246] In some embodiments, the conjugate is described by: Formula (D-III-6)

[0247]

[0248] or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, the conjugate is described by: Formula (D-III-7)

[0250]

[0251] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0252] In some embodiments, the conjugate is described by: Formula (D-III-8)

[0253]

[0254] or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, the conjugate is described by: Formula (D-III-9)

[0256]

[0257] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0258] In some embodiments, the conjugate is described by: Formula (D-IV)

[0259]

[0260] or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, the conjugate is described by: Formula (D-IV-1)

[0262]

[0263] or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, the conjugate is described by: Formula (D-IV-2)

[0265]

[0266] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0267] In some embodiments, the conjugate is described by: Formula (DV)

[0268]

[0269] or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, the conjugate is described by: Formula (DV-1)

[0271]

[0272] or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the conjugate is described by: Formula (DV-2)

[0274]

[0275] or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the conjugate is described by: Formula (DV-3)

[0277]

[0278] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0279] In some embodiments, the conjugate is described by: Formula (DV-4)

[0280]

[0281] or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, the conjugate is described by: Formula (DV-5)

[0283]

[0284] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0285] In some embodiments, the conjugate is described by: Formula (DV-6)

[0286]

[0287] or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the conjugate is described by: Formula (DV-7)

[0289]

[0290] or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, the conjugate is described by: Formula (DV-8)

[0292]

[0293] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0294] In some embodiments, the conjugate is described by: Formula (DV-9)

[0295]

[0296] or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, the conjugate is described by: Formula (DV-10)

[0298]

[0299] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0300] In some embodiments, the conjugate is described by Formula (D-VI)

[0301]

[0302] or a pharmaceutically acceptable salt thereof.

[0303] In some embodiments, the conjugate is described by: Formula (D-VI-1)

[0304]

[0305] or a pharmaceutically acceptable salt thereof.

[0306] In some embodiments, the conjugate is described by: Formula (D-VI-2)

[0307]

[0308] or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the conjugate is described by: Formula (D-VI-3)

[0310]

[0311] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0312] In some embodiments, the conjugate is described by: Formula (D-VI-4)

[0313]

[0314] or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the conjugate is described by: Formula (D-VI-5)

[0316]

[0317] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0318] In some embodiments, the conjugate is described by: Formula (D-VI-6)

[0319]

[0320] or a pharmaceutically acceptable salt thereof.

[0321] In some embodiments, the conjugate is described by: Formula (D-VI-7)

[0322]

[0323] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0324] In some embodiments, the conjugate is described by: Formula (D-VI-8)

[0325]

[0326] or a pharmaceutically acceptable salt thereof.

[0327] In some embodiments, the conjugate is described by: Formula (D-VI-9)

[0328]

[0329] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0330] In some embodiments, the conjugate is described by Formula (D-VII)

[0331]

[0332] or a pharmaceutically acceptable salt thereof.

[0333] In some embodiments of any aspect described herein, R1 is OH. In some embodiments of any aspect described herein, R1 is NH2. In some embodiments of any aspect described herein, R1 is -NHC(=NH)NH2.

[0334] In some embodiments, the conjugate is described by: Formula (D-VIII)

[0335]

[0336] or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, the conjugate is described by: Formula (D-VIII-1)

[0338]

[0339] or a pharmaceutically acceptable salt thereof.

[0340] In some embodiments, the conjugate is described by: Formula (D-VIII-2)

[0341]

[0342] or a pharmaceutically acceptable salt thereof.

[0343] In some embodiments, the conjugate is described by: Formula (D-VIII-3)

[0344]

[0345] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0346] In some embodiments, the conjugate has a structure selected from the group consisting of:

[0347]

[0348] or a pharmaceutically acceptable salt thereof.

[0349] In some embodiments, the conjugate is described by: Formula (D-VIII-4)

[0350]

[0351] or a pharmaceutically acceptable salt thereof.

[0352] In some embodiments, the conjugate is described by: Formula (D-VIII-5)

[0353]

[0354] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0355] In some embodiments, the conjugate has a structure selected from the group consisting of:

[0356]

[0357] or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, the conjugate is described by the structure

[0359]

[0360] or a pharmaceutically acceptable salt thereof.

[0361] In some embodiments, the conjugate is described by: Formula (D-VIII-6)

[0362]

[0363] or a pharmaceutically acceptable salt thereof.

[0364] In some embodiments, the conjugate is described by: Formula (D-VIII-7)

[0365]

[0366] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0367] In some embodiments, the conjugate is described by: Formula (D-VIII-8)

[0368]

[0369] or a pharmaceutically acceptable salt thereof.

[0370] In some embodiments, the conjugate is described by: Formula (D-VIII-9)

[0371]

[0372] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0373] In some embodiments, the conjugate is described by: Formula (D-VIII-10)

[0374]

[0375] or a pharmaceutically acceptable salt thereof.

[0376] In some embodiments, the conjugate is described by: Formula (D-VIII-11)

[0377]

[0378] wherein L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 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. In some embodiments, L' is a nitrogen atom.

[0379] In some embodiments, the conjugate is described by: Formula (D-IX)

[0380]

[0381] or a pharmaceutically acceptable salt thereof.

[0382] In some embodiments, the conjugate is described by: Formula (D-IX-1)

[0383]

[0384] or a pharmaceutically acceptable salt thereof.

[0385] In some embodiments, the conjugate is described by: Formula (D-IX-2)

[0386]

[0387] or a pharmaceutically acceptable salt thereof.

[0388] In some embodiments, the conjugate is described by: Formula (D-IX-3)

[0389]

[0390] or a pharmaceutically acceptable salt thereof.

[0391] In some embodiments, the conjugate is described by: Formula (D-IX-4)

[0392]

[0393] or a pharmaceutically acceptable salt thereof.

[0394] In some embodiments, the conjugate is described by: Formula (D-IX-5)

[0395]

[0396] or a pharmaceutically acceptable salt thereof.

[0397] In some embodiments, the conjugate is described by: Formula (D-IX-6)

[0398]

[0399] or a pharmaceutically acceptable salt thereof.

[0400] In some embodiments, the conjugate is described by: Formula (DX)

[0401]

[0402] or a pharmaceutically acceptable salt thereof.

[0403] In some embodiments, the conjugate is described by: Formula (DX-1)

[0404]

[0405] or a pharmaceutically acceptable salt thereof.

[0406] In some embodiments, the conjugate is described by: Formula (DX-2)

[0407]

[0408] or a pharmaceutically acceptable salt thereof.

[0409] In some embodiments, the conjugate is described by: Formula (DX-3)

[0410]

[0411] or a pharmaceutically acceptable salt thereof.

[0412] In some embodiments of any of the aspects described herein, L or L' comprises one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino, wherein R iand H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0413] In some embodiments of any of the aspects described herein, the backbone of L or L' is composed of one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino, wherein R i and H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0414] In some embodiments of any aspect described herein, L or L' is substituted with oxo. In some embodiments, the backbone of L or L' comprises no more than 250 atoms. In some embodiments, L or L' is capable of forming an amide, carbamate, sulfonyl, or urea linkage. In some embodiments,

[0415] L or L' is a bond. In some embodiments, L or L' is an atom.

[0416] In some embodiments of any of the aspects described herein, each L is described by: Formula (DLI)

[0417]

[0418] Among them L A From formula G A1 -(Z A1 ) g1 -(Y A1 ) h1 -(Z A2 ) i1 -(Y A2 ) j1 -(Z A3 ) k1 -(Y A3 ) l1 -(Z A4 ) m1 -(Y A4 ) n1 -(Z A5 )o1-G A2 Description; L B From formula G B1 -(Z B1 ) g2 -(Y B1 ) h2 -(Z B2 ) i2 -(Y B2 ) j2 -(Z B3 ) k2 -(Y B3 ) l2 -(Z B4 ) m2 -(Y B4 ) n2 -(Z B5 )o2-G B2 Description; L C From formula G C1 -(Z C1 ) g3 -(Y C1 ) h3 -(Z C2 ) i3 -(Y C2 ) j3 -(Z C3 ) k3 -(Y C3 ) l3 -(Z C4 ) m3 -(Y C4 ) n3 -(ZC5 )o3-G C2 Description; G A1 is the key attached to Q; G A2 is the key attached to A1; G B1 is a bond attached to Q); G B2 is the key attached to A2; G C1 is the key attached to Q; G C2 is a bond attached to E or a functional group capable of reacting with a functional group conjugated to E (e.g., maleimide and cysteine, amine and activated carboxylic acid, thiol and maleimide, activated sulfonic acid and amine, isocyanate and amine, azide and alkyne, and olefin and tetrazine); Z A1 、Z A2 、Z A3 、Z A4 、Z A5 、Z B1 、Z B2 、Z B3 、Z B4 、Z B5 、Z C1 、Z C2 、Z C3 、Z C4 and Z C5 each of which is independently optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene; A1 、Y A2 、Y A3 、Y A4 、Y B1 、Y B2 、Y B 3 、Y B4 、Y C1 、Y C2 、Y C3 and Y C4 Each of which is independently O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino; R iis H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl; g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g each of h3, i3, j3, k3, l3, m3, n3 and o3 is independently 0 or 1; Q is a nitrogen atom, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene.

[0419] In some embodiments, L C There may be two points of attachment to an Fc domain, an Fc binding peptide, albumin or an albumin binding peptide (e.g., two G C2 ).

[0420] In some embodiments of any of the aspects described herein, L comprises a polyethylene glycol (PEG) linker. The PEG linker comprises a repeating unit structure (-CH2CH2O-) n wherein n is an integer from 2 to 100. The polyethylene glycol linker can covalently bind the neuraminidase inhibitor and E (e.g., in a conjugate of any one of formulas (MI)-(M-XI)). The polyethylene glycol linker can covalently bind the first neuraminidase inhibitor and the second neuraminidase inhibitor (e.g., in a conjugate of any one of formulas (DI)-(D-XI)). The polyethylene glycol linker can covalently bind the neuraminidase inhibitor dimer and E (e.g., in a conjugate of any one of formulas (DI)-(D-XI)). The polyethylene glycol linker can be selected from PEG2 to PEG 100 Any of (e.g., PEG2, PEG3, PEG4, PEG5, PEG5-PEG 10 PEG10 -PEG 20 PEG 20 -PEG 30 PEG 30 -PEG 40 PEG 50 -PEG 60 PEG 60 -PEG 70 PEG 70 -PEG 80 PEG 80 -PEG 90 PEG 90 -PEG 100 ). In some embodiments, L c Including PEG linker, where L C Covalently attached to each of Q and E.

[0421] In some embodiments, L is

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433] wherein z1 and z2 are each independently an integer from 1 to 20; and R9 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl.

[0434] In some embodiments, L is

[0435]

[0436]

[0437]

[0438]

[0439]

[0440] wherein R* is a bond or comprises optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate and imino groups or more, and wherein R i and H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0441] In some embodiments, Y is: (-NH(C=O)O-) and L is:

[0442] In some embodiments, Y is: (-NH(C=O)O-) and L is:

[0443] In some embodiments, Y is: (-NH(C=O)O-) and L is:

[0444] In some embodiments, Y is: (-O-) and L is:

[0445] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0446]

[0447] wherein each A1 is independently selected from any one of formulas (AI)-(A-XII);

[0448] Each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 139-141), an albumin-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); and L is a linker covalently attached to each of E and A1, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of Formulas (AI)-(A-XII). In some embodiments, each A1 can be independently selected from any one of Formula (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each A1 can be independently selected from Formula (AI).

[0449] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0450]

[0451] wherein each A1 is independently selected from any one of Formulae (AI)-(AV); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 139-141), an albumin-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); and L is a linker covalently attached to each of E and A1, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (eg, T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of Formulae (AI)-(AV).

[0452] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0453]

[0454] wherein each A1 is independently selected from any one of Formulae (A-VI)-(A-IX); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 139-141), an albumin-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); and L is a linker covalently attached to each of E and A1, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (eg, T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of Formulae (A-VI) to (A-IX).

[0455] In some embodiments, the conjugate is described by: Formula (M-II)

[0456]

[0457] or a pharmaceutically acceptable salt thereof.

[0458] In some embodiments, the conjugate is described by: Formula (M-II-1)

[0459]

[0460] or a pharmaceutically acceptable salt thereof.

[0461] In some embodiments, the conjugate is described by: Formula (M-II-2)

[0462]

[0463] or a pharmaceutically acceptable salt thereof.

[0464] In some embodiments, the conjugate is described by: Formula (M-II-3)

[0465]

[0466] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0467] In some embodiments, the conjugate is described by: Formula (M-II-4)

[0468]

[0469] or a pharmaceutically acceptable salt thereof.

[0470] In some embodiments, the conjugate is described by: Formula (M-II-5)

[0471]

[0472] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0473] In some embodiments, the conjugate has the structure

[0474]

[0475] or a pharmaceutically acceptable salt thereof.

[0476] In some embodiments, the conjugate is described by: Formula (M-II-6)

[0477]

[0478] wherein R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; or a pharmaceutically acceptable salt thereof. In some embodiments, R7 is selected from C1-C20 alkyl (e.g., methyl, ethyl, propyl, or butyl).

[0479] In some embodiments, the conjugate is described by: Formula (M-II-7)

[0480]

[0481] or a pharmaceutically acceptable salt thereof.

[0482] In some embodiments, the conjugate is described by: Formula (M-II-8)

[0483]

[0484] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0485] In some embodiments, the conjugate has the following structure:

[0486]

[0487] In some embodiments, the conjugate is described by: Formula (M-II-9)

[0488]

[0489] or a pharmaceutically acceptable salt thereof.

[0490] In some embodiments, the conjugate is described by: Formula (M-II-10)

[0491]

[0492] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0493] In some embodiments, the conjugate has the structure

[0494]

[0495] or a pharmaceutically acceptable salt thereof.

[0496] In some embodiments, the conjugate is described by: Formula (M-III)

[0497]

[0498] or a pharmaceutically acceptable salt thereof.

[0499] In some embodiments, the conjugate is described by: Formula (M-III-1)

[0500]

[0501] or a pharmaceutically acceptable salt thereof.

[0502] In some embodiments, the conjugate is described by: Formula (M-III-2)

[0503]

[0504] or a pharmaceutically acceptable salt thereof.

[0505] In some embodiments, the conjugate is described by: Formula (M-III-3)

[0506]

[0507] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0508] In some embodiments, the conjugate is described by: Formula (M-III-4)

[0509]

[0510] or a pharmaceutically acceptable salt thereof.

[0511] In some embodiments, the conjugate is described by: Formula (M-III-5)

[0512]

[0513] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0514] In some embodiments, the conjugate is described by: Formula (M-III-6)

[0515]

[0516] or a pharmaceutically acceptable salt thereof.

[0517] In some embodiments, the conjugate is described by: Formula (M-III-7)

[0518]

[0519] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0520] In some embodiments, the conjugate is described by: Formula (M-III-8)

[0521]

[0522] or a pharmaceutically acceptable salt thereof.

[0523] In some embodiments, the conjugate is described by: Formula (M-III-9)

[0524]

[0525] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0526] In some embodiments, the conjugate is described by: Formula (M-IV)

[0527]

[0528] or a pharmaceutically acceptable salt thereof.

[0529] In some embodiments, the conjugate is described by: Formula (M-IV-1)

[0530]

[0531] or a pharmaceutically acceptable salt thereof.

[0532] In some embodiments, the conjugate is described by: Formula (M-IV-2)

[0533]

[0534] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0535] In some embodiments, the conjugate is described by: Formula (MV)

[0536]

[0537] or a pharmaceutically acceptable salt thereof.

[0538] In some embodiments, the conjugate is described by: Formula (MV-1)

[0539]

[0540] or a pharmaceutically acceptable salt thereof.

[0541] In some embodiments, the conjugate is described by: Formula (MV-2)

[0542]

[0543] or a pharmaceutically acceptable salt thereof.

[0544] In some embodiments, the conjugate is described by: Formula (MV-3)

[0545]

[0546] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0547] In some embodiments, the conjugate is described by: Formula (MV-4)

[0548]

[0549] or a pharmaceutically acceptable salt thereof.

[0550] In some embodiments, the conjugate is described by: Formula (MV-5)

[0551]

[0552] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0553] In some embodiments, the conjugate is described by: Formula (MV-6)

[0554]

[0555] or a pharmaceutically acceptable salt thereof.

[0556] In some embodiments, the conjugate is described by: Formula (MV-7)

[0557]

[0558] or a pharmaceutically acceptable salt thereof.

[0559] In some embodiments, the conjugate is described by: Formula (MV-8)

[0560]

[0561] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0562] In some embodiments, the conjugate is described by: Formula (MV-9)

[0563]

[0564] or a pharmaceutically acceptable salt thereof.

[0565] In some embodiments, the conjugate is described by: Formula (MV-10)

[0566]

[0567] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0568] In some embodiments, the conjugate is described by: Formula (M-VI)

[0569]

[0570] or a pharmaceutically acceptable salt thereof.

[0571] In some embodiments, the conjugate is described by: Formula (M-VI-1)

[0572]

[0573] or a pharmaceutically acceptable salt thereof.

[0574] In some embodiments, the conjugate is described by: Formula (M-VI-2)

[0575]

[0576] or a pharmaceutically acceptable salt thereof.

[0577] In some embodiments, the conjugate is described by: Formula (M-VI-3)

[0578]

[0579] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0580] In some embodiments, the conjugate is described by: Formula (M-VI-4)

[0581]

[0582] or a pharmaceutically acceptable salt thereof.

[0583] In some embodiments, the conjugate is described by: Formula (M-VI-5)

[0584]

[0585] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0586] In some embodiments, the conjugate is described by: Formula (M-VI-6)

[0587]

[0588] or a pharmaceutically acceptable salt thereof.

[0589] In some embodiments, the conjugate is described by: Formula (M-VI-7)

[0590]

[0591] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0592] In some embodiments, the conjugate is described by: Formula (M-VI-8)

[0593]

[0594] or a pharmaceutically acceptable salt thereof.

[0595] In some embodiments, the conjugate is described by: Formula (M-VI-9)

[0596]

[0597] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0598] In some embodiments, the conjugate is described by Formula (M-VII)

[0599]

[0600] or a pharmaceutically acceptable salt thereof.

[0601] In some embodiments of any aspect described herein, R1 is OH. In some embodiments of any aspect described herein, R1 is NH2. In some embodiments of any aspect described herein, R1 is -NHC(=NH)NH2.

[0602] In some embodiments, the conjugate is described by: Formula (M-VIII)

[0603]

[0604] or a pharmaceutically acceptable salt thereof.

[0605] In some embodiments, the conjugate is described by: Formula (M-VIII-1)

[0606]

[0607] or a pharmaceutically acceptable salt thereof.

[0608] In some embodiments, the conjugate is described by: (M-VIII-2)

[0609]

[0610] or a pharmaceutically acceptable salt thereof.

[0611] In some embodiments, the conjugate is described by: Formula (M-VIII-3)

[0612]

[0613] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0614] In some embodiments, the conjugate is described by: Formula (M-VIII-4)

[0615]

[0616] or a pharmaceutically acceptable salt thereof.

[0617] In some embodiments, the conjugate is described by: Formula (M-VIII-5)

[0618]

[0619] wherein L' is the remainder of L, and y1 is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

[0620] In some embodiments, the conjugate has the following structure:

[0621]

[0622] or a pharmaceutically acceptable salt thereof.

[0623] In some embodiments, the conjugate is described by: Formula (M-VIII-6)

[0624]

[0625] or a pharmaceutically acceptable salt thereof.

[0626] In some embodiments, the conjugate is described by: Formula (M-VIII-7)

[0627]

[0628] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0629] In some embodiments, the conjugate is described by: Formula (M-VIII-8)

[0630]

[0631] or a pharmaceutically acceptable salt thereof.

[0632] In some embodiments, the conjugate is described by: Formula (M-VIII-9)

[0633]

[0634] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0635] In some embodiments, the conjugate is described by: Formula (M-VIII-10)

[0636]

[0637] or a pharmaceutically acceptable salt thereof.

[0638] In some embodiments, the conjugate is described by: Formula (M-VIII-11)

[0639]

[0640] wherein L' is the remainder of L, and y1 is an integer from 1 to 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.

[0641] In some embodiments, the conjugate is described by: Formula (M-IX)

[0642]

[0643] or a pharmaceutically acceptable salt thereof.

[0644] In some embodiments, the conjugate is described by: Formula (M-IX-1)

[0645]

[0646] or a pharmaceutically acceptable salt thereof.

[0647] In some embodiments, the conjugate is described by: Formula (M-IX-2)

[0648]

[0649] or a pharmaceutically acceptable salt thereof.

[0650] In some embodiments, the conjugate is described by: Formula (M-IX-3)

[0651]

[0652] or a pharmaceutically acceptable salt thereof.

[0653] In some embodiments, the conjugate is described by: Formula (M-IX-4)

[0654]

[0655] or a pharmaceutically acceptable salt thereof.

[0656] In some embodiments, the conjugate is described by: Formula (M-IX-5)

[0657]

[0658] or a pharmaceutically acceptable salt thereof.

[0659] In some embodiments, the conjugate is described by: Formula (M-IX-6)

[0660]

[0661] or a pharmaceutically acceptable salt thereof.

[0662] In some embodiments, the conjugate is described by: Formula (MX)

[0663]

[0664] or a pharmaceutically acceptable salt thereof.

[0665] In some embodiments, the conjugate is described by Formula (MX-1)

[0666]

[0667] or a pharmaceutically acceptable salt thereof.

[0668] In some embodiments, the conjugate is described by Formula (MX-2)

[0669]

[0670] or a pharmaceutically acceptable salt thereof.

[0671] In some embodiments, the conjugate is described by Formula (MX-3)

[0672]

[0673] or a pharmaceutically acceptable salt thereof.

[0674] In some embodiments of any of the aspects described herein, L or L' comprises one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino, wherein R i and H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0675] In some embodiments of any of the aspects described herein, the backbone of L or L' is composed of one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino, wherein R i and H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0676] In some embodiments of any aspect described herein, L or L' is oxo-substituted. In some embodiments, the backbone of L or L' comprises no more than 250 atoms. In some embodiments, L or L' is capable of forming an amide, carbamate, sulfonyl, or urea linkage. In some embodiments, L or L' is a bond. In some embodiments, L or L' is an atom. In some embodiments, L' is a nitrogen atom.

[0677] In some embodiments, each L is described by: Formula (ML-1)

[0678] 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

[0679] Among them: J 1 is the key attached to A1; J 2 is a bond attached to E or a functional group capable of reacting with a functional group conjugated to E (e.g., maleimide and cysteine, amine and activated carboxylic acid, thiol and maleimide, activated sulfonic acid and amine, isocyanate and amine, azide and alkyne, and olefin and tetrazine); Q 1 , Q 2 , Q 3 , Q 4 and Q 5 each of which is independently optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene; T 1 、T 2 、T 3 、T 4 Each of which is independently O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino; R i is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl or optionally substituted C2-C15 heteroaryl; and g, h, i, j, k, l, m, n and o are each independently 0 or 1; or a pharmaceutically acceptable salt thereof.

[0680] In some embodiments, J 2 There may be two points of attachment to an Fc domain, an Fc binding peptide, albumin or an albumin binding peptide (e.g., two J2 ).

[0681] In some embodiments, L is

[0682]

[0683] wherein d is an integer from 1 to 20 (e.g., d is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).

[0684] In some embodiments, L is

[0685]

[0686]

[0687] wherein d and e are each independently an integer from 1 to 26; or a pharmaceutically acceptable salt thereof.

[0688] In some embodiments of any of the aspects described herein, L comprises a polyethylene glycol (PEG) linker. The PEG linker comprises a repeating unit structure (-CH2CH2O-) n wherein n is an integer from 2 to 100. The polyethylene glycol linker can covalently bind the neuraminidase inhibitor and E (e.g., in a conjugate of any one of formulas (MI)-(M-XI)). The polyethylene glycol linker can covalently bind the first neuraminidase inhibitor and the second neuraminidase inhibitor (e.g., in a conjugate of any one of formulas (DI)-(D-XI)). The polyethylene glycol linker can covalently bind the neuraminidase inhibitor dimer and E (e.g., in a conjugate of any one of formulas (DI)-(D-XI)). The polyethylene glycol linker can be selected from PEG2 to PEG 100 Any of (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 -PEG 90 PEG 90 -PEG 100 ). In some embodiments, Lc Including PEG linker, where L C Covalently attached to each of Q and E.

[0689] In some embodiments of any aspect described herein, R1 is -NHC(=NH)NH2. In some embodiments of any aspect described herein, R2 is -F. In some embodiments of any aspect described herein, R3 is -F. In some embodiments of any aspect described herein, R4 is -CO2H. In some embodiments of any aspect described herein, R5 is -COCH3.

[0690] In some embodiments of any of the aspects described herein, L is covalently attached to the nitrogen atom of a surface-exposed lysine of E or L is covalently attached to the sulfur atom of a surface-exposed cysteine ​​of E.

[0691] In some embodiments of any aspect described herein, E is an Fc domain monomer. In some embodiments, n is 2 and each E dimerizes to form an Fc domain.

[0692] In some embodiments, n is 2, each E is an Fc domain monomer, each E dimerizes to form an Fc domain, and the conjugate is described by: Formula (DI-1)

[0693]

[0694] wherein J is an Fc domain; and 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), or a pharmaceutically acceptable salt thereof.

[0695] In some embodiments, the conjugate has the following structure:

[0696]

[0697] or a pharmaceutically acceptable salt thereof.

[0698] In some embodiments, n is 2, each E is an Fc domain monomer, each E dimerizes to form an Fc domain, and the conjugate is described by: Formula (MI-1)

[0699]

[0700] wherein J is an Fc domain; and 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), or a pharmaceutically acceptable salt thereof.

[0701] In some embodiments of any of the aspects described herein, E has the sequence of any one of SEQ ID NOs: 1-138.

[0702] In some embodiments of any of the aspects described herein, E is albumin, an albumin binding peptide, or an Fc binding peptide. In some embodiments wherein E is albumin, an albumin binding peptide, or an Fc binding peptide, n is 1.

[0703] In some embodiments, n is 1, E is albumin, an albumin binding peptide, or an Fc binding peptide and the conjugate is described by: Formula (DI-2)

[0704]

[0705] wherein E is albumin, an albumin-binding peptide or an Fc-binding peptide; and T is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

[0706] In some embodiments, n is 1, E is albumin, an albumin binding peptide, or an Fc binding peptide and the conjugate is described by: Formula (MI-2)

[0707]

[0708] wherein E is albumin, an albumin-binding peptide or an Fc-binding peptide; and T is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

[0709] In some embodiments of any of the aspects described herein, E is an albumin having the sequence of any one of SEQ ID NOs: 139-141.

[0710] In some embodiments of any aspect described herein, T is 1, 2, 3, 4, or 5.

[0711] In another aspect, the invention provides a population of conjugates having the structure of any of the conjugates described herein (e.g., a population of conjugates having any of Formulae (I)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)), wherein the average value of T is from 1 to 20 (e.g., the average value of T is from 1 to 2, from 1 to 3, from 1 to 4, from 1 to 5, from 5 to 10, from 10 to 15, from 15 to 20, from 1.5 to 3.5, from 2.5 to 4.5, from 3.5 to 5.5, from 4.5 to 6.5, from 5.5 to 7.5, from 6.5 to 8.5, from 7.5 to 9.5, or from 8.5 to 10.5). In some embodiments, the average value of T is about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20.

[0712] In some embodiments of any aspect described herein, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein). In some embodiments, E can be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different A1-L-A2 moieties. In some embodiments, E is conjugated to a first A1-L-A2 moiety and a second A1-L-A2 moiety. In some embodiments, A1 and A2 of the first A1-L-A2 moiety are independently selected from any one of Formulas (A-III)-(AV), and A1 and A2 of the second A1-L-A2 moiety are independently selected from any one of Formulas (AI), (A-II), (A-VI), (A-VII), (A-VIII), and (A-IX).

[0713] In some embodiments, each of the first Al-L-A2 moieties is specifically conjugated to a lysine residue of E (e.g., a nitrogen atom of a surface-exposed lysine residue of E), and each of the second Al-L-A2 moieties is specifically conjugated to a cysteine ​​residue of E (e.g., a sulfur atom of a surface-exposed cysteine ​​residue of E). In some embodiments, each of the first Al-L-A2 moieties is specifically conjugated to a cysteine ​​residue of E (e.g., a sulfur atom of a surface-exposed cysteine ​​residue of E), and each of the second Al-L-A2 moieties is specifically conjugated to a lysine residue of E (e.g., a nitrogen atom of a surface-exposed lysine residue of E).

[0714] In some embodiments, the number of first A1-L-A2 moieties conjugated to E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the number of second A1-L-A2 moieties conjugated to E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0715] In some embodiments of any aspect described herein, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L can be independently selected (e.g., independently selected from any of the A1-L structures described herein). In some embodiments, E can be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different A1-L moieties. In some embodiments, E is conjugated to a first A1-L moiety and a second A1-L moiety. In some embodiments, A1 of the first A1-L moiety is selected from any one of Formulas (A-III)-(AV),

[0716] And A1 of the second A1-L moiety is selected from any one of Formulas (AI), (A-II), (A-VI), (A-VII), (A-VIII) or (A-IX).

[0717] In some embodiments, each of the first Al-L moieties is specifically conjugated to a lysine residue of E (e.g., a nitrogen atom of a surface-exposed lysine residue of E), and each of the second Al-L moieties is specifically conjugated to a cysteine ​​residue of E (e.g., a sulfur atom of a surface-exposed cysteine ​​residue of E). In some embodiments, each of the first Al-L moieties is specifically conjugated to a cysteine ​​residue of E (e.g., a sulfur atom of a surface-exposed cysteine ​​residue of E), and each of the second Al-L moieties is specifically conjugated to a lysine residue of E (e.g., a nitrogen atom of a surface-exposed lysine residue of E).

[0718] In some embodiments, the number of first A1-L moieties conjugated to E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the number of second A1-L moieties conjugated to E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0719] In another aspect, the present invention provides a conjugate described by the following formula (D'-I)

[0720]

[0721] wherein each A1 is independently selected from any one of Formulae (A-III)-(AV); wherein each A2 is independently selected from any one of Formulae (AI), (A-II), (A-VI), (A-VII), (A-VIII) and (A-IX); and each E comprises an Fc domain monomer (e.g., an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138), an albumin (e.g., an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138), NO: 139-141), albumin-binding peptide or Fc-binding peptide; n is 1 or 2; T1 is an integer from 1 to 10 (e.g., T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L1 is a linker covalently conjugated to E and to each A1; T1 is an integer from 1 to 10 (e.g., T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L2 is a linker covalently conjugated to E and each A2; T2 is an integer from 1 to 10 (e.g., T2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), or a pharmaceutically acceptable salt thereof.

[0722] In some embodiments, each A1-L-A1 is specifically conjugated to a lysine residue of E (e.g., a nitrogen atom of a surface-exposed lysine residue of E), and each A2-L-A2 is specifically conjugated to a cysteine ​​residue of E (e.g., a sulfur atom of a surface-exposed cysteine ​​residue of E). In some embodiments, each A1-L-A1 moiety is specifically conjugated to a cysteine ​​residue of E (e.g., a sulfur atom of a surface-exposed cysteine ​​residue of E), and each A2-L-A2 moiety is specifically conjugated to a lysine residue of E (e.g., a nitrogen atom of a surface-exposed lysine residue of E).

[0723] In another aspect, the present invention provides a conjugate described by the following formula (M'-I)

[0724]

[0725] wherein each A1 is independently selected from any one of formulas (A-III)-(AV) (M-IX); wherein each A2 is independently selected from any one of formulas (AI), (A-II), (A-VI), (A-VII), (A-VIII) and (A-IX); and each E comprises an Fc domain monomer (e.g., an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138), an albumin (e.g., an Fc domain monomer having a sequence of SEQ ID NOs: 1-138), ID NO: 139-141 of any one of the albumin), albumin binding peptide or Fc binding peptide; n is 1 or 2; T1 is an integer from 1 to 10 (for example, T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L1 is a linker covalently conjugated to E and A1; T1 is an integer from 1 to 10 (for example, T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L2 is a linker covalently conjugated to E and A2; T2 is an integer from 1 to 10 (for example, T2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), or a pharmaceutically acceptable salt thereof.

[0726] In some embodiments, each A1-L is specifically conjugated to a lysine residue of E (e.g., a nitrogen atom of a surface-exposed lysine residue of E), and each A2-L is specifically conjugated to a cysteine ​​residue of E (e.g., a sulfur atom of a surface-exposed cysteine ​​residue of E). In some embodiments, each A1-L moiety is specifically conjugated to a cysteine ​​residue of E (e.g., a sulfur atom of a surface-exposed cysteine ​​residue of E), and each A2-L moiety is specifically conjugated to a lysine residue of E (e.g., a nitrogen atom of a surface-exposed lysine residue of E).

[0727] In another aspect, the present invention provides a pharmaceutical composition comprising any one of the conjugates described herein (e.g., a conjugate of any one of Formulas (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0728] In another aspect, the present invention provides a method for treating a subject having or suspected of having a viral infection, comprising administering to the subject an effective amount of any of the conjugates or compositions described herein (e.g., a conjugate of any of Formulas (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)).

[0729] In another aspect, the present invention provides a method for prophylactically treating a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of any of the conjugates or compositions described herein (e.g., a conjugate of any of Formulas (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)).

[0730] In some embodiments, the viral infection is caused by influenza virus or parainfluenza virus. In some embodiments, the viral infection is influenza virus A, B or C or parainfluenza virus.

[0731] In some embodiments, the subject is immunocompromised.

[0732] In some embodiments, the subject has been diagnosed with a humoral immunity deficiency, a T-cell deficiency, neutropenia, asplenia, or a complement deficiency.

[0733] In some embodiments, the subject is being treated or is about to be treated with immunosuppressive therapy.

[0734] In some embodiments, the subject has been diagnosed with a disease that causes immunosuppression. In some embodiments, the disease is cancer or acquired immunodeficiency syndrome. In some embodiments, the cancer is leukemia, lymphoma, or multiple myeloma.

[0735] In some embodiments, the subject has undergone or is about to undergo a hematopoietic stem cell transplant.

[0736] In some embodiments, the subject has undergone or is about to undergo an organ transplant.

[0737] In some embodiments, the subject suffers from secondary infection or is in the risk of secondary infection. In some embodiments, the secondary infection is bacterial infection (for example, methicillin-resistant Staphylococcus aureus (Staphylococcus aureus) (MRSA), Streptococcus pneumoniae (Streptococcus pneumoniae), Pseudomonas aeruginosa (Pseudomonas aeruginosa) and / or Haemophilus influenzae (Haemophilus influenzae)), viral infection or fungal infection. In specific embodiments, the secondary infection is MRSA. In certain embodiments, the secondary infection is Streptococcus pneumoniae. In some embodiments, the secondary infection is respiratory tract infection (for example, respiratory tract infection). In some embodiments, the secondary infection is associated with (for example, causing) pneumonia (for example, bacterial or viral pneumonia). In some embodiments, the subject suffers from pneumonia or is in the risk of pneumonia.

[0738] In another aspect, the present disclosure provides a method for preventing secondary infection in a subject diagnosed with influenza infection, wherein the method comprises administering to the subject a conjugate or composition described herein. In some embodiments, the method comprises administering to the subject conjugate 45 or a pharmaceutical composition comprising conjugate 45.

[0739] In some embodiments, administration of a conjugate or composition of the invention to a subject diagnosed with influenza infection reduces, for example, the likelihood of developing a secondary infection by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500% or more (e.g., compared to a subject with influenza who was not treated with the conjugate or composition). For example, administration of a conjugate or composition of the invention to a subject diagnosed with influenza infection reduces, for example, the likelihood of developing a secondary bacterial infection (e.g., MRSA, S. pneumoniae, P. aeruginosa and / or H. influenzae) by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500% or more. In some embodiments, the conjugate or composition is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, transperitoneally, subcutaneously, subconjunctivally, intracapsularly, transmucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, by inhalation, by injection, or by infusion.

[0740] In some embodiments, the subject is treated with a second therapeutic agent. In some embodiments, the second therapeutic agent is an antiviral agent. In some embodiments, the antiviral agent is selected from pimovidir, oseltamivir, zanamivir, peramivir, laninamivir, amantadine, or rimantadine. In specific embodiments, the second therapeutic agent is pimovidir. In some embodiments, the second therapeutic agent is a viral vaccine. In some embodiments, the viral vaccine induces an immune response against influenza virus A, B, or C or parainfluenza virus in the subject.

[0741] In some embodiments, the conjugate is administered in combination with an antiviral agent, wherein the antiviral agent is baloxavir. In certain embodiments, the conjugate is described by formula (D-II-6). In other embodiments, the conjugate is described by formula (D-II-7). In certain embodiments, each E comprises an Fc domain having an amino acid sequence at least 95% identical to the sequence of any one of SEQ ID NOs: 63-138. In certain embodiments, each E comprises an Fc domain having an amino acid sequence at least 95% identical to the sequence of any one of SEQ ID NOs: 63-138. In certain embodiments, each E comprises an Fc domain having an amino acid sequence at least 95% identical to the sequence of any one of SEQ ID NOs: 63, 64, 67, 68, 72, 73, 76, 77, 81, 82, 85, or 86. In specific embodiments, each E comprises an Fc domain having an amino acid sequence of any one of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85, or SEQ ID NO: 86. In preferred embodiments, the conjugate is conjugate 45 (e.g., conjugate 45a or conjugate 45b) or conjugate 46.

[0742] In certain embodiments, the conjugate and baloxavir are administered sequentially. In other embodiments, the conjugate and baloxavir are administered simultaneously.

[0743] In one aspect, the present disclosure provides a method for treating or preventing a viral infection in a subject, the method comprising administering to the subject: a) an effective amount of a conjugate or composition according to any one of claims 1 to 215; and b) a second therapeutic agent. In certain embodiments, the conjugate is administered to the subject after the subject has a viral infection, is presumed to have a viral infection, or has been exposed to a virus. In some embodiments, the conjugate is administered to the subject prophylactically. In certain embodiments, the second therapeutic agent is administered to the subject after the subject has a viral infection, is presumed to have a viral infection, or has been exposed to a virus. In some embodiments, the second therapeutic agent is administered to the subject prophylactically. In some embodiments, the second therapeutic agent is administered within 30 days, 14 days, 7 days, 2 days, or 24 hours of the conjugate. In specific embodiments, the second therapeutic agent is administered within 2 days of the conjugate. In certain embodiments, the second therapeutic agent is an antiviral agent (e.g., pimodesvir, oseltamivir, zanamivir, peramivir, laninamivir, amantadine, baloxavir marboxil, baloxavir acid, rimantadine, or a pharmaceutically acceptable salt thereof). In specific embodiments, the antiviral agent is baloxavir marboxil, baloxavir acid, or a pharmaceutically acceptable salt thereof. In certain embodiments, the baloxavir marboxil is administered in an amount between 20 mg and 90 mg (e.g., between 25 mg and 50 mg, between 45 mg and 70 mg, or between 65 and 90 mg). In some embodiments, the baloxavir marboxil is administered orally. In certain embodiments, the baloxavir marboxil is administered in a single dose form. In other embodiments, the baloxavir marboxil is administered in more than one dose form. In specific embodiments, the baloxavir marboxil is administered in an amount between 20 mg and 40 mg. In other embodiments, the baloxavir mabocil is administered in an amount between 30 and 80 mg. In certain embodiments, the conjugate is described by formula (D-II-6). In other embodiments, the conjugate is described by formula (D-II-7). In certain embodiments, each E has a sequence at least 95% identical to the sequence of any one of SEQ ID NO:63-138. In specific embodiments, each E comprises an Fc domain having an amino acid sequence at least 95% identical to the sequence of any one of SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:85 or SEQ ID NO:86.In certain embodiments, each E comprises an Fc domain having the amino acid sequence of any one of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85, or SEQ ID NO: 86. In certain embodiments, the conjugate is conjugate 45 (e.g., conjugate 45a or conjugate 45b) or conjugate 46. In certain embodiments, the conjugate is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, transperitoneally, subcutaneously, subconjunctivally, intracapsularly, transmucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, by inhalation, by injection, or by infusion. In some embodiments, the conjugate is administered intravenously. In some embodiments, the conjugate is administered intramuscularly. In some embodiments, the viral infection is caused by influenza virus or parainfluenza virus. In certain embodiments, the virus is influenza virus A, B or C or parainfluenza virus.

[0744] In some embodiments, in any one of formulas (1)-(5), (D-I)-(D-XI), (D’-I), (M-I)-(M-XI) or (M’-I) (e.g., formula (1), (2), (3), (4), (5), (D-I), (D-II), (D-II-1), (D-II-2), (D-II-3), (D-II-4), (D-II-5), (D-II-6), (D-II-7), (D-II-8), (D-II-9), (D-II-10), (D-III), (D-III-1), (D-III-2), (D-III-3), (D-III-4), (D-III-5), (D-III-6), (D-III-7), (D-III-8), (D-III-9), (D-IV), (D-IV-1), (D-IV-2), (D-V), (D-V-1), (D-V-2), (D-V-3), (D-V-4), (D-V-5), (D-V-6), (D-V-7), (D-V-8), (D-V-9), (D-V-10), (D-VI), (D-VI-1), (D-VI-2), (D-VI-3), (D-VI-4), (D-VI-5), (D-VI-6), (D-VI-7), (D-VI-8), (D-VI-9), (D-VII), (D-VIII), (D-VIII-1), (D-VIII-2), (D-VIII-3), (D-VIII-4), (D-VIII-5), (D-VIII-6), (D-VIII-7), (D-VIII-8), (D-VIII-9), (D-VIII-10), (D-VIII-11), (D-IX), (D-IX-1), (D-IX-2), (D-IX-3), (D-IX-4), (D-IX-5), (D-IX-6), (D-X), (D-X-1), (D-X-2), (D-X-3), (D-XI), (D-XI-1), (D’-I), (M-I), (M-II), (M-II-1), (M-II-2), (M-II-3), (M-II-4), (M-II-5), (M-II-6), (M-II-7), (M-II-8), (M-II-9), (M-II-10), (M-III), (M-III-1), (M-III-2), (M-III-3), (M-III-4), (M-III-5), (M-III-6), (M-III-7), (M-III-8), (M-III-9), (M-IV), (M-IV-1), (M-IV-2), (M-V), (M-V-1), (M-V-2), (M-V-3),(MV-4), (MV-5), (MV-6), (MV-7), (MV-8), (MV-9), (MV-10), (M-VI), (M-VI-1), (M-VI-2), (M-VI-3), (M-VI-4), (M-VI-5), (M-VI- 6), (M-VI-7), (M-VI-8), (M-VI-9), (M-VII), (M-VIII), (M-VIII-1), (M-VIII-2), (M-VIII-3), (M-VIII-4), (M-VIII-5), (M-VIII In any of the formulae described herein (e.g., any of Formulae (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)), when n is 1, E is an Fc domain-containing monomer composition. In any of the formulae described herein (e.g., any of formulae (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)), when n is 2, E is an Fc domain-containing composition.

[0745] In certain embodiments, the Fc domain-containing composition is an antibody or antibody fragment. Antibodies may include any form of immunoglobulin, heavy chain antibody, light chain antibody, LRR-based antibody or other protein skeleton with antibody-like properties, as well as any other immune binding portion known in the art, including antibody fragments (e.g., Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, scFv or SMIP). The subunit structure and three-dimensional configuration of different classes of antibodies are known in the art. Antibody fragments may include the following binding portion, which includes a portion derived from an antibody or having significant homology with an antibody, such as an antigenic determinant region of an antibody. Exemplary antibody fragments include Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, scFv and SMIP.

[0746] In certain embodiments, the antibody or antibody fragment is a human, mouse, camelid (e.g., llama, alpaca, or camel), goat, sheep, rabbit, chicken, guinea pig, hamster, horse, or rat antibody or antibody fragment. In certain embodiments, the antibody is IgG, IgA, IgD, IgE, IgM, or endosomal. In certain embodiments, the antibody fragment comprises a scFv, sdAb, dAb, Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, or SMIP.

[0747] In some embodiments, the Fc domain-containing composition (eg, antibody or antibody fragment) confers binding specificity to one or more targets (eg, antigens).

[0748] In some embodiments, the one or more targets (e.g., antigens) bound by the Fc domain-containing composition (e.g., antibody or antibody fragment) are viral (e.g., influenza) proteins, such as neuraminidase or hemagglutinin. In some embodiments, the antibody or antibody fragment recognizes viral surface antigens. In some embodiments, the antibody or antibody fragment targets hemagglutinin. Hemagglutinin targeting antibodies include monoclonal antibodies such as CR6261, CR8020, MEDI8852, MHAA4549A, and VIS410. In some embodiments, the antibody or antibody fragment is a broadly neutralizing antibody or antibody fragment targeting influenza hemagglutinin (e.g., an antibody or antibody fragment described in Wu et al., J. Mol. Biol. 429: 2694-2709 (2017)). In some embodiments, the antibody or antibody fragment targets viral matrix proteins (e.g., matrix 2 protein). TCN032 is a matrix 2 protein targeting monoclonal antibody.

[0749] In some embodiments, the Fc domain-containing composition (e.g., an antibody or antibody fragment) comprises one or more single domain antibodies (sdAbs). In some embodiments, the Fc domain-containing composition is an antibody or antibody fragment comprising an sdAb with influenza A reactivity, such as an sdAb that binds to the hemagglutinin of influenza A (e.g., SD36 or SD38, described in Laursen et al. Science. 362: 598-602 (2018)). In some embodiments, the Fc domain-containing composition is an antibody or antibody fragment comprising an sdAb with influenza B reactivity, such as an sdAb that binds to the hemagglutinin of influenza B (e.g., SD83 or SD84, described in Laursen et al. Science. 362: 598-602 (2018)).

[0750] In some embodiments, the Fc domain-containing composition is a multi-domain antibody (MDAb) or a multi-domain antibody fragment comprising two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more) sdAbs. In some embodiments, the MDAb or its fragment comprises one or more sdAbs that bind to the hemagglutinin of influenza A and one or more sdAbs that bind to the hemagglutinin of influenza B. In some embodiments, the MDAb is JNJ-7445 (also known as MD3606), which is described in Laursen et al. Science. 362: 598-602 (2018). In short, JNJ-7445 is an MDAb that comprises two sdAbs (SD36 and SD38) that bind to the hemagglutinin of influenza A and two sdAbs (SD83 and SD84) that bind to the hemagglutinin of influenza B, which are connected to the Fc domain (IgG1). The sdAbs were generated by immunizing llamas with influenza vaccine and H7 and H2 recombinant hemagglutinins.

[0751] In another aspect, the present invention includes any one of the formulas (1)-(5), (D-I)-(D-XI), (D'-I), (M-I)-(M-XI) or (M'-I) (e.g., formula (1), (2), (3), (4), (5), (D-I), (D-II), (D-II-1), (D-II-2), (D-II-3), (D-II-4), (D-II-5), (D-II-6), (D-II-7), (D-II-8), (D-II-9), (D-II-10), (D-III), (D-III-1), (D-III-2), (D-III-3), (D-III-4), (D-III-5), (D-III-6), (D-III-7), (D-III-8), (D-III-9), (D-IV), (D-IV-1), (D-IV-2), (D-V), (D-V-1), (D-V-2), (D-V-3), (D-V-4), (D-V-5), (D-V-6), (D-V-7), (D-V-8), (D-V-9), (D-V-10), (D-VI), (D-VI-1), (D-VI-2), (D-VI-3), (D-VI-4), (D-VI-5), (D-VI-6), (D-VI-7), (D-VI-8), (D-VI-9), (D-VII), (D-VIII), (D-VIII-1), (D-VIII-2), (D-VIII-3), (D-VIII-4), (D-VIII-5), (D-VIII-6), (D-VIII-7), (D-VIII-8), (D-VIII-9), (D-VIII-10), (D-VIII-11), (D-IX), (D-IX-1), (D-IX-2), (D-IX-3), (D-IX-4), (D-IX-5), (D-IX-6), (D-X), (D-X-1), (D-X-2), (D-X-3), (D-XI), (D-XI-1), (D'-I), (M-I), (M-II), (M-II-1), (M-II-2), (M-II-3), (M-II-4), (M-II-5), (M-II-6), (M-II-7), (M-II-8), (M-II-9), (M-II-10), (M-III), (M-III-1), (M-III-2), (M-III-3), (M-III-4), (M-III-5), (M-III-6), (M-III-7), (M-III-8), (M-III-9), (M-IV), (M-IV-1), (M-IV-2), (M-V), (M-V-1), (M-V-2)(MV-3), (MV-4), (MV-5), (MV-6), (MV-7), (MV-8), (MV-9), (MV-10), (M-VI), (M-VI-1), (M-VI-2), (M-VI-3), (M-VI-4), (M-VI-5), (M-VI-6), (M-VI-7), (M-VI-8), (M-VI-9), (M-VII), (M-VIII), (M-VIII-1), (M-VIII-2), (M-VIII-3), (M-VII In some embodiments, the present invention provides a conjugate described in any one of (M-I-4), (M-VIII-5), (M-VIII-6), (M-VIII-7), (M-VIII-8), (M-VIII-9), (M-VIII-10), (M-VIII-11), (M-IX), (M-IX-1), (M-IX-2), (M-IX-3), (M-IX-4), (M-IX-5), (M-IX-6), (MX), (MX-1), (MX-2), (MX-3) or (M'-I)), wherein E is an antibody or antibody fragment. In a preferred embodiment wherein E is an antibody or antibody fragment, n is 1. In some embodiments, the antibody or antibody fragment includes any antibody or antibody fragment described herein, such as a monoclonal antibody that binds to viral hemagglutinin (e.g., CR6261, CR8020, MEDI8852, MHAA4549A, or VIS410); a broadly neutralizing antibody or antibody fragment targeting viral hemagglutinin (e.g., an antibody or antibody fragment described in Wu et al., J. Mol. Biol. 429:2694-2709 (2017)); an sdAb targeting viral hemagglutinin (e.g., SD36, SD38, SD83, or SD84); or an MDAb or fragment thereof targeting viral hemagglutinin (e.g., JNJ-7445).

[0752] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, E comprises 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: 1.

[0753] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, E comprises 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: 2.

[0754] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 3. In some embodiments, E comprises 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: 3.

[0755] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, E comprises 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: 4.

[0756] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments, E comprises 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: 5.

[0757] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, E comprises 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: 6.

[0758] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 7. In some embodiments, E comprises 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: 7.

[0759] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, E comprises 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.

[0760] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, E comprises 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.

[0761] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, E comprises 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: 10.

[0762] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, E comprises 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: 11.

[0763] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, E comprises 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: 12.

[0764] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 13. In some embodiments, E comprises 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: 13.

[0765] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, E comprises 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: 14.

[0766] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, E comprises 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: 15.

[0767] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments, E comprises 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: 16.

[0768] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments, E comprises 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: 17.

[0769] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 18. In some embodiments, E comprises 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: 18.

[0770] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 19. In some embodiments, E comprises 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: 19.

[0771] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments, E comprises 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: 20.

[0772] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 21. In some embodiments, E comprises 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: 21.

[0773] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 22. In some embodiments, E comprises 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.

[0774] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments, E comprises 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.

[0775] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 24. In some embodiments, E comprises 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: 24.

[0776] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 25. In some embodiments, E comprises 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: 25.

[0777] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 26. In some embodiments, E comprises 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: 26.

[0778] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 27. In some embodiments, E comprises 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: 27.

[0779] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 28. In some embodiments, E comprises 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: 28.

[0780] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 29. In some embodiments, E comprises 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: 29.

[0781] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 30. In some embodiments, E comprises 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: 30.

[0782] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 31. In some embodiments, E comprises 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: 31.

[0783] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 32. In some embodiments, E comprises 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: 32.

[0784] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 33. In some embodiments, E comprises 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: 33.

[0785] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 34. In some embodiments, E comprises 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.

[0786] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 35. In some embodiments, E comprises 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.

[0787] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 36. In some embodiments, E comprises 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: 36.

[0788] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 37. In some embodiments, E comprises 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: 37.

[0789] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 38. In some embodiments, E comprises 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: 38.

[0790] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 39. In some embodiments, E comprises 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: 39.

[0791] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 40. In some embodiments, E comprises 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: 40.

[0792] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 41. In some embodiments, E comprises 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: 41.

[0793] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 42. In some embodiments, E comprises 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: 42.

[0794] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 43. In some embodiments, E comprises 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: 43.

[0795] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 44. In some embodiments, E comprises 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.

[0796] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 46. In some embodiments, E comprises 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.

[0797] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 47. In some embodiments, E comprises 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: 47.

[0798] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, E comprises 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: 48.

[0799] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 49. In some embodiments, E comprises 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: 49.

[0800] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 50. In some embodiments, E comprises 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: 50.

[0801] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 51. In some embodiments, E comprises 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: 51.

[0802] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, E comprises 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: 52.

[0803] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 53. In some embodiments, E comprises 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: 53.

[0804] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 54. In some embodiments, E comprises 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: 54.

[0805] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 55. In some embodiments, E comprises 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: 55.

[0806] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 56. In some embodiments, E comprises 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: 56.

[0807] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 57. In some embodiments, E comprises 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: 57.

[0808] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 58. In some embodiments, E comprises 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: 58.

[0809] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 59. In some embodiments, E comprises 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: 59.

[0810] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 60. In some embodiments, E comprises 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: 60.

[0811] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, E comprises 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: 61.

[0812] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 62. In some embodiments, E comprises 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: 62.

[0813] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 63. In some embodiments, E comprises 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: 63.

[0814] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 64. In some embodiments, E comprises 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: 64.

[0815] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 65. In some embodiments, E comprises 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: 65.

[0816] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 66. In some embodiments, E comprises 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: 66.

[0817] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 67. In some embodiments, E comprises 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: 67.

[0818] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 68. In some embodiments, E comprises 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: 68.

[0819] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 69. In some embodiments, E comprises 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: 69.

[0820] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 70. In some embodiments, E comprises 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.

[0821] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 71. In some embodiments, E comprises 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.

[0822] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 72. In some embodiments, E comprises 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: 72.

[0823] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 73. In some embodiments, E comprises 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: 73.

[0824] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 74. In some embodiments, E comprises 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: 74.

[0825] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 75. In some embodiments, E comprises 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: 75.

[0826] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 76. In some embodiments, E comprises 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: 76.

[0827] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 77. In some embodiments, E comprises 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.

[0828] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 78. In some embodiments, E comprises 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.

[0829] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 79. In some embodiments, E comprises 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.

[0830] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 80. In some embodiments, E comprises 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.

[0831] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 81. In some embodiments, E comprises 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.

[0832] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 82. In some embodiments, E comprises 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: 82.

[0833] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 83. In some embodiments, E comprises 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: 83.

[0834] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 84. In some embodiments, E comprises 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.

[0835] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 85. In some embodiments, E comprises 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.

[0836] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 86. In some embodiments, E comprises 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.

[0837] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 87. In some embodiments, E comprises 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.

[0838] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 88. In some embodiments, E comprises 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.

[0839] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, E comprises 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: 89.

[0840] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 90. In some embodiments, E comprises 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: 90.

[0841] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 91. In some embodiments, E comprises 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: 91.

[0842] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 92. In some embodiments, E comprises 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: 92.

[0843] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 93. In some embodiments, E comprises 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: 93.

[0844] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 94. In some embodiments, E comprises 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: 94.

[0845] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 95. In some embodiments, E comprises 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: 95.

[0846] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 96. In some embodiments, E comprises 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.

[0847] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 97. In some embodiments, E comprises 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.

[0848] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 98. In some embodiments, E comprises 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.

[0849] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 99. In some embodiments, E comprises 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: 99.

[0850] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 100. In some embodiments, E comprises 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: 100.

[0851] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 101. In some embodiments, E comprises 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.

[0852] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 102. In some embodiments, E comprises 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.

[0853] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 103. In some embodiments, E comprises 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: 103.

[0854] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 104. In some embodiments, E comprises 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: 104.

[0855] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 105. In some embodiments, E comprises 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: 105.

[0856] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 106. In some embodiments, E comprises 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.

[0857] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 107. In some embodiments, E comprises 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: 107.

[0858] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 108. In some embodiments, E comprises 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: 108.

[0859] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 109. In some embodiments, E comprises 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.

[0860] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 110. In some embodiments, E comprises 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.

[0861] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 111. In some embodiments, E comprises 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.

[0862] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 112. In some embodiments, E comprises 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.

[0863] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 113. In some embodiments, E comprises 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: 113.

[0864] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 114. In some embodiments, E comprises 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.

[0865] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, E comprises 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.

[0866] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 116. In some embodiments, E comprises 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.

[0867] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, E comprises 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: 117.

[0868] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 118. In some embodiments, E comprises 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: 118.

[0869] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 119. In some embodiments, E comprises 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.

[0870] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 120. In some embodiments, E comprises 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.

[0871] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 121. In some embodiments, E comprises 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.

[0872] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 122. In some embodiments, E comprises 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.

[0873] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 123. In some embodiments, E comprises 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.

[0874] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 124. In some embodiments, E comprises 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.

[0875] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 125. In some embodiments, E comprises 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.

[0876] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 126. In some embodiments, E comprises 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.

[0877] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 127. In some embodiments, E comprises 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.

[0878] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 128. In some embodiments, E comprises 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.

[0879] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 129. In some embodiments, E comprises 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.

[0880] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 130. In some embodiments, E comprises 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.

[0881] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 131. In some embodiments, E comprises 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.

[0882] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 132. In some embodiments, E comprises 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.

[0883] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 133. In some embodiments, E comprises 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: 133.

[0884] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 134. In some embodiments, E comprises 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: 134.

[0885] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 135. In some embodiments, E comprises 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.

[0886] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 136. In some embodiments, E comprises 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.

[0887] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 137. In some embodiments, E comprises 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: 137.

[0888] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 138. In some embodiments, E comprises 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: 138.

[0889] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 139. In some embodiments, E comprises 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: 139.

[0890] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 140. In some embodiments, E comprises 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: 140.

[0891] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 145. In some embodiments, E comprises 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: 141.

[0892] In some embodiments of any aspect described herein where E comprises an Fc domain monomer, the Fc domain monomer (e.g., an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138) comprises a triple mutation corresponding to M252Y / S254T / T256E (YTE). As used herein, it is understood that "amino acids corresponding to a particular amino acid residue" (e.g., of a particular SEQ ID NO.) include any amino acid residue that one skilled in the art would understand to align with the particular residue (e.g., of the particular sequence). For example, any one of SEQ ID NOs: 1-138 can be mutated to comprise a YTE mutation.

[0893] In some embodiments of any aspect described herein where E comprises an Fc domain monomer, the Fc domain monomer (e.g., an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138) comprises a double mutant corresponding to M428L / N434S (LS). As used herein, it is understood that "an amino acid corresponding to a particular amino acid residue" (e.g., of a particular SEQ ID NO.) includes any amino acid residue that one skilled in the art would understand to align with the particular residue (e.g., of the particular sequence). For example, any one of SEQ ID NOs: 1-138 can be mutated to comprise an LS mutation.

[0894] In some embodiments of any aspect described herein where E comprises an Fc domain monomer, the Fc domain monomer (e.g., an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138) comprises a mutant corresponding to N434H. As used herein, it is understood that an amino acid residue "corresponding to a particular amino acid residue" (e.g., of a particular SEQ ID NO.) includes any amino acid residue that one skilled in the art would understand to align with the particular residue (e.g., of the particular sequence). For example, any one of SEQ ID NOs: 1-138 can be mutated to comprise an N434H mutation.

[0895] In some embodiments of any aspect described herein where E comprises an Fc domain monomer, the Fc domain monomer (e.g., an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138) comprises a mutant corresponding to C220S. As used herein, it is understood that an amino acid residue "corresponding to a particular amino acid residue" (e.g., of a particular SEQ ID NO.) includes any amino acid residue that one skilled in the art would understand to align with the particular residue (e.g., of the particular sequence). For example, any one of SEQ ID NOs: 1-138 can be mutated to comprise a C220S mutation.

[0896] In some embodiments of any aspect described herein, the Fc domain monomer (e.g., an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-95) comprises a triple mutation corresponding to V309D / Q311H / N434S (DHS). As used herein, it is understood that "amino acids corresponding to a particular amino acid residue" (e.g., of a particular SEQ ID NO.) include any amino acid residue that one skilled in the art would understand to align with the particular residue (e.g., of the particular sequence). For example, any one of SEQ ID NOs: 1-95 can be mutated to comprise a DHS mutation.

[0897] In some embodiments of any aspect described herein wherein E comprises an Fc domain monomer, the Fc domain monomer (e.g., an 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., 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, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 94, 95, 96, 97, 98, 99, 100, or more) consecutive amino acids in length).

[0898] In some embodiments of any aspect described herein (e.g., conjugates of any of Formulas (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)), 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 of E are covalently conjugated to a linker (e.g., PEG2-PEG 20 Linker). The linker conjugated to E can be functionalized so that it can react to form a covalent bond with any A1-L or any A2-L-A1 described herein. In a preferred embodiment, E is conjugated to a linker functionalized with an azide group and the L of A1-L or any A2-L-A1 is functionalized with an alkynyl group. The linker-azide group of E and the linker-alkyne group of A1-L or A2-L-A1 are conjugated (e.g., by click chemistry) to form a conjugate of the invention, such as a conjugate described by any of formulas (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I). In yet other embodiments, E is conjugated to a linker functionalized with an alkynyl group and the L of any A1-L or any A2-L-A1 is functionalized with an azide group. Linker-alkyne conjugation of E and linker-azido conjugation of A1-L or A2-L-A1 (e.g., by click chemistry, see e.g., Figure 103 ) to form a conjugate of the invention, such as a conjugate described by formula (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I). In some embodiments of any aspect described herein, the wavy line in any of formula (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I) may represent a covalent bond between E and L of A1-L or A2-L-A1.

[0899] In some embodiments of any aspect described herein, the wavy line in any of Formulas (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I) can indicate that one or more amino acid side chains of E (e.g., 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 of E) have been conjugated to a linker (e.g., PEG2-PEG 20 linker), wherein the linker has been functionalized with a reactive moiety such that the reactive moiety forms a covalent bond with the L of any A1-L or any A2-L-A1 described herein (e.g., by click chemistry between an azide-functionalized linker and an alkyne-functionalized linker, as described above; see, e.g., Figure 103 ).

[0900] In some embodiments of any aspect described herein, A1 and / or A2 has the structure described by (AI):

[0901]

[0902] In a preferred embodiment, wherein A1 and / or A2 has a structure described by (AI): R1 is -NHC(=NH)NH2, R4 is -CO2H, R5 is -COCH3 and / or X is -O-. In a preferred embodiment, A1 and / or A2 has a zanamivir structure described by:

[0903]

[0904] In some embodiments of any of the aspects described herein, A1 and / or A2 has the structure depicted by (A-II):

[0905]

[0906] In a preferred embodiment, wherein A1 and / or A2 has a structure described by (A-II): R1 is -NHC(=NH)NH2, R2 is H or F, R3 is H or F, R4 is -CO2H, R5 is -COCH3 and / or X is -O-. In a preferred embodiment, A1 and / or A2 has a structure described by:

[0907]

[0908] In some embodiments of any of the aspects described herein, A1 and / or A2 has the structure depicted by (A-III):

[0909]

[0910] In a preferred embodiment, wherein A1 and / or A2 has the structure described by (A-III): R1 is -NHC(=NH)NH2, R4 is -CO2H and / or R5 is -COCH3. In a preferred embodiment, A1 and / or A2 has the structure of peramivir described by:

[0911]

[0912] In some embodiments of any of the aspects described herein, A1 and / or A2 has the structure depicted by (A-IV):

[0913]

[0914]

[0915] In a preferred embodiment, wherein A1 and / or A2 has a structure described by (A-IV): R1 is -NHC(=NH)NH2, R4 is -CO2H and / or R5 is -COCH3. In a preferred embodiment, A1 and / or A2 has a structure described by:

[0916]

[0917] In some embodiments of any aspect described herein, A1 and / or A2 has the structure described by (AV):

[0918]

[0919] In a preferred embodiment, wherein A1 and / or A2 has a structure described by (AV): R1 is -NHC(=NH)NH2, R4 is -CO2H and / or R5 is -COCH3. In a preferred embodiment, A1 and / or A2 has a structure described by:

[0920]

[0921] In some embodiments of any of the aspects described herein, A1 and / or A2 has the structure depicted by (A-VI):

[0922]

[0923] In a preferred embodiment, wherein A1 and / or A2 has the structure described by (A-VI): R1 is -NHC(=NH)NH2, R4 is -CO2H, R5 is -COCH3 and / or X is -O-. In a preferred embodiment, A1 and / or A2 has the structure of zanamivir described by:

[0924]

[0925] In some embodiments of any of the aspects described herein, A1 and / or A2 has the structure depicted by (A-VII):

[0926]

[0927] In a preferred embodiment, wherein A1 and / or A2 has a structure described by (A-VII): R1 is -NHC(=NH)NH2, R2 is H or F, R3 is H or F, R4 is -CO2H, R5 is -COCH3 and / or X is -O-. In a preferred embodiment, A1 and / or A2 has a structure described by:

[0928]

[0929] In some embodiments of any of the aspects described herein, A1 and / or A2 has the structure depicted by (A-VIII):

[0930]

[0931] In a preferred embodiment, wherein A1 and / or A2 has a structure described by (A-VIII): R1 is -NHC(=NH)NH2, R5 is -COCH3 and / or X is -O-. In a preferred embodiment, wherein A1 and / or A2 has a structure described by:

[0932]

[0933] In some embodiments of any of the aspects described herein, A1 and / or A2 has the structure depicted by (A-IX):

[0934]

[0935] In a preferred embodiment, wherein A1 and / or A2 has a structure described by (A-IX): R1 is -NHC(=NH)NH2, R2 is H or F, R3 is H or F, R5 is -COCH3 and / or X is -O-. In a preferred embodiment, A1 and / or A2 has a structure described by:

[0936]

[0937] In some embodiments of any aspect described herein, A1 and / or A2 has the structure described by (AX):

[0938]

[0939] In a preferred embodiment, wherein A1 and / or A2 has a structure described by (AX): R1 is -NHC(=NH)NH2, R3 is H, R5 is -COCH3 and / or X is -O-. In a preferred embodiment, A1 and / or A2 has a sulfonamivir structure described by:

[0940]

[0941] In some embodiments of any of the aspects described herein, A1 and / or A2 has the structure depicted by (A-XI):

[0942]

[0943] In a preferred embodiment, wherein A1 and / or A2 has the structure described by (A-XI): R4 is -CO2H and / or R5 is -COCH3. In a preferred embodiment, the olefin is (E), (Z), or a racemic mixture of (E) / (Z). In a preferred embodiment, A1 and / or A2 has the structure of A-315675 (Abbott) described below:

[0944]

[0945] In some embodiments of any of the aspects described herein, A1 and / or A2 has the structure depicted by (A-XII):

[0946]

[0947] In a preferred embodiment, wherein A1 and / or A2 have the structure described by (A-XII): R4 is -CO2H. In a preferred embodiment, A1 and / or A2 have the structure of A-315675 (Abbott) described by:

[0948]

[0949] In some embodiments, the conjugate is Conjugate 1 or any regioisomer thereof and the drug:antibody ratio (DAR) (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 1, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0950] In some embodiments, the conjugate is Conjugate 2 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, .7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 2, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0951] In some embodiments, the conjugate is conjugate 3 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, .7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 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 another aspect, the invention provides a population of conjugates, each conjugate having a Conjugate 3 structure, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0952] In some embodiments, the conjugate is conjugate 4 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, .7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 4, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0953] In some embodiments, the conjugate is conjugate 5 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, .7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 5, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0954] In some embodiments, the conjugate is conjugate 6 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, .7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 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 another aspect, the invention provides a population of conjugates, each conjugate having a Conjugate 6 structure, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0955] In some embodiments, the conjugate is conjugate 7 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, .7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 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 another aspect, the invention provides a population of conjugates, each conjugate having a Conjugate 7 structure, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0956] In some embodiments, the conjugate is conjugate 8 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, .7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate B, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0957] In some embodiments, the conjugate is conjugate 9 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, .7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 9, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0958] In some embodiments, the conjugate is conjugate 10 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 10, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0959] In some embodiments, the conjugate is conjugate 11 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 11, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0960] In some embodiments, the conjugate is conjugate 12 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 12, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0961] In some embodiments, the conjugate is conjugate 13 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 13, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0962] In some embodiments, the conjugate is conjugate 14 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 14, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0963] In some embodiments, the conjugate is conjugate 15 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 15, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0964] In some embodiments, the conjugate is conjugate 16 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 16, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0965] In some embodiments, the conjugate is conjugate 17 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having the structure of Conjugate 17, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0966] In some embodiments, the conjugate is conjugate 18 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 18, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0967] In some embodiments, the conjugate is conjugate 19 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 19, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0968] In some embodiments, the conjugate is conjugate 20 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 20, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0969] In some embodiments, the conjugate is conjugate 21 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 21, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0970] In some embodiments, the conjugate is conjugate 22 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 22, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0971] In some embodiments, the conjugate is conjugate 23 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 23, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0972] 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, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 24, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0973] In some embodiments, the conjugate is conjugate 25 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 25, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0974] 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, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 26, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0975] In some embodiments, the conjugate is conjugate 27 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having the structure Conjugate 27, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0976] In some embodiments, the conjugate is conjugate 28 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having the structure Conjugate 28, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0977] In some embodiments, the conjugate is conjugate 29 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 29, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0978] In some embodiments, the conjugate is conjugate 30 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 30, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0979] In some embodiments, the conjugate is conjugate 31 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 31, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0980] In some embodiments, the conjugate is conjugate 32 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 32, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0981] In some embodiments, the conjugate is conjugate 33 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 33, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0982] In some embodiments, the conjugate is conjugate 34 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 34, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0983] In some embodiments, the conjugate is conjugate 35 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 35, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0984] In some embodiments, the conjugate is conjugate 36 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 36, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0985] In some embodiments, the conjugate is conjugate 37 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 37, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0986] In some embodiments, the conjugate is conjugate 38 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 38, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0987] In some embodiments, the conjugate is conjugate 39 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 39, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0988] In some embodiments, the conjugate is conjugate 40 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 40, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0989] In some embodiments, the conjugate is conjugate 41 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 41, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0990] In some embodiments, the conjugate is conjugate 42 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 42, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0991] In some embodiments, the conjugate is conjugate 43 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 43, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0992] In some embodiments, the conjugate is conjugate 44 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 44, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0993] In some embodiments, the conjugate is conjugate 45 (e.g., conjugate 45a or conjugate 45b) or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4 , 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 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 another aspect, the invention provides a population of conjugates, each conjugate having the structure of conjugate 45 (e.g., conjugate 45a or conjugate 45b), wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0994] In some embodiments, the conjugate is conjugate 46 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 46, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0995] In some embodiments, the conjugate is conjugate 47 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 47, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0996] In some embodiments, the conjugate is conjugate 48 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, about 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, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 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 another aspect, the invention provides a population of conjugates, each conjugate having a structure of Conjugate 48, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0997] In some embodiments of any of the aspects described herein, the invention provides a conjugate described by any of Formula (DI), (MI), (1), or (2); wherein each A1 and each A2 is independently selected from any one of Formulas (A-XIII):

[0998]

[0999] wherein R1 is selected from -OH, -NH2, -NHC(=NH)NH2 and -NHC(=NH)NHR6; R4 is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5 is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[1000]

[1001]

[1002] R6 is selected from

[1003] R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl;

[1004] R8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl and C2-C15 heteroaryl;

[1005] R9 is selected from -H, halogen (eg, Cl or F), -OR 10 , -NHC(=O)R7, optionally substituted C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl;

[1006] R 10 Selected from C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl;

[1007] n is 1 or 2;

[1008] Each E comprises an Fc domain monomer, albumin, an albumin-binding peptide, or an Fc-binding peptide;

[1009] L is a linker covalently attached to E and to each A1 or each Y of each A1 and A2;

[1010] T is an integer from 1 to 20, and

[1011] Each wavy line in formula (DI), (MI), (1), or (2) indicates that L is covalently attached to each E;

[1012] or a pharmaceutically acceptable salt thereof.

[1013] In some embodiments, each A1 and each A2 is described by Formula (A-XIII-1):

[1014]

[1015] In some embodiments, each A1 and each A2 are independently selected from any one of the following: Formula (A-XIII-1a)-(A-XIII-1d)

[1016]

[1017] In some embodiments, the conjugate is described by: Formula (D-XI)

[1018]

[1019] or a pharmaceutically acceptable salt thereof.

[1020] In some embodiments, the conjugate is described by: Formula (D-XI-1)

[1021]

[1022]

[1023] wherein R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; or a pharmaceutically acceptable salt thereof.

[1024] In some embodiments, the conjugate is described by: Formula (M-XI)

[1025]

[1026] or a pharmaceutically acceptable salt thereof.

[1027] In some embodiments, the conjugate is described by: Formula (M-XI-1)

[1028]

[1029] wherein R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; or a pharmaceutically acceptable salt thereof.

[1030] definition

[1031] To facilitate understanding of the present invention, various terms are defined below. The terms defined herein have the meanings commonly understood by one of ordinary skill in the art to which the present invention relates. Terms such as "a," "an," and "the" are not intended to refer to only a single entity, but rather encompass the general class to which the specific examples used for illustration belong. These terms are used herein to describe specific embodiments of the present invention, but their use does not limit the present invention except as outlined in the claims.

[1032] As used herein, the term "neuraminidase inhibitor" or "viral neuraminidase inhibitor" refers to a compound that reduces the activity of the enzyme influenza virus neuraminidase (e.g., from influenza virus A, B, or C). Neuraminidase inhibitors can be identified by methods known to those skilled in the art, such as by a reduction in viral replication in an influenza virus plaque reduction assay, e.g., at a concentration of less than 20 μM (e.g., less than 10 μM, 5 μM, 2 μM, 1 μM, 500 nM, or 100 nM). Viral neuraminidase inhibitors known to those skilled in the art include zanamivir, sulfozanamivir, peramivir, and A-315675 (Abbott) (see, for example, Hadházi et al. A sulfozanamivir analogue has potent anti-influenzavirus activity. ChemMedChem Comm. 13: 785-789 (2018) and In vitro characterization of A-315675, a highly potent inhibitor of A and B strain of influenza virus neuraminidases and influenza virus replication. Antimicrobial Agents and Chemotherapy 46 (4): 1014-1021 (2002)). The viral neuraminidase inhibitors of the present invention include zanamivir, sulfozanamivir, peramivir, A-315675, and analogs thereof, such as viral neuraminidase inhibitors of formula (AI)-(A-XIII):

[1033]

[1034] wherein R1 is selected from -OH, -NH2, -NHC(=NH)NH2 and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5 is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[1035]

[1036]

[1037] R6 is selected from

[1038] R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; and R8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl and C2-C15 heteroaryl; R9 is selected from -H, halogen (e.g., Cl, F or Br), -OR 10 , -NHC(=O)R7, optionally substituted C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; and R 10 Selected from C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl.

[1039] As used herein, the term "inhibits neuraminidase activity" refers to an IC of less than or equal to 1,000 nM. 50 , for example, as measured according to the neuraminidase inhibition assay in Example 2 herein. Specifically, IC 50 represents the concentration of influenza virus neuraminidase inhibitor required for 50% inhibition in vitro. In some aspects, the concentration is less than or equal to 100 nM or less than or equal to 10 nM according to the neuraminidase inhibition assay. 50 Indicates compounds that inhibit neuraminidase activity.

[1040] "Viral infection" means the pathogenic growth of a virus (e.g., influenza virus) in a host organism (e.g., a human subject). A viral infection can be any situation in which the presence of a viral population is damaging the host body. Thus, a subject is "suffering from" a viral infection when an excess viral population is present in or on the subject's body, or when the presence of a viral population is damaging the subject's cells or other tissues.

[1041] As used herein, the term "Fc domain monomer" refers to a polypeptide chain comprising at least one hinge domain and second and third antibody constant domains (C H 2 and C H3) or its functional fragment (e.g., a fragment capable of (i) dimerizing with another Fc domain monomer to form an Fc domain, and (ii) binding to an Fc receptor). The Fc domain monomer can be any immunoglobulin antibody isotype, including IgG, IgE, IgM, IgA or IgD (e.g., IgG). In addition, the Fc domain monomer can be an IgG subtype (e.g., IgG1, IgG2a, IgG2b, IgG3 or IgG4) (e.g., IgG1). The Fc domain monomer does not include any part of the immunoglobulin that can serve as an antigen-recognition region, such as a variable domain or a complementary determining region (CDR). The Fc domain monomer in the conjugate as described herein may contain one or more changes (e.g., 1-10, 1-8, 1-6, 1-4 amino acid substitutions, additions or deletions) relative to the wild-type Fc domain monomer sequence that alter the interaction between the Fc domain and the Fc receptor. Examples of suitable changes are known in the art. In certain embodiments, a human Fc domain monomer (e.g., an IgG heavy chain, such as IgG1) comprises a region extending from any one of Asn208, Glu216, Asp221, Lys222, or Cys226 to the heavy chain carboxyl terminus at Lys447. The C-terminal Lys447 of the Fc region may or may not be present without affecting the structure or stability of the Fc region. After expression of the polypeptide, the C-terminal Lys 447 may be proteolytically cleaved. In some embodiments of any Fc domain monomer described herein, the C-terminal Lys 447 is optionally present or absent. The present disclosure specifically contemplates any of SEQ ID NOs: 1-4, 11, 16, 19, 20, 32-37, 48-53, and 60-68 that do not include a C-terminal Lys corresponding to Lys447. The N-terminal N (Asn) of the Fc region (e.g., any one of SEQ ID NOs: 60-77) may or may not be present without affecting the structure or stability of the Fc region. After expression of the polypeptide, the N-terminal Asn may be deamidated. In some embodiments of any Fc domain monomer described herein, the N-terminal Asn is optionally present or absent. The present disclosure specifically contemplates any one of SEQ ID NOs: 60-77 that does not include an N-terminal Asn. Unless otherwise specified herein, the numbering of amino acid residues in the IgG or Fc domain monomer is according to the EU numbering system for antibodies, also known as the Kabat EU index, as described in, for example, Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[1042] As used herein, the term "Fc domain" refers to a dimer of two Fc domain monomers that is capable of binding to an Fc receptor. In a wild-type Fc domain, the two Fc domain monomers are bound by two C H 3. Interactions between antibody constant domains Dimerization. In some embodiments, one or more disulfide bonds are formed between the hinge domains of two dimerized Fc domain monomers.

[1043] The term "covalently attached" refers to two parts of a conjugate being linked to each other by a covalent bond formed between two atoms in the two parts of the conjugate.

[1044] As used herein, the term "Fc-binding peptide" refers to a polypeptide having an amino acid sequence of 5 to 50 (e.g., 5 to 40, 5 to 30, 5 to 20, 5 to 15, 5 to 10, 10 to 50, 10 to 30, or 10 to 20) amino acid residues that has an affinity for and functions to bind to an Fc domain (such as any Fc domain described herein). Fc-binding peptides may be of different origins, such as synthetic, human, mouse, or rat. The Fc-binding peptides of the present invention include Fc-binding peptides that have been engineered to include one or more (e.g., two, three, four, or five) solvent-exposed cysteine ​​or lysine residues that can provide a site for conjugation to a compound of the invention (e.g., conjugation to a neuraminidase inhibitor monomer or dimer, including via a linker). Most preferably, the Fc-binding peptide will contain a single solvent-exposed cysteine ​​or lysine, thereby enabling site-specific conjugation of the 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. When included, non-naturally occurring amino acid residues (e.g., side chains of non-naturally occurring amino acid residues) can be used as attachment points for compounds of the invention (e.g., neuraminidase inhibitor monomers or dimers, including with the aid of a linker). The Fc binding peptides of the present invention may be linear or cyclic. The Fc binding peptides of the present invention include any Fc binding peptide known to those skilled in the art.

[1045] As used herein, the term "albumin" refers to a polypeptide comprising an amino acid sequence corresponding to a naturally occurring albumin (e.g., human serum albumin) or a variant thereof (such as an engineered variant of a naturally occurring albumin). Variants of albumin include polymorphisms, fragments such as domains and subdomains, and fusion proteins (e.g., albumin with a C-terminal or N-terminal fusion such as a polypeptide linker). Preferably, the albumin 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 of the present invention includes proteins having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 139-141. The albumins of the present invention include albumins that have been engineered to include one or more (e.g., two, three, four, or five) solvent-exposed cysteine ​​or lysine residues that can provide sites for conjugation to a compound of the invention (e.g., to a neuraminidase inhibitor monomer or dimer, including via a linker). Most preferably, the albumin will contain a single solvent-exposed cysteine ​​or lysine, thereby enabling site-specific conjugation of a compound of the invention. Albumin may comprise only naturally occurring amino acid residues, or may comprise one or more non-naturally occurring amino acid residues. When included, the non-naturally occurring amino acid residue (e.g., the side chain of a non-naturally occurring amino acid residue) can serve as an attachment point for a compound of the invention (e.g., a neuraminidase inhibitor monomer or dimer, including via a linker).

[1046] As used herein, the term "albumin-binding peptide" refers to a polypeptide having an amino acid sequence of 5 to 50 (e.g., 5 to 40, 5 to 30, 5 to 20, 5 to 15, 5 to 10, 10 to 50, 10 to 30, or 10 to 20) amino acid residues that has an affinity for and functions to bind to an albumin (such as any of the albumins described herein). Preferably, the albumin-binding peptide binds to naturally occurring serum albumin, most preferably human serum albumin. The albumin-binding peptide may be of different origins, such as synthetic, human, mouse, or rat. The albumin-binding peptides of the present invention include those that 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., to a neuraminidase inhibitor monomer or dimer, including via a linker). Most preferably, the albumin-binding peptide will contain a single solvent-exposed cysteine ​​or lysine, thereby enabling site-specific conjugation of a compound of the invention. The albumin-binding peptides may comprise only naturally occurring amino acid residues, or may comprise one or more non-naturally occurring amino acid residues. When included, the non-naturally occurring amino acid residues (e.g., side chains of non-naturally occurring amino acid residues) may serve as attachment points for the compounds of the invention (e.g., neuraminidase inhibitor monomers or dimers, including via linkers). The albumin-binding peptides of the invention may be linear or cyclic. The albumin-binding peptides of the invention include any albumin-binding peptides known to those skilled in the art, examples of which are provided herein. Further exemplary albumin-binding peptides are provided in U.S. Patent Application No. 2005 / 0287153, which is incorporated herein by reference in its entirety.

[1047] As used herein, a "surface exposed amino acid" or "solvent exposed amino acid," such as a surface exposed cysteine ​​or surface exposed lysine, refers to an amino acid that is accessible to the solvent surrounding the protein. A surface exposed amino acid may be naturally occurring or an engineered variant (e.g., a substitution or insertion) of the protein. In some embodiments, a surface exposed amino acid is an amino acid that, when substituted, does not substantially alter the three-dimensional structure of the protein.

[1048] As used herein, the terms "linker," "L," and "L'" refer to a covalent linkage between two or more components of a conjugate (e.g., between two neuraminidase inhibitors in a conjugate described herein, between a neuraminidase inhibitor and an Fc domain or albumin in a conjugate described herein, and between a dimer of two neuraminidase inhibitors and an Fc domain or albumin in a conjugate described herein). In some embodiments, the conjugates described herein may contain a linker having a trivalent structure (e.g., a trivalent linker). A trivalent linker has three arms, each of which is covalently attached to a component of the conjugate (e.g., a first arm conjugated to a first neuraminidase inhibitor, a second arm conjugated to a second neuraminidase inhibitor, and a third arm conjugated to an Fc domain or albumin).

[1049] The molecule that can be used as a linker comprises at least two functional groups, which can be the same or different, such as two carboxyl groups, two amino groups, two sulfonic acid groups, a carboxyl group and a maleimide group, a carboxyl group and an alkynyl group, a carboxyl group and an amino group, a carboxyl group and a sulfonic acid group, an amino group and a maleimide group, an amino group and an alkynyl group, or an amino group and a sulfonic acid group. The first functional group can form a covalent bond with the first component in the conjugate and the second functional group can form a covalent bond with the second component in the conjugate. In some embodiments of a trivalent linker, the two arms of the linker can contain two dicarboxylic acids, wherein the first carboxylic acid can form a covalent bond with the first neuraminidase inhibitor in the conjugate and the second carboxylic acid can form a covalent bond with the second neuraminidase inhibitor in the conjugate and the third arm of the linker can form a covalent bond with the Fc domain or albumin in the conjugate. Examples of dicarboxylic acids are further described herein. In some embodiments, molecules containing one or more maleimide groups can be used as linkers, wherein the maleimide group can form a carbon-sulfur linkage with a cysteine ​​of a component in the conjugate (e.g., an Fc domain or albumin). In some embodiments, molecules containing one or more alkynyl groups can be used as linkers, wherein the alkynyl group can form a 1,2,3-triazole linkage with an azide of a component in the conjugate (e.g., an Fc domain or albumin). In some embodiments, molecules containing one or more azide groups can be used as linkers, wherein the azide group can form a 1,2,3-triazole linkage with an alkyne of a component in the conjugate (e.g., an Fc domain or albumin). In some embodiments, molecules containing one or more bissulfone groups can be used as linkers, wherein the bissulfone group can form a linkage with an amino group of a component in the conjugate (e.g., an Fc domain or albumin). In some embodiments, molecules containing one or more sulfonic acid groups can be used as linkers, wherein the sulfonic acid group can form a sulfonamide linkage with a component in the conjugate. In some embodiments, molecules containing one or more isocyanate groups can be used as linkers, wherein the isocyanate groups can form urea linkages with components in the conjugate. In some embodiments, molecules containing one or more haloalkyl groups can be used as linkers, wherein the haloalkyl groups can form covalent linkages, such as CN and CO linkages, with components in the conjugate.

[1050] In some embodiments, the linker provides space, rigidity and / or flexibility between two or more components. In some embodiments, the linker may be a bond, such as a covalent bond. The term "bond" refers to a chemical bond, such as an amide bond, a disulfide bond, a CO bond, a CN bond, a N-N bond, a C-S bond, or any type of bond produced by a chemical reaction (e.g., chemical conjugation). In some embodiments, the linker comprises no more than 250 atoms. In some embodiments, the linker comprises no more than 250 non-hydrogen atoms. In some embodiments, the skeleton of the linker comprises no more than 250 atoms. The "skeleton" of the linker refers to the atoms in the linker that together form the shortest path from one part of the conjugate to another part of the conjugate (e.g., the shortest path connecting the first neuraminidase inhibitor and the second neuraminidase inhibitor). The atoms in the skeleton of the linker directly participate in connecting one part of the conjugate to another part of the conjugate (e.g., connecting the first neuraminidase inhibitor and the second neuraminidase inhibitor). For example, hydrogen atoms attached to carbons in the skeleton of the linker are not considered to be directly involved in connecting one part of the conjugate to another part of the conjugate.

[1051] In some embodiments, the linker can comprise a synthetic group derived from, for example, a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer). In some embodiments, the linker can comprise one or more amino acid residues, such as D- or L-amino acid residues. In some embodiments, the linker can be a residue of an amino acid sequence (e.g., 1-25 amino acids, 1-10 amino acids, 1-9 amino acids, 1-8 amino acids, 1-7 amino acids, 1-6 amino acids, 1-5 amino acids, 1-4 amino acids, 1-3 amino acids, 1-2 amino acids, or 1 amino acid sequence). In some embodiments, the linker can comprise one or more (e.g., 1-100, 1-50, 1-25, 1-10, 1-5, or 1-3) optionally substituted alkylene, optionally substituted heteroalkylene (e.g., PEG units), optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted cycloalkenylene, optionally substituted heterocycloalkenylene, optionally substituted cycloalkynylene, optionally substituted heterocycloalkynylene, optionally substituted arylene, optionally substituted heteroarylene (e.g., pyridine), O, S, NR i (R iwherein R is H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkenyl, optionally substituted cycloalkynyl, optionally substituted heterocycloalkynyl, optionally substituted aryl or optionally substituted heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino. For example, the linker can comprise one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene (e.g., PEG units), optionally substituted C2-C20 alkenylene (e.g., C2 alkenylene), optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene (e.g., C6 arylene), optionally substituted C2-C15 heteroarylene (e.g., imidazole, pyridine), O, S, NR i (R i wherein the alkyl radical is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino.

[1052] As used herein, the terms "alkyl," "alkenyl," and "alkynyl" include linear and branched monovalent substituents, and combinations thereof, that contain only C and H when unsubstituted. When an alkyl group contains at least one carbon-carbon double bond or carbon-carbon triple bond, the alkyl group may be referred to as an "alkenyl" or "alkynyl," respectively. The unit value of an alkyl, alkenyl, or alkynyl group does not include optional substituents on the alkyl, alkenyl, or alkynyl group. For example, if an alkyl, alkenyl, or alkynyl group is attached to a compound, the unit value of the alkyl, alkenyl, or alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl, alkenyl, or alkynyl group. In some embodiments, an alkyl or heteroalkyl group can contain, for example, 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, the alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl group can contain, for example, 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-propenyl, and 3-butynyl.

[1053] As used herein, the term "cycloalkyl" refers to a monovalent saturated or unsaturated non-aromatic cyclic alkyl group. A cycloalkyl group may have, for example, three to twenty carbon atoms (e.g., C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. When a cycloalkyl group includes at least one carbon-carbon double bond, the cycloalkyl group may be referred to as a "cycloalkenyl group." A cycloalkenyl group may have, for example, four to twenty carbon atoms (e.g., C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl groups). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. When a cycloalkyl group includes at least one carbon-carbon triple bond, the cycloalkyl group may be referred to as a "cycloalkynyl group." A cycloalkynyl group may have, for example, eight to twenty carbon atoms (e.g., C8-C9, C8-C10, C8-C11, C8-C12, C8-C14, C8-C16, C8-C18, or C8-C20 cycloalkynyl groups). The term "cycloalkyl" also includes cyclic compounds having bridged polycyclic structures (e.g., bicyclo[2.2.1.]heptyl and adamantane), in which one or more carbon atoms bridge two non-adjacent members of a monocyclic ring. The term "cycloalkyl" also includes bicyclic, tricyclic, and tetracyclic fused ring structures, such as decalin and spirocyclic compounds.

[1054] As used herein, the term "aryl" refers to any monocyclic or fused bicyclic or tricyclic ring system having aromatic characteristics in terms of electron distribution in the ring system, such as phenyl, naphthyl, or phenanthrene. In some embodiments, the ring system contains 5-15 ring member atoms or 5-10 ring member atoms. Aryl groups can have, for example, five to fifteen carbon atoms (e.g., C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C11, C5-C12, C5-C13, C5-C14, or C5-C15 aryl). The term "heteroaryl" also refers to such monocyclic or fused bicyclic ring systems containing one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms selected from O, S, and N. Heteroaryl groups can have, for example, two to fifteen carbon atoms (e.g., C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C2-C11, C2-C12, C2-C13, C2-C14, or C2-C15 heteroaryl groups). The inclusion of heteroatoms allows for the inclusion of 5-membered rings and 6-membered rings that would be considered aromatic. Thus, typical heteroaryl systems include, for example, pyridyl, pyrimidinyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzisoxazolyl, and imidazolyl. Because tautomers are possible, groups such as phthalimido are also considered heteroaryl groups. In some embodiments, aryl or heteroaryl is a 5- or 6-membered aromatic ring system optionally containing 1-2 nitrogen atoms. In some embodiments, aryl or heteroaryl is an optionally substituted phenyl, pyridyl, indolyl, pyrimidinyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl or imidazopyridinyl. In some embodiments, aryl is phenyl. In some embodiments, aryl may be optionally substituted with a substituent such as an aryl substituent (e.g., biphenyl).

[1055] The term "alkaryl" refers to an aryl group attached to an alkylene, alkenylene, or alkynylene group. Generally, if a compound is attached to an alkaryl group, the alkylene, alkenylene, or alkynylene portion of the alkaryl group is attached to the compound. In some embodiments, the alkaryl group is a C6-C35 alkaryl group (e.g., C6-C16, C6-C14, C6-C12, C6-C10, C6-C9, C6-C8, C7, or C6 alkaryl group), where the carbon number indicates the total number of carbons in the aryl portion and the alkylene, alkenylene, or alkynylene portion of the alkaryl group. Examples of alkaryl groups include, but are not limited to, (C1-C8)alkylene(C6-C12)aryl, (C2-C8)alkenylene(C6-C12)aryl, or (C2-C8)alkynylene(C6-C12)aryl. In some embodiments, the alkaryl group is benzyl or phenethyl. In a heteroalkaryl group, one or more heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the alkaryl group and / or may be present in the aryl portion of the alkaryl group. In an optionally substituted alkaryl group, substituents may be present on the alkylene, alkenylene, or alkynylene portion of the alkaryl group and / or may be present on the aryl portion of the alkaryl group.

[1056] As used herein, the term "amino" refers to -N(R x )2 or -N + (R x )3, where R x Each independently represents H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x In some embodiments, the amino group is -NH2.

[1057] As used herein, the term "alkylamino" refers to an amino group as described herein that is attached to an alkylene group (e.g., C1-C5 alkylene), an alkenylene group (e.g., C2-C5 alkenylene), or an alkynylene group (e.g., C2-C5 alkenylene). Generally, if a compound is attached to an alkylamino group, the alkylene, alkenylene, or alkynylene portion of the alkylamino group is attached to the compound. The amino portion of an alkylamino group refers to -N(R x )2 or -N + (R x )3, where R x Each independently represents H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R xIn some embodiments, the amino group of an alkylamino group is -NH2. Examples of alkylamino groups are C1-C5 alkylamino groups, such as C2 alkylamino groups (e.g., CH2CH2NH2 or CH2CH2N(CH3)2). In heteroalkylamino groups, one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkylamino group. In some embodiments, the alkylamino group may be optionally substituted. In substituted alkylamino groups, substituents may be present on the alkylene, alkenylene, or alkynylene portion of the alkylamino group and / or on the amino group of the alkylamino group.

[1058] As used herein, the term "alkanoamide" refers to an amide group that is attached to an alkylene group (e.g., C1-C5 alkylene), an alkenylene group (e.g., C2-C5 alkenylene), or an alkynylene group (e.g., C2-C5 alkenylene). Generally, if a compound is attached to an alkanoamide group, the alkylene, alkenylene, or alkynylene portion of the alkanoamide is attached to the compound. The amide portion of an alkanoamide refers to -C(O)-N(R x )2, where R x Each independently represents H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x In some embodiments, the amide portion of the alkanoyl group is -C(O)NH2. The alkanoyl group may be -(CH2)2-C(O)NH2 or -CH2-C(O)NH2. In a heteroalkanoyl group, one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkanoyl group. In some embodiments, the alkanoyl group may be optionally substituted. In a substituted alkanoyl group, substituents may be present on the alkylene, alkenylene, or alkynylene portion of the alkanoyl group and / or on the amide portion of the alkanoyl group.

[1059] As used herein, the terms "alkylene," "alkenylene," and "alkynylene" refer to divalent groups of the specified size. In some embodiments, the alkylene group may contain, for example, 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, the alkenylene or alkynylene group may contain, for example, 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Alkylene, alkenylene, and / or alkynylene groups include both straight and branched chain forms, as well as combinations thereof. The divalency of an alkylene, alkenylene, or alkynylene group does not include optional substituents on the alkylene, alkenylene, or alkynylene group. For example, two neuraminidase inhibitors can be attached to each other via a linker comprising an alkylene, alkenylene, and / or alkynylene group, or a combination thereof. Each of the alkylene, alkenylene, and / or alkynylene groups in the linker is considered divalent with respect to two attachments to either terminus of the alkylene, alkenylene, and / or alkynylene group. For example, if a linker comprises -(optionally substituted alkylene)-(optionally substituted alkenylene)-(optionally substituted alkylene)-, the alkenylene group is considered divalent with respect to its attachment to two alkylene groups at the termini of the linker. Optional substituents on the alkenylene group are not included in the divalency of the alkenylene group. The divalent nature of an alkylene, alkenylene, or alkynylene group (e.g., an alkylene, alkenylene, or alkynylene group in a linker) refers to both termini of the group and does not include optional substituents that may be present in the alkylene, alkenylene, or alkynylene group. Because it is divalent, it allows for the attachment of multiple (e.g., two) moieties of a conjugate (e.g., a first neuraminidase inhibitor and a second neuraminidase inhibitor) together. Alkylene, alkenylene, and / or alkynylene groups may be substituted with groups typically suitable as substituents for alkyl, alkenyl, and alkynyl groups as described herein. For example, C═O is a C₁ alkylene group substituted with oxo (═O). For example, -HCR-C≡C- is considered an optionally substituted alkynylene group and is considered a divalent group, even though it has the optional substituent R. Heteroalkylene, heteroalkenylene, and / or heteroalkynylene groups refer to alkylene, alkenylene, and / or alkynylene groups that include one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms (e.g., N, O, and S). For example, a polyethylene glycol (PEG) polymer or a PEG unit in a PEG polymer, -(CH2)2-O-, is considered a heteroalkylene group containing one or more oxygen atoms.

[1060] As used herein, "combination therapy" or "combination administration" means administering a conjugate described herein (e.g., a conjugate of any of Formulas (I)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)) and one (or more) different agents or treatments to a subject as part of a defined treatment regimen for a viral infection. The treatment regimen determines the dosage and periodicity of administration of each agent so that the effects of the different agents on the subject overlap. In some embodiments, the delivery of the conjugate and one or more agents is synchronous or simultaneous and the conjugate and one or more agents may be co-formulated. In some embodiments, the conjugate and one or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, the combined administration of the conjugate and one or more agents or treatments results in a reduction in symptoms or other parameters associated with a viral infection that is greater than that which would be observed if only one of the agents or treatments were delivered or if only one were present. The effects of the conjugate and one or more agents may be partially additive, fully additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a conjugate described herein can be administered by intravenous injection, while a second therapeutic agent of the combination can be administered orally.

[1061] As used herein, the term "cycloalkylene" refers to a divalent cyclic group that connects two parts of a compound together. For example, one carbon in a cycloalkylene group may be connected to a part of the compound, and another carbon in a cycloalkylene group may be connected to another part of the compound. Cycloalkylene groups may include saturated or unsaturated non-aromatic cyclic groups. Cycloalkylene groups may have, for example, three to twenty carbons (for example, C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18 or C3-C20 cycloalkylene groups) in the cyclic portion of the cycloalkylene group. When a cycloalkylene group includes at least one carbon-carbon double bond, the cycloalkylene group may be referred to as a "cycloalkenylene group." Cycloalkenylene can have, for example, four to twenty carbon atoms in the cyclic portion of the cycloalkenylene (e.g., C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenylene). When a cycloalkylene group contains at least one carbon-carbon triple bond, the cycloalkylene group can be referred to as a "cycloalkynylene group." A cycloalkynylene group can have, for example, four to twenty carbon atoms in the cyclic portion of the cycloalkynylene group (e.g., C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C8-C20 cycloalkynylene). Cycloalkylene groups may be substituted with groups typically suitable as substituents for alkyl, alkenyl, and alkynyl groups as described herein. Heterocycloalkylene groups refer to cycloalkylene groups containing one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms (e.g., N, O, and S). Examples of cycloalkylene groups include, but are not limited to, cyclopropylene and cyclobutylene. Tetrahydrofuran may be considered a heterocycloalkylene group.

[1062] As used herein, the term "arylene" refers to a polyvalent (e.g., divalent or trivalent) aromatic group that links together multiple (e.g., two or three) parts of a compound. For example, one carbon within an arylene group may be linked to one part of the compound, while another carbon within the arylene group may be linked to another part of the compound. An arylene group may have, for example, five to fifteen carbon atoms in the aryl portion of the arylene group (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C11, C5-C12, C5-C13, C5-C14, or C5-C15 arylene group). An arylene group may be substituted with groups that are typically suitable as substituents for alkyl, alkenyl, and alkynyl groups as described herein. A heteroarylene group refers to an aromatic group that contains one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms (e.g., N, O, and S). A heteroarylene group can have, for example, two to fifteen carbons (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C2-C11, C2-C12, C2-C13, C2-C14, or C2-C15 heteroarylene group).

[1063] As used herein, the term "optionally substituted" refers to having 0, 1 or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, alkaryl, acyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkaryl, halogen, oxo, cyano, nitro, amino, alkylamino, hydroxy, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, urea, amidinyl, any of the above groups or moieties, and hetero forms of any of the above groups or moieties. Substituents include, but are not limited to, F, Cl, methyl, phenyl, benzyl, OR, NR2, SR, SOR, S02R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, S03R, CONR2, SO2NR2, NRSO2NR2, CN, CF3, OCF3, SiR3, and NO2, wherein each R is independently H, alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, or heteroaryl, and wherein two optional substituents on the same or adjacent atoms may join to form a fused, optionally substituted, aromatic or non-aromatic, saturated or unsaturated ring containing 3-8 members, or two optional substituents on the same atom may join to form an optionally substituted, aromatic or non-aromatic, saturated or unsaturated ring containing 3-8 members.

[1064] An optionally substituted group or moiety refers to a group or moiety (e.g., any of the above groups or moieties) in which one atom (e.g., a hydrogen atom) is optionally replaced by another substituent. For example, an optionally substituted alkyl group may be an optionally substituted methyl group, wherein the hydrogen atom of the methyl group is replaced by, for example, OH. As another example, a substituent on a heteroalkyl group or its divalent counterpart, a heteroalkylene group, may replace a hydrogen on a carbon or a hydrogen on a heteroatom such as N. For example, a hydrogen atom in the group -R-NH-R- can be replaced by an alkanoamide substituent, such as -RN[(CH2C(O)N(CH3)2]-R. In general, the optional substituents are non-interfering substituents. A "non-interfering substituent" is a substituent that retains the ability of the conjugate described herein (e.g., a conjugate of any of Formulas (I)-(5), (DI)-(DX), (D'-I), (MI)-(M-XI), or (M'-I)) to bind to viral neuraminidase or inhibit the proliferation of influenza virus. Thus, in some embodiments, the substituent may alter the extent of the activity. However, as long as the conjugate retains the ability to bind to viral neuraminidase or inhibit viral proliferation, the substituent will be classified as "non-interfering." For example, a non-interfering substituent will retain the ability of the compound to bind to viral neuraminidase or inhibit viral proliferation based on a viral plaque reduction assay of 10 μM or less. IC50 values ​​(such as those based on an IC50 value of less than 500 nM for influenza virus neuraminidase in Example 2) provide an indication of the ability to achieve antiviral efficacy. Thus, the substituents may alter the degree of inhibition based on plaque reduction or influenza virus neuraminidase inhibition. However, as long as the compounds herein (such as compounds of Formula (AI), (A-II), (A-III), (A-IV), (AV), (A-VI), (A-VII), (A-VIII), (A-IX), (AX), (A-XI), (A-XII), and (A-XIII)) retain the ability to inhibit influenza virus neuraminidase activity, the substituents will be classified as "non-interfering." A variety of assays are available in the art for determining viral plaque reduction or the ability of any compound to inhibit influenza virus neuraminidase, and some are exemplified in the Examples below.

[1065] The term "hetero" when used to describe a chemical group or moiety refers to a group having at least one heteroatom other than carbon or hydrogen, such as N, O, and S. If any of the above groups or moieties contains at least one heteroatom, it may be referred to as hetero. For example, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl refers to a cycloalkyl, cycloalkenyl, or cycloalkynyl group having one or more heteroatoms independently selected from, for example, N, O, and S. An example of a heterocycloalkenyl group is maleimido. For example, heteroaryl refers to an aromatic group having one or more heteroatoms independently selected from, for example, N, O, and S. One or more heteroatoms may also be included in a substituent that replaces a hydrogen atom in a group or moiety as described herein. For example, in an optionally substituted heteroaryl group, if one of the hydrogen atoms in the heteroaryl group is replaced by a substituent (e.g., methyl), the substituent may also contain one or more heteroatoms (e.g., methanol).

[1066] As used herein, the term "acyl" refers to a group having the following structure: where R z is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, alkylamino, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaryl, heteroalkaryl, or heteroalkylamino.

[1067] As used herein, the term "halo" or "halogen" refers to any halogen atom, such as F, Cl, Br, or I. If any of the groups or moieties described herein contains at least one halogen atom, it can be referred to as a "halo moiety," such as a haloalkyl group.

[1068] As used herein, the term "hydroxy" refers to an -OH group.

[1069] As used herein, the term "oxo" refers to a substituent having the structure =0 where a double bond exists between the atom and the oxygen atom.

[1070] As used herein, the term "carbonyl" refers to a group having the following structure:

[1071] As used herein, the term "thiocarbonyl" refers to a group having the following structure:

[1072] As used herein, the term "phosphate group" refers to a group having the following structure:

[1073] As used herein, the term "phosphoryl" refers to a group having the following structure:

[1074] As used herein, the term "sulfonyl" refers to a group having the following structure:

[1075] As used herein, the term "imino" refers to a group having the following structure: wherein R is an optional substituent.

[1076] As used herein, the term "N-protecting group" refers to groups that are intended to protect amino groups from undesirable reactions during the synthesis procedure. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 5th edition (John Wiley & Sons, New York, 2014), which is incorporated herein by reference. N-protecting groups include, for example, acyl, aroyl, and carbamoyl groups, such as formyl, acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, carboxybenzyl (CBz), 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D,L-amino acid residues such as alanine, leucine, phenylalanine; sulfonyl-containing groups such as benzylsulfonyl and p-toluenesulfonyl; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, tert-butyloxycarbonyl (BOC), diisopropylmethoxy carbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl and phenylthiocarbonyl; alkaryl such as benzyl, triphenylmethyl and benzyloxymethyl; and silyl such as trimethylsilyl.

[1077] As used herein, the term "amino acid" means naturally occurring amino acids and non-naturally occurring amino acids.

[1078] As used herein, the term "naturally occurring amino acids" refers to amino acids including Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val.

[1079] As used herein, the term "non-naturally occurring amino acid" means an alpha amino acid that is not naturally produced or found in mammals. Examples of non-naturally occurring amino acids include D-amino acids; amino acids having an acetylaminomethyl group attached to the sulfur atom of cysteine; PEGylated amino acids; amino acids of the formula NH2(CH2) nCOOH ω amino acids, wherein n is 2-6, neutral non-polar amino acids such as sarcosine, tert-butylalanine, tert-butylglycine, N-methylisoleucine and norleucine; oxymethionine; phenylglycine; citrulline; methionine sulfoxide; cysteic acid; ornithine; diaminobutyric acid; 3-aminoalanine; 3-hydroxy-D-proline; 2,4-diaminobutyric acid; 2-aminopentanoic acid; 2-aminooctanoic acid, 2-carboxypiperazine; piperazine-2-carboxylic acid, 2-amino-4-phenylbutyric acid; 3-(2-naphthyl)alanine, and hydroxyproline. Other amino acids are α-aminobutyric acid, α-amino-α-methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, aminonorbornyl-carboxylate, L-cyclohexylalanine, cyclopentylalanine, LN-methylleucine, LN-methylmethionine, LN-methylnorvaline, LN-methylphenylalanine, LN-methylproline, LN-methylserine, LN-methyltryptophan, D-ornithine, LN-methylethylglycine, L-norleucine, α-methyl-aminoisobutyrate, α-methylcyclohexylalanine, D-α-methylalanine , D-α-methylarginine, D-α-methylasparagine, D-α-methylaspartate, D-α-methylcysteine, D-α-methylglutamine, D-α-methylhistidine, D-α-methylisoleucine, D-α-methylleucine, D-α-methyllysine, D-α-methylmethionine, D-α-methylornithine, D-α-methylphenylalanine, D-α-methylproline, D-α-methylserine, DN-methylserine, D-α-methylthreonine, D-α-methyltryptophan, D-α-methyltyrosine, D-α- Methylvaline, DN-methylalanine, DN-methylarginine, DN-methylasparagine, DN-methylaspartate, DN-methylcysteine, DN-methylglutamine, DN-methylglutamate, DN-methylhistidine, DN-methylisoleucine, DN-methylleucine, DN-methyllysine, N-methylcyclohexylalanine, DN-methylornithine, N-methylglycine, N-methylaminoisobutyrate, N-(1-methylpropyl)glycine, N-(2-methylpropyl)glycine, DN-methyltryptophan, DN- Methyltyrosine, DN-methylvaline, γ-aminobutyric acid, L-tert-butylglycine, L-ethylglycine, L-homophenylalanine, L-α-methylarginine, L-α-methylaspartate, L-α-methylcysteine, L-α-methylglutamine, L-α-methylhistidine, L-α-methylisoleucine, L-α-methylleucine, L-α-methylmethionine, L-α-methylnorvaline, L-α-methylphenylalanine, L-α-methylserine, L-α-methyltryptophan, L-α-methylvaline, N-(N-(2,2-Diphenylethyl)carbamoylmethylglycine, 1-carboxy-1-(2,2-diphenyl-ethylamino)cyclopropane, 4-hydroxyproline, ornithine, 2-aminobenzoyl (o-aminobenzoyl), D-cyclohexylalanine, 4-phenyl-phenylalanine, L-citrulline, α-cyclohexylglycine, L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4-carboxylic acid, L-homotyrosine, L-2-furylalanine, L-histidine (3-methyl), N-(3-guanidinopropyl)glycine, O-methyl-L-tyrosine, O-glycan-serine, m-tyrosine, n-tyrosine, LN,N′,N″-trimethyllysine, homolysine, n-lysine, N -polysaccharide asparagine, 7-hydroxy-1,2,3,4-tetrahydro-4-fluorophenylalanine, 4-methylphenylalanine, bis-(2-picolyl)amine, pentafluorophenylalanine, indoline-2-carboxylic acid, 2-aminobenzoic acid, 3-amino-2-naphthoic acid, asymmetric dimethylarginine, L-tetrahydroisoquinoline-1-carboxylic acid, D-tetrahydroisoquinoline-1-carboxylic acid, 1-amino-cyclohexaneacetic acid, D / L-allylglycine, 4-aminobenzoic acid, 1-amino-cyclobutanecarboxylic acid, 2 or 3 or 4-aminocyclohexanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic acid, 1-aminoindan-1-carboxylic acid, 4-amino-pyrrolidine-2-carboxylic acid, 2-aminotetralin-2-carboxylic acid, azetidine-3-carboxylic acid, 4- Benzyl-pyrrolidine-2-carboxylic acid, tert-butylglycine, b-(benzothiazolyl-2-yl)-alanine, b-cyclopropylalanine, 5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid, (2R,4S)4-hydroxypiperidine-2-carboxylic acid, (2S,4S) and (2S,4R)-4-(2-naphthylmethoxy)-pyrrolidine-2-carboxylic acid, (2S,4S) and (2S,4R)4-phenoxy-pyrrolidine-2-carboxylic acid, (2R,5S) and (2S,5R)-5-phenyl-pyrrolidine-2-carboxylic acid, (2S,4S)-4-amino-1-benzoyl-pyrrolidine-2-carboxylic acid, tert-butylalanine, (2S,5R)-5-phenyl-pyrrolidine-2-carboxylic acid, 1 -Aminomethyl-cyclohexane-acetic acid, 3,5-bis-(2-amino)ethoxy-benzoic acid, 3,5-diamino-benzoic acid, 2-methylamino-benzoic acid, N-methylanthranilic acid, LN-methylalanine, LN-methylarginine, LN-methylasparagine, LN-methylaspartic acid, LN-methylcysteine, LN-methylglutamine, LN-methylglutamic acid, LN-methylhistidine, LN-methylisoleucine, LN-methyllysine, LN-methylnorleucine, LN-methylornithine, LN-methylthreonine, LN-methyltyrosine, LN-methylvaline, LN-methyl-tert-butylglycine, L-norvaline, α-methyl-γ-aminobutyrate, 4,4'-Diphenylalanine, α-methylcyclopentylalanine, α-methyl-α-naphthylalanine, α-methylpenicillamine, N-(4-aminobutyl)glycine, N-(2-aminoethyl)glycine, N-(3-aminopropyl)glycine, N-amino-α-methylbutyrate, α-naphthylalanine, N-benzylglycine, N-(2-carbamoylethyl)glycine, N-(carbamoylmethyl)glycine, N-(2-carboxyethyl)glycine, N-(carboxymethyl)glycine, N-cyclobutylglycine, N-cyclodecylglycine, N-cycloheptylglycine, N-cyclohexylglycine, N-cyclodecylglycine, N-cyclododecylglycine, N-cyclooctylglycine, N-cyclopropylglycine, N-cyclodecanylglycine Monoalkylglycine, N-(2,2-diphenylethyl)glycine, N-(3,3-diphenylpropyl)glycine, N-(3-guanidinopropyl)glycine, N-(1-hydroxyethyl)glycine, N-(hydroxyethyl))glycine, N-(imidazolylethyl))glycine, N-(3-indolylethyl)glycine, N-methyl-γ-aminobutyrate, DN-methylmethionine, N-methylcyclopentylalanine, DN-methylphenylalanine, DN-methylproline, DN-methylthreonine, N-(1-methylethyl)glycine, N-methyl-naphthylalanine, N-methylpenicillamine, N-(p-hydroxyphenyl)glycine, N-(thiomethyl)glycine, penicillamine, L-α-methylalanine, L-α-methyl Asparagine, L-α-methyl-tert-butylglycine, L-methylethylglycine, L-α-methylglutamate, L-α-methylhomophenylalanine, N-(2-methylthioethyl)glycine, L-α-methyllysine, L-α-methylnorleucine, L-α-methylornithine, L-α-methylproline, L-α-methylthreonine, L-α-methyltyrosine, LN-methyl-homophenylalanine, N-(N-(3,3-diphenylpropyl)carbamoylmethylglycine, L-pyroglutamic acid, D-pyroglutamic acid, O-methyl-L-serine, O-methyl-L-homoserine, 5-hydroxylysine, α-carboxyglutamate, phenylglycine, L-pipecolic acid (homoproline), L-homoleucine, L-lysine amino acid (dimethyl), L-2-naphthylalanine, L-dimethyldopa or L-dimethoxy-phenylalanine, L-3-pyridylalanine, L-histidine (benzoyloxymethyl), N-cycloheptylglycine, L-diphenylalanine, O-methyl-L-homotyrosine, L-β-homolysine, O-polysaccharide-threonine, o-tyrosine, LN,N′-dimethyllysine, L-homoarginine, neotryptophan, 3-benzothienylalanine, isoquinoline-3-carboxylic acid, diaminopropionic acid, homocysteine, 3,4-dimethoxyphenylalanine, 4-chlorophenylalanine, L-1,2,3,4-tetrahydronorharman-3-carboxylic acid, adamantylalanine, symmetrical dimethylarginine, 3-carboxythiomorpholine, D-1,2,3,4-Tetrahydronorharman-3-carboxylic acid, 3-aminobenzoic acid, 3-amino-1-carboxymethyl-pyridin-2-one, 1-amino-1-cyclohexanecarboxylic acid, 2-aminocyclopentanecarboxylic acid, 1-amino-1-cyclopropanecarboxylic acid, 2-aminoindan-2-carboxylic acid, 4-amino-tetrahydrothiopyran-4-carboxylic acid, azetidine-2-carboxylic acid, b-(benzothiazol-2-yl)-alanine, neopentylglycine, 2-carboxymethylpiperidine, b-cyclobutylalanine, allylglycine, diaminopropionic acid, homo-cyclohexylalanine, (2S,4R)-4-hydroxypiperidin-2- Formic acid, octahydroindole-2-carboxylic acid, (2S,4R) and (2S,4R)-4-(2-naphthyl), pyrrolidine-2-carboxylic acid, piperidine carboxylic acid, (2S,4R) and (2S,4S)-4-(4-phenylbenzyl)pyrrolidine-2-carboxylic acid, (3S)-1-pyrrolidine-3-carboxylic acid, (2S,4S)-4-tritylmercapto-pyrrolidine-2-carboxylic acid, (2S,4S)-4-mercaptoproline, tert-butylglycine, N,N-bis(3-aminopropyl)glycine, 1-amino-cyclohexane-1-carboxylic acid, N-mercaptoethylglycine and selenocysteine. In some embodiments, the amino acid residues may be charged or polar. Charged amino acids include alanine, lysine, aspartic acid or glutamic acid, or non-naturally occurring analogs thereof. Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan, or non-naturally occurring analogs thereof. Specifically, it is contemplated that in some embodiments, the terminal amino group in an amino acid may be an amide group or a carbamate group.

[1080] As used herein, the term "percent (%) identity" refers to the percentage of amino acid residues in a candidate sequence (e.g., Fc-IgG or a fragment thereof) that are identical to the amino acid residues of a reference sequence after aligning the sequences and, if necessary, introducing gaps to achieve maximum percent identity (i.e., gaps can be introduced in one or both of the candidate and reference sequences for optimal alignment and non-homologous sequences can be ignored for comparison purposes). Alignment for the purpose of determining percent identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithm required to achieve maximum alignment over the full length of the compared sequences. In some embodiments, the percent amino acid sequence identity of a given candidate sequence relative to, with, or for a given reference sequence (which, alternatively, can be expressed as a given candidate sequence having or including a certain percent amino acid sequence identity relative to, with, or for a given reference sequence) is calculated as follows:

[1081] 100×(score of A / B)

[1082] wherein A is the number of amino acid residues scored as identical in an alignment of the candidate sequence with the reference sequence, and wherein B is the total number of amino acid residues in the reference sequence. In some embodiments where the length of the candidate sequence is not equal to the length of the reference sequence, the percent amino acid sequence identity of the candidate sequence to the reference sequence will not be equal to the percent amino acid sequence identity of the reference sequence to the candidate sequence.

[1083] Two polynucleotide or polypeptide sequences are said to be "identical" if the sequence of nucleotides or amino acids in the sequences is the same when aligned for maximum correspondence as described above. Comparisons between two sequences are typically performed by comparing the sequences in a comparison window to identify and compare local regions of sequence similarity. As used herein, a "comparison window" refers to a segment of at least about 15 contiguous positions, about 20 contiguous positions, about 25 contiguous positions, or more (e.g., about 30 to about 75 contiguous positions or about 40 to about 50 contiguous positions) over which the two sequences can be compared after the sequence and a reference sequence of the same number of contiguous positions have been optimally aligned.

[1084] As used herein, the term "treating" or "to treat" refers to the therapeutic treatment of a viral infection (e.g., a viral infection such as influenza infection) in a subject. In some embodiments, therapeutic treatment can slow the progression of the viral infection, improve the prognosis of the subject, and / or eliminate the infection. In some embodiments, therapeutic treatment of a viral infection in a subject can alleviate or improve one or more symptoms or conditions associated with the viral infection, reduce viral levels, stabilize (i.e., not worsen) the state of the viral infection, prevent the spread of the viral infection, and / or delay or slow the progression of the viral infection, as compared to the state and / or conditions of the viral infection in the absence of the therapeutic treatment.

[1085] As used herein, the term "average value of T" refers to the average number of neuraminidase inhibitor monomers or neuraminidase inhibitor dimers conjugated to the Fc domain or albumin within a conjugate population. In some embodiments, within the conjugate population, the average number of neuraminidase inhibitor monomers or neuraminidase inhibitor dimers conjugated to the Fc domain monomers may be 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, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5). In some embodiments, the average value of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[1086] As used herein, the term "subject" can be a human, non-human primate, or other mammal, such as, but not limited to, dogs, cats, horses, cows, pigs, turkeys, goats, fish, monkeys, chickens, rats, mice, and sheep.

[1087] As used herein, the term "therapeutically effective amount" refers to an amount, such as a drug dosage, that is effective to induce a desired effect in a subject or to treat a subject suffering from a condition or disorder described herein (e.g., a viral infection, such as influenza infection). It should also be understood herein that a "therapeutically effective amount" can be interpreted as an amount that gives the desired therapeutic and / or prophylactic effect, taken in one or more doses or by any dose or route, and / or taken alone or in combination with other therapeutic agents (e.g., an antiviral agent described herein). For example, in the case of administering a conjugate described herein (e.g., a conjugate of any of Formulas (I)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)) for the treatment of a viral infection, a therapeutically effective amount of the conjugate is, for example, an amount sufficient to prevent, slow, or reverse the progression of the viral infection, as compared to the response obtained without administration of the conjugate.

[1088] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical or pharmaceutical formulation containing at least one active ingredient (e.g., a conjugate of any of Formulas (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)) and one or more excipients and diluents that render the active ingredient suitable for administration. The pharmaceutical compositions of the present disclosure comprise pharmaceutically acceptable components that are compatible with the conjugates described herein (e.g., a conjugate of any of Formulas (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I).

[1089] As used herein, the term "pharmaceutically acceptable carrier" refers to an excipient or diluent in a pharmaceutical composition. For example, a pharmaceutically acceptable carrier may be a vehicle that is capable of suspending or dissolving the active conjugate (e.g., a conjugate of any of Formulas (I)-(5), (DI)-(D-XI), or (MI)-(M-VI)). A pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not harmful to the recipient. In the present disclosure, a pharmaceutically acceptable carrier must provide sufficient pharmaceutical stability for the conjugates described herein. The nature of the carrier varies depending on the mode of administration. For example, for oral administration, solid carriers are preferred; for intravenous administration, aqueous carriers (e.g., WFI and / or buffered solutions) are generally used.

[1090] As used herein, the term "pharmaceutically acceptable salt" refers to salts of the conjugates described herein (e.g., conjugates of any of Formulas (I)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)) that are suitable for use in the methods described herein without undue toxicity, irritation, and / or allergic response, within the scope of sound medical judgment. Pharmaceutical...

Claims

1. A conjugate described by any of the following: formula (D-I), (M-I), (1) or (2) wherein each A1 and each A2 are independently described by formula (A-I)-(A-XII): wherein R1 is selected from -OH, -NH2, -NHC(=NH)NH2 and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5 is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from: R6 is selected from R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; R8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl and C2-C15 heteroaryl; n is 1 or 2; each E comprises an Fc domain monomer, an albumin protein, an albumin protein-binding peptide or an Fc-binding peptide; L is a linker covalently attached to E and attached to each Y of each A1 or each A1 and A2; T is an integer from 1 to 20, and each wavy line in formula (D-I), (M-I), (1) or (2) indicates that L is covalently attached to each E; or a pharmaceutically acceptable salt thereof.

2. The conjugate according to claim 1, wherein the conjugate is described by: formula (D-I) wherein each A1 and each A2 are independently selected from any one of formula (A-I)-(A-XII); each E comprises an Fc domain monomer, an albumin protein, an albumin protein-binding peptide or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20; and The wavy line connected to said E indicates that the L of each A1-L-A2 is covalently attached to E, or a pharmaceutically acceptable salt thereof.

3. The conjugate according to any one of claims 1 or 2, wherein the conjugate is described by: formula (D-II) or a pharmaceutically acceptable salt thereof.

4. The conjugate according to claim 3, wherein the conjugate is described by: formula (D-II-1) or a pharmaceutically acceptable salt thereof.

5. The conjugate according to claim 4, wherein the conjugate is described by: formula (D-II-6) wherein R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; or a pharmaceutically acceptable salt thereof.

6. The conjugate according to claim 5, wherein R7 is selected from C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl.

7. The conjugate according to claim 5 or 6, wherein R7 is selected from methyl, ethyl, propyl or butyl.

8. The conjugate according to any one of claims 5-7, wherein the conjugate is described by: formula (D-II-7) or a pharmaceutically acceptable salt thereof.

9. The conjugate according to claim 8, wherein the conjugate is described by: formula (D-II-8) wherein L’ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

10. The conjugate according to claim 9, wherein the conjugate has the following structure: or a pharmaceutically acceptable salt thereof.

11. The conjugate according to claim 10, wherein the conjugate has the following structure: or a pharmaceutically acceptable salt thereof.

12. The conjugate according to claim 1, wherein the conjugate is described by the following: Formula (M-I) wherein each A1 is independently selected from any one of Formulas (A-I)-(A-XII); each E comprises an Fc domain monomer, an albumin protein, an albumin-binding peptide or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20; and L is a linker covalently attached to each of E and A1, the wavy line connected to the E indicates that the L of each A1-L is covalently attached to E; or a pharmaceutically acceptable salt thereof.

13. The conjugate according to claim 12, wherein the conjugate is described by the following: Formula (M-II) or a pharmaceutically acceptable salt thereof.

14. The conjugate according to claim 13, wherein the conjugate is described by the following: Formula (M-II-6) wherein R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; or a pharmaceutically acceptable salt thereof.

15. The conjugate according to claim 14, wherein R7 is selected from C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl.

16. The conjugate according to claim 14 or 15, wherein R7 is selected from methyl, ethyl, propyl or butyl.

17. The conjugate according to any one of claims 1-16, wherein the wavy line connected to E indicates that the L of each A1-L or each A1-L-A2 is covalently attached to the nitrogen atom of a solvent-exposed lysine of E.

18. The conjugate according to any one of claims 1-16, wherein the wavy line connected to E indicates that the L of each A1-L or each A1-L-A2 L is covalently attached to the sulfur atom of a solvent-exposed cysteine of E.

19. The conjugate according to any one of claims 1-18, wherein each E is a monomer of an Fc domain.

20. The conjugate according to claim 19, wherein n is 2, and each E dimerizes to form an Fc domain.

21. The conjugate according to claim 2, wherein n is 2, each E is a monomer of an Fc domain, each E dimerizes to form an Fc domain, and the conjugate is described by the following: formula (D-I-1) wherein J is an Fc domain; and T is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

22. The conjugate according to claim 21, wherein the conjugate has the following structure: or a pharmaceutically acceptable salt thereof.

23. The conjugate according to claim 12, wherein n is 2, each E is a monomer of an Fc domain, each E dimerizes to form an Fc domain, and the conjugate is described by the following: formula (M-I-1) wherein J is an Fc domain; and T is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

24. The conjugate according to any one of claims 19-23, wherein each E comprises an amino acid sequence that is at least 95% identical to any one of the sequences of SEQ ID NOs: 1-138.

25. The conjugate according to claim 24, wherein each E comprises an amino acid sequence that is at least 95% identical to any one of the following sequences: SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 94, SEQ ID NO:

95.

26. The conjugate according to claim 25, wherein each E comprises the amino acid sequence of SEQ ID NO:

72.

27. The conjugate according to claim 25, wherein each E comprises the amino acid sequence of SEQ ID NO:

73.

28. The conjugate according to claim 25, wherein each E comprises the amino acid sequence of SEQ ID NO:

76.

29. The conjugate according to claim 25, wherein each E comprises the amino acid sequence of SEQ ID NO:

77.

30. The conjugate according to any one of claims 19 - 29, wherein T is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

31. A population of conjugates according to any one of claims 19 - 29, wherein the average value of T is from 1 to 10, from 5 to 10, from 1 to 5, from 3 to 7 or from 3.5 to 5.

5.

32. A population of conjugates according to any one of claims 19 - 29, wherein the average value of T is about 4.

5.

33. A pharmaceutical composition comprising a conjugate or a population of conjugates according to any one of claims 1 - 32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

34. A method for treating a subject suffering from or suspected of suffering from a viral infection, the method comprising administering to the subject an effective amount of a conjugate, a population of conjugates or a pharmaceutical composition according to any one of claims 1 - 33.

35. A method for prophylactically treating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, a population of conjugates or a pharmaceutical composition according to any one of claims 1 - 33.

36. The method according to claim 34 or 35, wherein the viral infection is caused by an influenza virus or a parainfluenza virus.

37. A method for preventing secondary infection in a subject diagnosed with an influenza infection, the method comprising administering to the subject a conjugate, a population of conjugates or a pharmaceutical composition according to any one of claims 1 - 33.

38. The method according to any one of claims 34 - 37, wherein the subject is treated with a second therapeutic agent.

39. A method for treating or preventing a viral infection in a subject, the method comprising administering to the subject: a) a conjugate, a population of conjugates or a composition according to any one of claims 1 - 33; and b) a second therapeutic agent.

40. The method according to any one of claims 38 or 39, wherein the second therapeutic agent is an antiviral agent.

41. The method according to claim 40, wherein the antiviral agent is pimodivir, oseltamivir, zanamivir, peramivir, laninamivir, amantadine, baloxavir marboxil, baloxavir acid, rimantadine, or a pharmaceutically acceptable salt thereof.

42. The method according to any one of claims 39-41, wherein the viral infection is caused by an influenza virus or a parainfluenza virus.

43. The method according to any one of claims 34-42, wherein the conjugate is described by formula (D-II-6).

44. The method according to claims 34-43, wherein the conjugate is described by formula (D-II-7).

45. The method according to any one of claims 34-44, wherein each E has a sequence that is at least 95% identical to the following sequences: SEQ ID NO:72 or SEQ ID NO:73, SEQ ID NO:76 or SEQ ID NO:

77.

46. The method according to any one of claims 34-45, wherein the conjugate is conjugate 45 or conjugate 46.

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