Compositions and methods for treating viral infections

Abstract

Compositions and methods for treating viral infections include conjugates containing viral neuraminidase inhibitors (e.g., zanamivir, peramivir, or their analogs) linked to Fc monomers, Fc domains, Fc binding peptides, albumin proteins, or albumin binding peptides. Specifically, the conjugates can be used to treat viral infections (e.g., influenza virus infections).

Description

Background Art

[0001] The need for novel antiviral treatments for influenza is significant and particularly important in the medical field. Influenza virus (the causative agent of influenza) or influenza causes three to five million severe illnesses 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 people with advanced HIV infection or transplant patients (whose immune systems are medically suppressed to prevent transplant organ rejection), are at greater risk of complications associated with influenza. Pregnant women and young children are also at high risk of complications.

[0002] The development of antiviral treatments for influenza has been an ongoing challenge. Several influenza antiviral agents have been approved for clinical use, and when vaccines are prepared, these agents play an important role in modulating disease severity and controlling epidemics. However, resistant strains to the most commonly used inhibitors have emerged.

[0003] Flu antiviral agents mainly target proteins presented on the surface of influenza virus particles. The envelope of influenza virus contains two immunodominant glycoproteins, i.e., hemagglutinin and neuraminidase, which play a key role in viral infection and spread. Hemagglutinin achieves the attachment of the virus to the host cell via its interaction with surface sialic acid, thereby starting 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. Neuraminidase inhibition therefore serves as a pharmacological target for antiviral drugs. Viral neuraminidase inhibitors for reducing viral spread have been determined, including oseltamivir (Tamiflu TM ), zanamivir (Relenza TM ) and peramivir (Rapivab TM ).

[0004] However, influenza in transplant recipients is still characterized by prolonged viral masking, increasing the likelihood of developing drug-resistant strains. New, more effective therapies for treating influenza are needed. Summary of the invention

[0005] 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 analog) that inhibits influenza virus neuraminidase, which is conjugated to an Fc monomer, an Fc domain, an Fc binding peptide, an albumin or an albumin binding peptide. The neuraminidase inhibitor (e.g., zanamivir, peramivir or its analog) 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.

[0006] In a first aspect, the present invention provides a conjugate described by any one of the following: formula (DI), (MI), (1) or (2)

[0007]

[0008] Each of A 1 And each A 2 Independently selected from any one of formula (AI)-(A-XII):

[0009]

[0010] Where R 1 Selected from -OH, -NH 2 、-NHC(=NH)NH 2 and -NHC(=NH)NHR 6 ; R 2 and R 3 are each independently selected from -H, -OH, -F, -Cl and -Br; R 4 Selected from -CO 2 H, -P(=O)(OH) 2 、-SO 3 H; R 5 Selected from -COCH 3 , -COCF 3 、-SO 2 CH3 ; X is selected from -O- and -S-; Y is selected from

[0011]

[0012] R 6 Selected from

[0013] R 7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; R 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl and C2-C15 heteroaryl;

[0014] n is 1 or 2;

[0015] Each E comprises an Fc domain monomer, albumin, an albumin binding peptide, or an Fc binding peptide;

[0016] L is covalently attached to E and to each A 1 or each A 1 and A 2 The connector of each Y;

[0017] T is an integer from 1 to 20, and

[0018] Each wavy line in formula (DI), (MI), (1) or (2) indicates that L is covalently attached to each E;

[0019] or a pharmaceutically acceptable salt thereof.

[0020] 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;

[0021] In some embodiments, n is 2 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), wherein the Fc domain monomer dimerizes to form an Fc domain;

[0022] L is covalently attached to each E and to each Y or each A 1 and / or A 2 The connector;

[0023] 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 A 1 -L or each A 1 -LA 2 can be independently selected (e.g., independently selected from A described herein 1 -L or A 1 -LA 2 structure).

[0024] 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 a 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), (2), (DI) (wherein n is equal to 2), or (MI) (wherein n is equal to 2), the Fc domain monomers dimerize to form an Fc domain.

[0025] In another aspect, the present invention provides a conjugate described by: Formula (DI)

[0026]

[0027] wherein each E comprises an Fc domain monomer (eg, an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138); each A 1 -LA 2 L in is covalently attached to the sulfur atom of the hinge cysteine ​​in E and to A 1 and A 2 ; 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 each A 1 -LA 2covalently 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 A 1 -LA 2 can be independently selected (e.g., independently selected from A described herein 1 -LA 2 structure).

[0028] In another aspect, the present invention provides a conjugate described by: Formula (DI)

[0029]

[0030] wherein each E comprises an Fc domain monomer (eg, an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138); each A 1 -LA 2 L in the sequence is covalently attached to the nitrogen atom of the surface-exposed lysine in E and to A 1 and A 2 ; 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 each A 1 -LA 2 covalently attached (e.g., by means of 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 A 1 -LA 2 can be independently selected (e.g., independently selected from A described herein 1 -LA 2 In some embodiments, A 1 and A 2 Each of A can be independently selected from any one of formula (AI), (A-II), (A-VI) or (A-VII). In other embodiments, A 1 and A 2 Each of can be independently selected from Formula (AI).

[0031] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0032]

[0033] wherein each E comprises an Fc domain monomer (eg, an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138); each LA 1 L in is covalently attached to the sulfur atom of the hinge cysteine ​​in E and to A 1 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 each LA 1 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 A 1 Can be independently selected from any structure described by formula (AI)-(A-XII). In some embodiments, each A 1 Can be independently selected from any one of formula (AI), (A-II), (A-VI) or (A-VII). In other embodiments, each A 1 may be independently selected from formula (AI).

[0034] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0035]

[0036] wherein each E comprises an Fc domain monomer (eg, an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138); each LA 1 L in the sequence is covalently attached to the nitrogen atom of the surface-exposed lysine in E and to A 1 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 each LA 1covalently attached (e.g., by means of 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 A 1 Can be independently selected from any structure described by formula (AI)-(A-XII). In some embodiments, each A 1 Can be independently selected from any one of formula (AI), (A-II), (A-VI) or (A-VII). In other embodiments, each A 1 may be independently selected from formula (AI).

[0037] In one aspect, the present disclosure provides a conjugate described by the following: Formula (1)

[0038]

[0039] Each of A 1 And each A 2 Independently selected from any one of formula (AI)-(A-XII);

[0040] Each E comprises an Fc domain monomer (eg, an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138); each A 1 -LA 2 L in the chain is covalently attached to the sulfur atom of each hinge cysteine ​​in E and to A 1 and A 2 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 the two E indicate that each A 1 -LA 2 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 A 1 -LA 2 can be independently selected (e.g., independently selected from A described herein 1 -LA 2 In some embodiments, A 1 and A 2Each of A can be independently selected from any one of formula (AI), (A-II), (A-VI) or (A-VII). In other embodiments, A 1 , A 2 Each of which can be independently selected from Formula (AI).

[0041] In another aspect, the present disclosure provides a conjugate described by the following: Formula (1)

[0042]

[0043] Each of A 1 And each A 2 are independently selected from any one of formulae (AI)-(AV); each E comprises an Fc domain monomer (eg, an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138); each A 1 -LA 2 L in the chain is covalently attached to the sulfur atom of each hinge cysteine ​​in E and to A 1 and A 2 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 the two E indicate that each A 1 -LA 2 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 A 1 -LA 2 can be independently selected (e.g., independently selected from A described herein 1 -LA 2 structure).

[0044] In another aspect, the present disclosure provides a conjugate described by the following: Formula (1)

[0045]

[0046] Each of A 1 And each A 2 Independently selected from any one of formula (A-VI)-(A-IX);

[0047] Each E comprises an Fc domain monomer (eg, an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138); each A1 -LA 2 L in the chain is covalently attached to the sulfur atom of each hinge cysteine ​​in E and to A 1 and A 2 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 the two E indicate that each A 1 -LA 2 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 A 1 -LA 2 can be independently selected (e.g., independently selected from A described herein 1 -LA 2 structure).

[0048] In another aspect, the present invention provides a conjugate described by the following formula (2)

[0049]

[0050] Each of A 1 are independently selected from any one of formulae (AI)-(A-XII); each E comprises an Fc domain monomer (eg, an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138); each LA 1 L in is covalently attached to the sulfur atom of the hinge cysteine ​​in E and to A 1 T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the two wavy lines connected to the two sulfur atoms indicate each LA 1 covalently (e.g., by means of a covalent bond or a linker) attached 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 A 1 Can be independently selected from any one of formula (AI)-(A-XII). In some embodiments, A 1 and A 2Each of A can be independently selected from any one of formula (AI), (A-II), (A-VI) or (A-VII). In other embodiments, A 1 , A 2 Each of which can be independently selected from Formula (AI).

[0051] In another aspect, the present invention provides a conjugate described by the following formula (2)

[0052]

[0053] Each of A 1 are independently selected from any one of formulae (AI)-(AV); each E comprises an Fc domain monomer (eg, an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138); each LA 1 L in is covalently attached to the sulfur atom of the hinge cysteine ​​in E and to A 1 T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the two wavy lines connected to the two sulfur atoms indicate each LA 1 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 A 1 Can be independently selected from any one of formulas (AI)-(AV).

[0054] In another aspect, the present invention provides a conjugate described by the following formula (2)

[0055]

[0056] Each of A 1 are independently selected from any one of Formulae (A-VI)-(A-IX); each E comprises an Fc domain monomer (eg, an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1-138); each LA 1 L in is covalently attached to the sulfur atom of the hinge cysteine ​​in E and to A 1 T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the two wavy lines connected to the two sulfur atoms indicate each LA 1covalently 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 A 1 Can be independently selected from any one of formula (A-VI)-(A-IX).

[0057] 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.

[0058] In some embodiments, at least one of the sulfur atom pair is a sulfur atom corresponding to (eg, a sulfur atom of) a hinge cysteine ​​of SEQ ID NO: 10 or SEQ ID NO: 11 (ie, 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).

[0059] 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).

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[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; 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 Cys14 (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 Cys14 (e.g., a sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another 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.

[0066] In some embodiments, the conjugate has the following structure:

[0067]

[0068] 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.

[0069] 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 c 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.

[0070] In some embodiments, each E comprises the sequence

[0071] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:4).

[0072] In some embodiments, each E comprises the sequence

[0073] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:33).

[0074] In some embodiments, at least one of the sulfur atom pair is a sulfur atom corresponding to the hinge cysteine ​​(i.e., Cys10 and / or Cys13) (e.g., the sulfur atom thereof) of SEQ ID NO: 4 or SEQ ID NO: 33. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 and Cys13 (e.g., the sulfur atom thereof) in SEQ ID NO: 4 or SEQ ID NO: 33.

[0075] In some embodiments, the sulfur atom pair comprises a 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., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) 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., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) 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.

[0076] In some embodiments, the conjugate has the following structure:

[0077]

[0078] 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.

[0079] In some embodiments, at least one of the sulfur atom pair is a sulfur atom corresponding to (e.g., a sulfur atom thereof) a hinge cysteine ​​(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., a sulfur atom thereof) Cys10 and Cys13 in SEQ ID NO: 8.

[0080] 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., 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, and 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.

[0081] In some embodiments, the conjugate has the following structure:

[0082]

[0083] 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.

[0084] In some embodiments, the conjugate has the following structure:

[0085]

[0086] 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.

[0087] In some embodiments, the conjugate has the following structure:

[0088]

[0089] 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.

[0090] In some embodiments, the conjugate has the following structure:

[0091]

[0092] 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.

[0093] In some embodiments of the previous three aspects, the nitrogen atom is a nitrogen of a surface exposed lysine, 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.

[0094] In some embodiments, the conjugate has the following structure:

[0095]

[0096] 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 NH 2In 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 e are 1 and b and d 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.

[0097] 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.

[0098] In another aspect, the invention provides a conjugate described by: (DI)

[0099]

[0100] wherein E comprises an albumin (eg, an albumin having a sequence of any one of SEQ ID NOs: 139-141), an albumin binding peptide, or an Fc binding peptide; each A 1 -LA 2 L in the above is independently covalently attached to the sulfur atom of the surface-exposed cysteine ​​or the nitrogen atom of the surface-exposed lysine in E and attached to A 1 and A 2; 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 each A 1 -LA 2 is independently covalently attached to the sulfur atom of the solvent-exposed cysteine ​​or the nitrogen atom of the 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 A 1 -LA 2 can be independently selected (e.g., independently selected from A described herein 1 -LA 2 In some embodiments, A 1 , A 2 Each of A can be independently selected from any one of formula (AI), (A-II), (A-VI) or (A-VII). In other embodiments, A 1 , A 2 Each of which can be independently selected from Formula (AI).

[0101] In the above preferred embodiments, x is 2.

[0102] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0103]

[0104] wherein E comprises albumin (eg, an albumin having a sequence of any one of SEQ ID NOs: 139-141), an albumin binding peptide, or an Fc binding peptide; each LA 1 L in the above is independently covalently attached to the sulfur atom of the surface-exposed cysteine ​​or the nitrogen atom of the surface-exposed lysine in E and attached to A 1 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 each LA 1 is independently covalently attached to the sulfur atom of the solvent-exposed cysteine ​​or the nitrogen atom of the 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 A 1Can be independently selected from any structure described by formula (AI)-(A-XII). In some embodiments, each A 1 Can be independently selected from any one of formula (AI), (A-II), (A-VI) or (A-VII). In other embodiments, each A 1 In the preferred embodiment above, x is 2.

[0105] In some embodiments, each E comprises an albumin having the sequence of any one of SEQ ID NOs: 139-141.

[0106] In some embodiments, T is 1 and LA 1 Covalently attached to the sulfur atom corresponding to Cys34 of SEQ ID NO:139.

[0107] The intermediates of Table 1a can be conjugated to an Fc domain or an Fc domain monomer (e.g., with the aid of 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 an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having a sequence of any one of SEQ ID NOs: 1-138). In a preferred embodiment, 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., PEG 2 -PEG 20 Linker). 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 a linker functionalized with an azido group and Int (e.g., Int of Table 1a) is functionalized with an alkynyl group. Linker-azido of E and linker-alkyne of Int are conjugated (e.g., by click chemistry) to form a conjugate of the invention, such as a conjugate described by formula (5). In yet other embodiments, E is conjugated to a linker functionalized with an alkynyl group and Int (e.g., Int of Table 1a) is functionalized with an azido group. Linker-alkyne of E and linker-azido of Int are conjugated (e.g., by click chemistry; see, e.g., Fig.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).

[0108] Table 1a: Intermediates

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123] 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 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., PEG 2 -PEG 20 linker), which in turn is conjugated to the amino acid side chains of E (see, e.g., Fig.103 ).

[0124] In some embodiments of the conjugate 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 a sequence of any one of SEQ ID NOs: 1-138), 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. When n is 2, 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), and the Fc domain monomers dimerize to form an Fc domain.

[0125] 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 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, 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. In certain embodiments, the average T is 1 to 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).

[0126] 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.

[0127] Table 1b: Conjugates corresponding to the intermediates of Table 1a

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150] 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.

[0151] In another aspect, the present invention provides a conjugate comprising (i) a first part A 1 (ii) Part II A 2 ; (iii) an Fc domain monomer or an Fc domain; and (iv) covalently attached to A 1 and A 2 and attached to said Fc domain monomer or a linker of said Fc domain; wherein each A 1And each A 2 is independently selected from any one of formula (AI)-(A-XII). In some embodiments, A 1 and A 2 Each of A can be independently selected from any one of formula (AI), (A-II), (A-VI) or (A-VII). In other embodiments, A 1 and A 2 Each of may be independently selected from formula (AI). In the above preferred embodiments, x is 2.

[0152] In another aspect, the present invention provides a conjugate comprising (i) a first part 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 in Table 1a.

[0153] In another aspect, the present invention provides a conjugate comprising (i) a first part A 1 (ii) Part II A 2 ; (iii) albumin, an albumin binding peptide or an Fc binding peptide; and (iv) covalently attached to A 1 and A 2 and a linker attached to the albumin, the albumin binding peptide or the Fc binding peptide; wherein each A 1 And each A 2 is independently selected from any one of formula (AI)-(A-XII). In some embodiments, A 1 and A 2 Each of A can be independently selected from any one of formula (AI), (A-II), (A-VI) or (A-VII). In other embodiments, A 1 and A 2 Each of may be independently selected from formula (AI). In the above preferred embodiments, x is 2.

[0154] In another aspect, the present invention provides a conjugate described by: Formula (DI)

[0155]

[0156] Each of A 1 And each A 2independently selected from any one of formulas (AI)-(A-XII); 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 albumin having a 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 covalently attached to E, A 1 and A 2 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 A 1 -LA 2 can be independently selected (e.g., independently selected from A described herein 1 -LA 2 In some embodiments, A 1 and A 2 Each of A can be independently selected from any one of formula (AI), (A-II), (A-VI) or (A-VII). In other embodiments, A 1 and A 2 Each of can be independently selected from Formula (AI).

[0157] In another aspect, the present invention provides a conjugate described by: Formula (DI)

[0158]

[0159] Each of A 1 And each A 2 independently selected from any one of formulas (AI)-(AV); 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 albumin having a 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 covalently attached to E, A 1 and A 2When 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 A 1 -LA 2 can be independently selected (e.g., independently selected from A described herein 1 -LA 2 structure).

[0160] In another aspect, the present invention provides a conjugate described by: Formula (DI)

[0161]

[0162] Each of A 1 And each A 2 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 a sequence of any one of SEQ ID NOs: 1-138), 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; 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 covalently attached to E, A 1 and A 2 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 A 1 -LA 2 can be independently selected (e.g., independently selected from A described herein 1 -LA 2 structure).

[0163] In some embodiments, the conjugate is described by: Formula (D-II)

[0164]

[0165] or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the conjugate is described by: Formula (D-II-1)

[0167]

[0168] or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the conjugate is described by: Formula (D-II-2)

[0170]

[0171] or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the conjugate is described by: Formula (D-II-3)

[0173]

[0174] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0175] In some embodiments, the conjugate has a structure selected from:

[0176]

[0177]

[0178] In some embodiments, the conjugate is described by: Formula (D-II-4)

[0179]

[0180] or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the conjugate is described by: Formula (D-II-5)

[0182]

[0183]

[0184] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0185] In some embodiments, the conjugate has a structure selected from the group consisting of:

[0186]

[0187] or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the conjugate has a structure selected from the group consisting of:

[0189]

[0190] or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, the conjugate is described by: Formula (D-II-6)

[0192]

[0193] Where R 7 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. 7 is selected from C1-C20 alkyl (eg, methyl, ethyl, propyl or butyl).

[0194] In some embodiments, the conjugate is described by: Formula (D-II-7)

[0195]

[0196] or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the conjugate is described by: Formula (D-II-8)

[0198]

[0199] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0200] In some embodiments, the conjugate has the structure

[0201]

[0202]

[0203] or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, the conjugate has the structure

[0205]

[0206] or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the conjugate has the structure

[0208]

[0209]

[0210] or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the conjugate has the structure

[0212]

[0213]

[0214] or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the conjugate is described by: Formula (D-II-9)

[0216]

[0217] or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the conjugate is described by: Formula (D-II-10)

[0219]

[0220] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g.,1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0221] In some embodiments, the conjugate has the structure

[0222]

[0223] or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the conjugate has the following structure:

[0225]

[0226] or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the conjugate is described by: Formula (D-III)

[0228]

[0229] or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the conjugate is described by: Formula (D-III-1)

[0231]

[0232] or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the conjugate is described by: Formula (D-III-2)

[0234]

[0235] or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, the conjugate is described by: Formula (D-III-3)

[0237]

[0238] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0239] In some embodiments, the conjugate is described by: Formula (D-III-4)

[0240]

[0241] or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the conjugate is described by: Formula (D-III-5)

[0243]

[0244] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0245] In some embodiments, the conjugate is described by: Formula (D-III-6)

[0246]

[0247] or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, the conjugate is described by: Formula (D-III-7)

[0249]

[0250] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0251] In some embodiments, the conjugate is described by: Formula (D-III-8)

[0252]

[0253] or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, the conjugate is described by: Formula (D-III-9)

[0255]

[0256] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0257] In some embodiments, the conjugate is described by: Formula (D-IV)

[0258]

[0259] or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, the conjugate is described by: Formula (D-IV-1)

[0261]

[0262] or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, the conjugate is described by: Formula (D-IV-2)

[0264]

[0265] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0266] In some embodiments, the conjugate is described by: Formula (DV)

[0267]

[0268] or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, the conjugate is described by: Formula (DV-1)

[0270]

[0271] or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the conjugate is described by: Formula (DV-2)

[0273]

[0274] or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the conjugate is described by: Formula (DV-3)

[0276]

[0277] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y 1 and 2 Each is 1, y 1 and 2 Each is 2, or y 1 and 2 Each is 3.

[0278] In some embodiments, the conjugate is described by: Formula (DV-4)

[0279]

[0280] or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the conjugate is described by: Formula (DV-5)

[0282]

[0283] where L' is the remainder of L, and y1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y 1 and 2 Each is 1, y 1 and 2 Each is 2, or y 1 and 2 Each is 3.

[0284] In some embodiments, the conjugate is described by: Formula (DV-6)

[0285]

[0286] or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, the conjugate is described by: Formula (DV-7)

[0288]

[0289] or a pharmaceutically acceptable salt thereof.

[0290] In some embodiments, the conjugate is described by: Formula (DV-8)

[0291]

[0292] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y 1 and 2 Each is 1, y 1 and 2 Each is 2, or y 1 and 2 Each is 3.

[0293] In some embodiments, the conjugate is described by: Formula (DV-9)

[0294]

[0295] or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the conjugate is described by: Formula (DV-10)

[0297]

[0298] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y 1 and 2 Each is 1, y 1 and 2 Each is 2, or y 1 and 2 Each is 3.

[0299] In some embodiments, the conjugate is described by: Formula (D-VI)

[0300]

[0301] or a pharmaceutically acceptable salt thereof.

[0302] In some embodiments, the conjugate is described by: Formula (D-VI-1)

[0303]

[0304] or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the conjugate is described by: Formula (D-VI-2)

[0306]

[0307] or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the conjugate is described by: Formula (D-VI-3)

[0309]

[0310] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y 1 and 2 Each is 1, y 1 and 2 Each is 2, or y 1 and 2 Each is 3.

[0311] In some embodiments, the conjugate is described by: Formula (D-VI-4)

[0312]

[0313] or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the conjugate is described by: Formula (D-VI-5)

[0315]

[0316] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y 1 and 2 Each is 1, y 1 and 2 Each is 2, or y 1 and 2 Each is 3.

[0317] In some embodiments, the conjugate is described by: Formula (D-VI-6)

[0318]

[0319] or a pharmaceutically acceptable salt thereof.

[0320] In some embodiments, the conjugate is described by: Formula (D-VI-7)

[0321]

[0322] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y 1 and 2 Each is 1, y 1 and 2 Each is 2, or y 1 and 2 Each is 3.

[0323] In some embodiments, the conjugate is described by: Formula (D-VI-8)

[0324]

[0325] or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the conjugate is described by: Formula (D-VI-9)

[0327]

[0328] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y 1 and 2 Each is 1, y 1 and 2 Each is 2, or y 1 and 2 Each is 3.

[0329] In some embodiments, the conjugate is described by: Formula (D-VII)

[0330]

[0331] or a pharmaceutically acceptable salt thereof.

[0332] In some embodiments of any aspect described herein, R 1 is OH. In some embodiments of any aspect described herein, R 1 For NH 2 In some embodiments of any aspect described herein, R 1 -NHC(=NH)NH 2 .

[0333] In some embodiments, the conjugate is described by: Formula (D-VIII)

[0334]

[0335] or a pharmaceutically acceptable salt thereof.

[0336] In some embodiments, the conjugate is described by: Formula (D-VIII-1)

[0337]

[0338] or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, the conjugate is described by: Formula (D-VIII-2)

[0340]

[0341] or a pharmaceutically acceptable salt thereof.

[0342] In some embodiments, the conjugate is described by: Formula (D-VIII-3)

[0343]

[0344] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0345] In some embodiments, the conjugate has a structure selected from:

[0346]

[0347] or a pharmaceutically acceptable salt thereof.

[0348] In some embodiments, the conjugate is described by: Formula (D-VIII-4)

[0349]

[0350] or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the conjugate is described by: Formula (D-VIII-5)

[0352]

[0353] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0354] In some embodiments, the conjugate has a structure selected from the group consisting of:

[0355]

[0356] or a pharmaceutically acceptable salt thereof.

[0357] In some embodiments, the conjugate is described by the structure

[0358]

[0359] or a pharmaceutically acceptable salt thereof.

[0360] In some embodiments, the conjugate is described by: Formula (D-VIII-6)

[0361]

[0362] or a pharmaceutically acceptable salt thereof.

[0363] In some embodiments, the conjugate is described by: Formula (D-VIII-7)

[0364]

[0365] where L' is the remainder of L, and y1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0366] In some embodiments, the conjugate is described by: Formula (D-VIII-8)

[0367]

[0368] or a pharmaceutically acceptable salt thereof.

[0369] In some embodiments, the conjugate is described by: Formula (D-VIII-9)

[0370]

[0371] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2 Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0372] In some embodiments, the conjugate is described by: Formula (D-VIII-10)

[0373]

[0374] or a pharmaceutically acceptable salt thereof.

[0375] In some embodiments, the conjugate is described by: Formula (D-VIII-11)

[0376]

[0377] where L' is the remainder of L, and y 1 and 2 Each independently represents an integer from 1 to 20 (e.g., 1 and 2Each is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0378] In some embodiments, the conjugate is described by: Formula (D-IX)

[0379]

[0380] or a pharmaceutically acceptable salt thereof.

[0381] In some embodiments, the conjugate is described by: Formula (D-IX-1)

[0382]

[0383] or a pharmaceutically acceptable salt thereof.

[0384] In some embodiments, the conjugate is described by: Formula (D-IX-2)

[0385]

[0386] or a pharmaceutically acceptable salt thereof.

[0387] In some embodiments, the conjugate is described by: Formula (D-IX-3)

[0388]

[0389] or a pharmaceutically acceptable salt thereof.

[0390] In some embodiments, the conjugate is described by: Formula (D-IX-4)

[0391]

[0392] or a pharmaceutically acceptable salt thereof.

[0393] In some embodiments, the conjugate is described by: Formula (D-IX-5)

[0394]

[0395] or a pharmaceutically acceptable salt thereof.

[0396] In some embodiments, the conjugate is described by: Formula (D-IX-6)

[0397]

[0398] or a pharmaceutically acceptable salt thereof.

[0399] In some embodiments, the conjugate is described by: Formula (DX)

[0400]

[0401] or a pharmaceutically acceptable salt thereof.

[0402] In some embodiments, the conjugate is described by: Formula (DX-1)

[0403]

[0404] or a pharmaceutically acceptable salt thereof.

[0405] In some embodiments, the conjugate is described by: Formula (DX-2)

[0406]

[0407] or a pharmaceutically acceptable salt thereof.

[0408] In some embodiments, the conjugate is described by: Formula (DX-3)

[0409]

[0410] or a pharmaceutically acceptable salt thereof.

[0411] 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 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.

[0412] 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 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.

[0413] 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,

[0414] L or L' is a bond. In some embodiments, L or L' is an atom.

[0415] In some embodiments of any of the aspects described herein, each L is described by: Formula (DLI)

[0416]

[0417] Where L A By 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 ) 1 -G A2 Description; L B By 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 ) 2 -G B2 Description; L C By 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 -(Z C5 ) 3 -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 B3 , 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, 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.

[0418] In some embodiments, L C Can have two points of attachment to an Fc domain, an Fc binding peptide, albumin or an albumin binding peptide (e.g., two G C2 ).

[0419] 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 (—CH 2 CH 2 O-) 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 PEG 2 To PEG 100 Any of (e.g., PEG2 PEG 3 PEG 4 PEG 5 PEG 5 -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, L c Including PEG linker, where L C Covalently attached to each of Q and E.

[0420] In some embodiments, L is

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432] where z 1 and z 2 are each independently an integer from 1 to 20; and R 9is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl.

[0433] In some embodiments, L is

[0434]

[0435]

[0436]

[0437]

[0438]

[0439] 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, and wherein 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.

[0440] In some embodiments, Y is: (-NH(C=O)O-) and L is:

[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: (-O-) and L is:

[0444] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0445]

[0446] Each of A 1 Independently selected from any one of formula (AI)-(A-XII);

[0447] 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 albumin having a 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 covalently attached to E and A. 1 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 A 1 Can be independently selected from any one of formula (AI)-(A-XII). In some embodiments, each A 1 Can be independently selected from any one of formula (AI), (A-II), (A-VI) or (A-VII). In other embodiments, each A 1 may be independently selected from formula (AI).

[0448] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0449]

[0450] Each of A 1independently selected from any one of formulas (AI)-(AV); 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 albumin having a 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 covalently attached to E and A 1 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 A 1 Can be independently selected from any one of formulas (AI)-(AV).

[0451] In another aspect, the present invention provides a conjugate described by: Formula (MI)

[0452]

[0453] Each of A 1 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 a sequence of any one of SEQ ID NOs: 1-138), 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; 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 covalently attached to E and A 1 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 A 1 Can be independently selected from any one of formula (A-VI)-(A-IX).

[0454] In some embodiments, the conjugate is described by: Formula (M-II)

[0455]

[0456] or a pharmaceutically acceptable salt thereof.

[0457] In some embodiments, the conjugate is described by: Formula (M-II-1)

[0458]

[0459] or a pharmaceutically acceptable salt thereof.

[0460] In some embodiments, the conjugate is described by: Formula (M-II-2)

[0461]

[0462] or a pharmaceutically acceptable salt thereof.

[0463] In some embodiments, the conjugate is described by: Formula (M-II-3)

[0464]

[0465] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0466] In some embodiments, the conjugate is described by: Formula (M-II-4)

[0467]

[0468] or a pharmaceutically acceptable salt thereof.

[0469] In some embodiments, the conjugate is described by: Formula (M-II-5)

[0470]

[0471] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0472] In some embodiments, the conjugate has the structure

[0473]

[0474] or a pharmaceutically acceptable salt thereof.

[0475] In some embodiments, the conjugate is described by: Formula (M-II-6)

[0476]

[0477] Where R 7 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. 7 is selected from C1-C20 alkyl (eg, methyl, ethyl, propyl or butyl).

[0478] In some embodiments, the conjugate is described by: Formula (M-II-7)

[0479]

[0480] or a pharmaceutically acceptable salt thereof.

[0481] In some embodiments, the conjugate is described by: Formula (M-II-8)

[0482]

[0483] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0484] In some embodiments, the conjugate has the following structure:

[0485]

[0486] In some embodiments, the conjugate is described by: Formula (M-II-9)

[0487]

[0488] or a pharmaceutically acceptable salt thereof.

[0489] In some embodiments, the conjugate is described by: Formula (M-II-10)

[0490]

[0491] 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.

[0492] In some embodiments, the conjugate has the structure

[0493]

[0494] or a pharmaceutically acceptable salt thereof.

[0495] In some embodiments, the conjugate is described by: Formula (M-III)

[0496]

[0497] or a pharmaceutically acceptable salt thereof.

[0498] In some embodiments, the conjugate is described by: Formula (M-III-1)

[0499]

[0500] or a pharmaceutically acceptable salt thereof.

[0501] In some embodiments, the conjugate is described by: Formula (M-III-2)

[0502]

[0503] or a pharmaceutically acceptable salt thereof.

[0504] In some embodiments, the conjugate is described by: Formula (M-III-3)

[0505]

[0506] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0507] In some embodiments, the conjugate is described by: Formula (M-III-4)

[0508]

[0509] or a pharmaceutically acceptable salt thereof.

[0510] In some embodiments, the conjugate is described by: Formula (M-III-5)

[0511]

[0512] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0513] In some embodiments, the conjugate is described by: Formula (M-III-6)

[0514]

[0515] or a pharmaceutically acceptable salt thereof.

[0516] In some embodiments, the conjugate is described by: Formula (M-III-7)

[0517]

[0518] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0519] In some embodiments, the conjugate is described by: Formula (M-III-8)

[0520]

[0521] or a pharmaceutically acceptable salt thereof.

[0522] In some embodiments, the conjugate is described by: Formula (M-III-9)

[0523]

[0524] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0525] In some embodiments, the conjugate is described by: Formula (M-IV)

[0526]

[0527] or a pharmaceutically acceptable salt thereof.

[0528] In some embodiments, the conjugate is described by: Formula (M-IV-1)

[0529]

[0530] or a pharmaceutically acceptable salt thereof.

[0531] In some embodiments, the conjugate is described by: Formula (M-IV-2)

[0532]

[0533] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0534] In some embodiments, the conjugate is described by: Formula (MV)

[0535]

[0536] or a pharmaceutically acceptable salt thereof.

[0537] In some embodiments, the conjugate is described by: Formula (MV-1)

[0538]

[0539] or a pharmaceutically acceptable salt thereof.

[0540] In some embodiments, the conjugate is described by: Formula (MV-2)

[0541]

[0542] or a pharmaceutically acceptable salt thereof.

[0543] In some embodiments, the conjugate is described by: Formula (MV-3)

[0544]

[0545] where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., 1 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.

[0546] In some embodiments, the conjugate is described by: Formula (MV-4)

[0547]

[0548] or a pharmaceutically acceptable salt thereof.

[0549] In some embodiments, the conjugate is described by: Formula (MV-5)

[0550]

[0551] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0552] In some embodiments, the conjugate is described by: Formula (MV-6)

[0553]

[0554] or a pharmaceutically acceptable salt thereof.

[0555] In some embodiments, the conjugate is described by: Formula (MV-7)

[0556]

[0557] or a pharmaceutically acceptable salt thereof.

[0558] In some embodiments, the conjugate is described by: Formula (MV-8)

[0559]

[0560] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0561] In some embodiments, the conjugate is described by: Formula (MV-9)

[0562]

[0563] or a pharmaceutically acceptable salt thereof.

[0564] In some embodiments, the conjugate is described by: Formula (MV-10)

[0565]

[0566] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0567] In some embodiments, the conjugate is described by: Formula (M-VI)

[0568]

[0569] or a pharmaceutically acceptable salt thereof.

[0570] In some embodiments, the conjugate is described by: Formula (M-VI-1)

[0571]

[0572] or a pharmaceutically acceptable salt thereof.

[0573] In some embodiments, the conjugate is described by: Formula (M-VI-2)

[0574]

[0575] or a pharmaceutically acceptable salt thereof.

[0576] In some embodiments, the conjugate is described by: Formula (M-VI-3)

[0577]

[0578] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0579] In some embodiments, the conjugate is described by: Formula (M-VI-4)

[0580]

[0581] or a pharmaceutically acceptable salt thereof.

[0582] In some embodiments, the conjugate is described by: Formula (M-VI-5)

[0583]

[0584] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0585] In some embodiments, the conjugate is described by: Formula (M-VI-6)

[0586]

[0587] or a pharmaceutically acceptable salt thereof.

[0588] In some embodiments, the conjugate is described by: Formula (M-VI-7)

[0589]

[0590] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0591] In some embodiments, the conjugate is described by: Formula (M-VI-8)

[0592]

[0593] or a pharmaceutically acceptable salt thereof.

[0594] In some embodiments, the conjugate is described by: Formula (M-VI-9)

[0595]

[0596] where L' is the remainder of L, and y 1is an integer from 1 to 20 (e.g., 1 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.

[0597] In some embodiments, the conjugate is described by: Formula (M-VII)

[0598]

[0599] or a pharmaceutically acceptable salt thereof.

[0600] In some embodiments of any aspect described herein, R 1 is OH. In some embodiments of any aspect described herein, R 1 For NH 2 In some embodiments of any aspect described herein, R 1 -NHC(=NH)NH 2 .

[0601] In some embodiments, the conjugate is described by: Formula (M-VIII)

[0602]

[0603] or a pharmaceutically acceptable salt thereof.

[0604] In some embodiments, the conjugate is described by: Formula (M-VIII-1)

[0605]

[0606] or a pharmaceutically acceptable salt thereof.

[0607] In some embodiments, the conjugate is described by: (M-VIII-2)

[0608]

[0609] or a pharmaceutically acceptable salt thereof.

[0610] In some embodiments, the conjugate is described by: Formula (M-VIII-3)

[0611]

[0612] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 11, 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.

[0613] In some embodiments, the conjugate is described by: Formula (M-VIII-4)

[0614]

[0615] or a pharmaceutically acceptable salt thereof.

[0616] In some embodiments, the conjugate is described by: Formula (M-VIII-5)

[0617]

[0618] where L' is the remainder of L, and y 1 is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

[0619] In some embodiments, the conjugate has the following structure:

[0620]

[0621] or a pharmaceutically acceptable salt thereof.

[0622] In some embodiments, the conjugate is described by: Formula (M-VIII-6)

[0623]

[0624] or a pharmaceutically acceptable salt thereof.

[0625] In some embodiments, the conjugate is described by: Formula (M-VIII-7)

[0626]

[0627] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0628] In some embodiments, the conjugate is described by: Formula (M-VIII-8)

[0629]

[0630] or a pharmaceutically acceptable salt thereof.

[0631] In some embodiments, the conjugate is described by: Formula (M-VIII-9)

[0632]

[0633] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0634] In some embodiments, the conjugate is described by: Formula (M-VIII-10)

[0635]

[0636] or a pharmaceutically acceptable salt thereof.

[0637] In some embodiments, the conjugate is described by: Formula (M-VIII-11)

[0638]

[0639] where L' is the remainder of L, and y 1 is an integer from 1 to 20 (e.g., 1 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.

[0640] In some embodiments, the conjugate is described by: Formula (M-IX)

[0641]

[0642] or a pharmaceutically acceptable salt thereof.

[0643] In some embodiments, the conjugate is described by: Formula (M-IX-1)

[0644]

[0645] or a pharmaceutically acceptable salt thereof.

[0646] In some embodiments, the conjugate is described by: Formula (M-IX-2)

[0647]

[0648] or a pharmaceutically acceptable salt thereof.

[0649] In some embodiments, the conjugate is described by: Formula (M-IX-3)

[0650]

[0651] or a pharmaceutically acceptable salt thereof.

[0652] In some embodiments, the conjugate is described by: Formula (M-IX-4)

[0653]

[0654] or a pharmaceutically acceptable salt thereof.

[0655] In some embodiments, the conjugate is described by: Formula (M-IX-5)

[0656]

[0657] or a pharmaceutically acceptable salt thereof.

[0658] In some embodiments, the conjugate is described by: Formula (M-IX-6)

[0659]

[0660] or a pharmaceutically acceptable salt thereof.

[0661] In some embodiments, the conjugate is described by: Formula (MX)

[0662]

[0663] or a pharmaceutically acceptable salt thereof.

[0664] In some embodiments, the conjugate is described by: Formula (MX-1)

[0665]

[0666] or a pharmaceutically acceptable salt thereof.

[0667] In some embodiments, the conjugate is described by: Formula (MX-2)

[0668]

[0669] or a pharmaceutically acceptable salt thereof.

[0670] In some embodiments, the conjugate is described by: Formula (MX-3)

[0671]

[0672] or a pharmaceutically acceptable salt thereof.

[0673] 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 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.

[0674] 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 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.

[0675] 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 connection. 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.

[0676] In some embodiments, each L is described by: Formula (ML-1)

[0677] 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

[0678] 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 5T is independently an optionally substituted C1-C20 alkylene, an optionally substituted C1-C20 heteroalkylene, an optionally substituted C2-C20 alkenylene, an optionally substituted C2-C20 heteroalkenylene, an optionally substituted C2-C20 alkynylene, an optionally substituted C2-C20 heteroalkynylene, an optionally substituted C3-C20 cycloalkylene, an optionally substituted C3-C20 heterocycloalkylene, an optionally substituted C4-C20 cycloalkenylene, an optionally substituted C4-C20 heterocycloalkenylene, an optionally substituted C8-C20 cycloalkynylene, an optionally substituted C8-C20 heterocycloalkynylene, an optionally substituted C5-C15 arylene, or an 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.

[0679] In some embodiments, J 2 Can have two points of attachment to an Fc domain, an Fc binding peptide, albumin or an albumin binding peptide (e.g., two J 2 ).

[0680] In some embodiments, L is

[0681]

[0682] 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).

[0683] In some embodiments, L is

[0684]

[0685]

[0686] wherein d and e are each independently an integer from 1 to 26; or a pharmaceutically acceptable salt thereof.

[0687] 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 (—CH 2 CH 2 O-) 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 PEG 2 To PEG 100 Any of (e.g., PEG 2 PEG 3 PEG 4 PEG 5 PEG 5 -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, L c Including PEG linker, where L C Covalently attached to each of Q and E.

[0688] In some embodiments of any aspect described herein, R 1 -NHC(=NH)NH 2 In some embodiments of any aspect described herein, R 2 In some embodiments of any aspect described herein, R 3In some embodiments of any aspect described herein, R 4 For –CO 2 H. In some embodiments of any aspect described herein, R 5 For –COCH 3 .

[0689] In some embodiments of any of the aspects described herein, L is covalently attached to a nitrogen atom of a surface-exposed lysine of E or L is covalently attached to a sulfur atom of a surface-exposed cysteine ​​of E.

[0690] In some embodiments of any of the aspects described herein, E is an Fc domain monomer. In some embodiments, n is 2 and each E dimerizes to form an Fc domain.

[0691] 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)

[0692]

[0693] 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.

[0694] In some embodiments, the conjugate has the following structure:

[0695]

[0696] or a pharmaceutically acceptable salt thereof.

[0697] 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)

[0698]

[0699] 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.

[0700] In some embodiments of any of the aspects described herein, E has the sequence of any one of SEQ ID NOs: 1-138.

[0701] 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.

[0702] 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)

[0703]

[0704] 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.

[0705] 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)

[0706]

[0707] 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.

[0708] 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.

[0709] In some embodiments of any of the aspects described herein, T is 1, 2, 3, 4, or 5.

[0710] 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, 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 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.

[0711] 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 A 1 -LA 2 can be independently selected (e.g., independently selected from A described herein 1 -LA 2 In some embodiments, E can be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different A 1 -LA 2 In some embodiments, E is conjugated to the first A 1 -LA 2 Part and 2A 1 -LA 2 In some embodiments, the first A 1 -LA 2 Part A 1 and A 2 are independently selected from any one of formulae (A-III)-(AV), and the second A 1 -LA 2 Part A 1 and A 2 Independently selected from any one of Formula (AI), (A-II), (A-VI), (A-VII), (A-VIII) and (A-IX).

[0712] In some embodiments, the first A 1 -LA 2 Each of the moieties is specifically conjugated to a lysine residue of E (eg, a nitrogen atom of a lysine residue is exposed on the surface of E), and the second A 1 -LA 2 Each of the moieties is specifically conjugated to a cysteine ​​residue of E (eg, a sulfur atom of a surface-exposed cysteine ​​residue of E). 1 -LA 2 Each of the moieties is specifically conjugated to a cysteine ​​residue of E (eg, a sulfur atom of a surface-exposed cysteine ​​residue of E), and the second A 1 -LA 2 Each of the moieties is specifically conjugated to a lysine residue of E (eg, a nitrogen atom of a surface-exposed lysine residue of E).

[0713] In some embodiments, the first A conjugated to E 1 -LA 2The number of moieties is an integer from 1 to 10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the second A conjugated to E 1 -LA 2 The number of parts is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0714] 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 A 1 -L can be independently selected (e.g., independently selected from A described herein 1 In some embodiments, E can be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different A 1 -L moiety. In some embodiments, E is conjugated to the first A 1 -Part L and Second A 1 -L part. In some embodiments, the first A 1 -A of L part 1 Selected from any one of formula (A-III)-(AV),

[0715] And the second A 1 -A of L part 1 is selected from any one of Formula (AI), (A-II), (A-VI), (A-VII), (A-VIII) or (A-IX).

[0716] In some embodiments, the first A 1 Each of the -L moieties is specifically conjugated to a lysine residue of E (eg, a nitrogen atom of a lysine residue is exposed on the surface of E), and the second A 1 Each of the -L moieties is specifically conjugated to a cysteine ​​residue of E (eg, a sulfur atom of a surface-exposed cysteine ​​residue of E). 1 Each of the -L moieties is specifically conjugated to a cysteine ​​residue of E (eg, a sulfur atom of a surface-exposed cysteine ​​residue of E), and the second A 1 Each of the -L moieties is specifically conjugated to a lysine residue of E (eg, a nitrogen atom of a surface-exposed lysine residue of E).

[0717] In some embodiments, the first A conjugated to E 1 -L moieties are an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the second A conjugated to E1 - The number of L moieties is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0718] In another aspect, the present invention provides a conjugate described by the following: Formula (D'-I)

[0719]

[0720] Each of A 1 Independently selected from any one of formula (A-III)-(AV); wherein each A 2 is independently selected from any one of Formulas (AI), (A-II), (A-VI), (A-VII), (A-VIII) and (A-IX); 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 albumin having a 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 1 is an integer from 1 to 10 (for example, T 1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L 1 is covalently conjugated to E and conjugated to each A 1 Connector; T 1 is an integer from 1 to 10 (for example, T 1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L 2 is covalently conjugated to E and each A 2 Connector; T 2 is an integer from 1 to 10 (for example, T 2 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), or a pharmaceutically acceptable salt thereof.

[0721] In some embodiments, each A 1 -LA 1 Specifically conjugated to a lysine residue of E (e.g., a nitrogen atom of a lysine residue exposed on the surface of E), and each A 2 -LA 2 Specifically conjugated to a cysteine ​​residue of E (e.g., a sulfur atom of a cysteine ​​residue exposed on the surface of E). 1 -LA 1 The moiety is specifically conjugated to a cysteine ​​residue of E (eg, a sulfur atom of a cysteine ​​residue exposed on the surface of E), and each A 2 -LA 2The moiety is specifically conjugated to a lysine residue of E (eg, a nitrogen atom of a lysine residue is exposed on the surface of E).

[0722] In another aspect, the present invention provides a conjugate described by the following: Formula (M'-I)

[0723]

[0724] Each of A 1 Independently selected from any one of (M-IX) in formula (A-III)-(AV); wherein each A 2 is independently selected from any one of Formulas (AI), (A-II), (A-VI), (A-VII), (A-VIII) and (A-IX); 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 albumin having a 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 1 is an integer from 1 to 10 (for example, T 1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L 1 Is covalently conjugated to E and A 1 Connector; T 1 is an integer from 1 to 10 (for example, T 1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L 2 Is covalently conjugated to E and A 2 Connector; T 2 is an integer from 1 to 10 (for example, T 2 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), or a pharmaceutically acceptable salt thereof.

[0725] In some embodiments, each A 1 -L is specifically conjugated to a lysine residue of E (eg, a nitrogen atom of a lysine residue is exposed on the surface of E), and each A 2 -L is specifically conjugated to a cysteine ​​residue of E (e.g., a sulfur atom of a surface-exposed cysteine ​​residue of E). 1 The -L moiety is specifically conjugated to a cysteine ​​residue of E (eg, a sulfur atom of a cysteine ​​residue exposed on the surface of E), and each A 2 The -L moiety is specifically conjugated to a lysine residue of E (eg, a nitrogen atom of a lysine residue is exposed on the surface of E).

[0726] In another aspect, the present invention provides a pharmaceutical composition comprising any of 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)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0727] In another aspect, the invention provides a method for treating a subject having or suspected of having a viral infection, the method 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)).

[0728] In another aspect, the invention provides 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 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 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.

[0730] In some embodiments, the subject is immunocompromised.

[0731] In some embodiments, the subject has been diagnosed with humoral immunity deficiency, T cell deficiency, neutropenia, asplenia, or complement deficiency.

[0732] In some embodiments, the subject is being treated or is about to be treated with immunosuppressive therapy.

[0733] 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.

[0734] In some embodiments, the subject has undergone or is about to undergo a hematopoietic stem cell transplant.

[0735] In some embodiments, the subject has undergone or is about to undergo an organ transplant.

[0736] In some embodiments, the subject suffers from secondary infection or is in the risk of secondary infection. In some embodiments, the secondary infection is a bacterial infection (e.g., methicillin-resistant Staphylococcus aureus (Staphylococcus aureus) (MRSA), Streptococcus pneumoniae (Streptococcus pneumoniae), Pseudomonas aeruginosa (Pseudomonas aeruginosa) and / or Haemophilus influenzae (Haemophilus influenzae)), a viral infection or a fungal infection. In a specific embodiment, the secondary infection is MRSA. In certain embodiments, the secondary infection is Streptococcus pneumoniae. In some embodiments, the secondary infection is a respiratory tract infection (e.g., an infection of the respiratory tract). In some embodiments, the secondary infection is associated with (e.g., causing) pneumonia (e.g., bacterial or viral pneumonia). In some embodiments, the subject suffers from pneumonia or is in the risk of pneumonia.

[0737] In another aspect, the present disclosure provides a method of 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.

[0738] In some embodiments, administration of a conjugate or composition of the invention to a subject diagnosed with influenza infection reduces, e.g., 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 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, e.g., the likelihood of developing a secondary bacterial infection (e.g., MRSA, S. pneumoniae, Pseudomonas aeruginosa, and / or Haemophilus 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.

[0739] 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 causes an immune response to influenza virus A, B or C or parainfluenza virus in the subject.

[0740] 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, SEQ ID NOs: 64, SEQ ID NOs: 67, SEQ ID NOs: 68, SEQ ID NOs: 72, SEQ ID NOs: 73, SEQ ID NOs: 76, SEQ ID NOs: 77, SEQ ID NOs: 81, SEQ ID NOs: 82, SEQ ID NOs: 85, or SEQ ID NOs: 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.

[0741] In certain embodiments, the conjugate and baloxavir are administered sequentially. In other embodiments, the conjugate and baloxavir are administered simultaneously.

[0742] 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 as described in any one of claims 1-215; 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 a specific embodiment, 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., pimodivir, 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 ester 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 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 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.

[0743] 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.

[0744] 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 skeletons with antibody-like properties, and any other immune binding moieties 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 antibodies of different classes are known in the art. Antibody fragments may include the following binding moieties, which include portions derived from antibodies or having significant homology with antibodies, such as antigenic determining regions of antibodies. Exemplary antibody fragments include Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, scFv and SMIP.

[0745] 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 scFv, sdAb, dAb, Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, or SMIP.

[0746] In some embodiments, the Fc domain-containing compositions (eg, antibodies or antibody fragments) confer binding specificity to one or more targets (eg, antigens).

[0747] 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.

[0748] In some embodiments, the Fc domain-containing composition (e.g., an antibody or antibody fragment) comprises one or more single domain antibodies (sdAb). 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)).

[0749] In some embodiments, the Fc domain-containing composition is a multi-domain antibody (MDAb) or a multi-domain antibody fragment comprising 2 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 bound to the hemagglutinin of influenza A and one or more sdAbs bound to the hemagglutinin of influenza B. In some embodiments, the MDAb is JNJ-7445 (also referred to as MD3606), which is described in Laursen et al. Science. 362: 598-602 (2018). In short, JNJ-7445 is a MDAb comprising two sdAbs (SD36 and SD38) bound to the hemagglutinin of influenza A and two sdAbs (SD83 and SD84) bound 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.

[0750] In another aspect, the present invention includes 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)(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 relates to 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'-1), wherein E is an antibody or an antibody fragment. In a preferred embodiment wherein E is an antibody or an 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 a viral hemagglutinin (e.g., CR6261, CR8020, MEDI8852, MHAA4549A, or VIS410); a broadly neutralizing antibody or antibody fragment targeting a viral hemagglutinin (e.g., an antibody or antibody fragment described in Wu et al., J. Mol. Biol. 429: 2694–2709 (2017)); an sdAb targeting a viral hemagglutinin (e.g., SD36, SD38, SD83, or SD84); or an MDAb or fragment thereof targeting a viral hemagglutinin (e.g., JNJ-7445).

[0751] 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.

[0752] 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.

[0753] 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.

[0754] 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.

[0755] 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.

[0756] 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.

[0757] 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.

[0758] 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.

[0759] 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.

[0760] 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.

[0761] 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.

[0762] 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.

[0763] 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.

[0764] 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.

[0765] 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.

[0766] 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.

[0767] 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.

[0768] 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.

[0769] 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.

[0770] 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.

[0771] 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.

[0772] 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.

[0773] 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.

[0774] 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.

[0775] 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.

[0776] 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.

[0777] 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.

[0778] 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.

[0779] 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.

[0780] 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.

[0781] 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.

[0782] 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.

[0783] 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.

[0784] 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.

[0785] 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.

[0786] 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.

[0787] 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.

[0788] 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.

[0789] 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.

[0790] 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.

[0791] 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.

[0792] 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.

[0793] 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.

[0794] 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.

[0795] 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.

[0796] 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.

[0797] 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.

[0798] 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.

[0799] 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.

[0800] 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.

[0801] 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.

[0802] 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.

[0803] 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.

[0804] 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.

[0805] 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.

[0806] 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.

[0807] 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.

[0808] 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.

[0809] 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.

[0810] 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.

[0811] 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.

[0812] 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.

[0813] 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.

[0814] 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.

[0815] 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.

[0816] 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.

[0817] 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.

[0818] 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.

[0819] 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.

[0820] 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.

[0821] 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.

[0822] 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.

[0823] 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.

[0824] 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.

[0825] 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.

[0826] 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.

[0827] 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.

[0828] 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.

[0829] 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.

[0830] 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.

[0831] 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.

[0832] 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.

[0833] 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.

[0834] 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.

[0835] 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.

[0836] 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.

[0837] 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.

[0838] 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.

[0839] 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.

[0840] 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.

[0841] 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.

[0842] 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.

[0843] 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.

[0844] 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.

[0845] 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.

[0846] 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.

[0847] 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.

[0848] 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.

[0849] 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.

[0850] 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.

[0851] 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.

[0852] 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.

[0853] 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.

[0854] 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.

[0855] 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.

[0856] 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.

[0857] 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.

[0858] 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.

[0859] 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.

[0860] 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.

[0861] 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.

[0862] 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.

[0863] 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.

[0864] 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.

[0865] 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.

[0866] 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.

[0867] 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.

[0868] 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.

[0869] 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.

[0870] 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.

[0871] 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.

[0872] 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.

[0873] 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.

[0874] 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.

[0875] 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.

[0876] 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.

[0877] 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.

[0878] 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.

[0879] 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.

[0880] 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.

[0881] 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.

[0882] 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.

[0883] 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.

[0884] 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.

[0885] 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.

[0886] 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.

[0887] 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.

[0888] 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.

[0889] 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.

[0890] 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.

[0891] 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 "an amino acid corresponding to a particular amino acid residue" (e.g., of a particular SEQ ID NO.) comprises any amino acid residue that one skilled in the art would understand to be aligned with the particular residue (e.g., of the particular sequence). For example, any one of SEQ ID NOs: 1-138 may be mutated to comprise a YTE mutation.

[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 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 may be mutated to comprise a LS 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 mutant corresponding to N434H. 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 may be mutated to comprise an N434H 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 C220S. 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.) comprises any amino acid residue that one skilled in the art would understand to be aligned with the particular residue (e.g., of the particular sequence). For example, any one of SEQ ID NOs: 1-138 may be mutated to comprise a C220S mutation.

[0895] 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 "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 be aligned with the particular residue (e.g., of the particular sequence). For example, any one of SEQ ID NOs: 1-95 may be mutated to comprise a DHS mutation.

[0896] 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 a 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, 100 or more) consecutive amino acids in length).

[0897] In some embodiments of any aspect described herein (e.g., a conjugate 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., PEG 2 -PEG 20 The linker conjugated to E may be functionalized so that it can react with any of A described herein. 1 -L or any A 2 -LA 1 In a preferred embodiment, E is conjugated to an azide-functionalized linker and A 1 -L or any A 2 -LA 1 The L of E is functionalized with an alkynyl group. 1 -L or A 2 -LA 1 The conjugates of the invention are formed by linker-alkyne conjugation (e.g., by click chemistry), such as conjugates 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 an alkyne-functionalized linker and any A 1 -L or any A 2 -LA 1 The L is functionalized with an azido group. The linker of E is an alkyne and A 1 -L or A 2 -LA 1 Linker-azido conjugation (e.g., by click chemistry, see e.g., Fig.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 that E and A 1 -L or A 2 -LA 1 The covalent bond between L.

[0898] 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) may 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., PEG 2 -PEG 20 A linker), wherein the linker has been functionalized with a reactive moiety such that the reactive moiety is compatible with any A described herein. 1 -L or any A 2 -LA 1 L forms a covalent bond (e.g., by click chemistry between an azide-functionalized linker and an alkyne-functionalized linker, as described above; see, e.g., Fig.103 ).

[0899] In some embodiments of any aspect described herein, A 1 and / or A 2 has the structure described by (AI):

[0900]

[0901] In a preferred embodiment, wherein A 1 and / or A 2 Has the structure described by (AI): R 1 Yes -NHC(=NH)NH 2 , R 4 Yes-CO 2 H, R 5 Yes-COCH 3 and / or X is -O-. In a preferred embodiment, A 1 and / or A 2 The zanamivir structure is described by:

[0902]

[0903] In some embodiments of any aspect described herein, A 1 and / or A 2 Having the structure described by (A-II):

[0904]

[0905] In a preferred embodiment, wherein A 1 and / or A 2 Having the structure described by (A-II): R 1Yes -NHC(=NH)NH 2 , R 2 H or F, R 3 H or F, R 4 Yes-CO 2 H, R 5 Yes-COCH 3 and / or X is -O-. In a preferred embodiment, A 1 and / or A 2 Having a structure described by:

[0906]

[0907] In some embodiments of any aspect described herein, A 1 and / or A 2 Having the structure described by (A-III):

[0908]

[0909] In a preferred embodiment, wherein A 1 and / or A 2 Having the structure described by (A-III): R 1 Yes -NHC(=NH)NH 2 , R 4 Yes-CO 2 H and / or R 5 Yes-COCH 3 In a preferred embodiment, A 1 and / or A 2 Peramivir has a structure described by:

[0910]

[0911] In some embodiments of any aspect described herein, A 1 and / or A 2 Having the structure described by (A-IV):

[0912]

[0913]

[0914] In a preferred embodiment, wherein A 1 and / or A 2 Having the structure described by (A-IV): R 1 Yes -NHC(=NH)NH 2 , R 4 Yes-CO 2 H and / or R 5 Yes-COCH3 In a preferred embodiment, A 1 and / or A 2 Having a structure described by:

[0915]

[0916] In some embodiments of any aspect described herein, A 1 and / or A 2 has the structure described by (AV):

[0917]

[0918] In a preferred embodiment, wherein A 1 and / or A 2 Having the structure described by (AV): R 1 Yes -NHC(=NH)NH 2 , R 4 Yes-CO 2 H and / or R 5 Yes-COCH 3 In a preferred embodiment, A 1 and / or A 2 Having a structure described by:

[0919]

[0920] In some embodiments of any aspect described herein, A 1 and / or A 2 Having the structure described by (A-VI):

[0921]

[0922] In a preferred embodiment, wherein A 1 and / or A 2 Having the structure described by (A-VI): R 1 Yes -NHC(=NH)NH 2 , R 4 Yes-CO 2 H, R 5 Yes-COCH 3 and / or X is -O-. In a preferred embodiment, A 1 and / or A 2 The zanamivir structure is described by:

[0923]

[0924] In some embodiments of any aspect described herein, A 1 and / or A2 Having the structure described by (A-VII):

[0925]

[0926] In a preferred embodiment, wherein A 1 and / or A 2 Having the structure described by (A-VII): R 1 Yes -NHC(=NH)NH 2 , R 2 H or F, R 3 H or F, R 4 Yes-CO 2 H, R 5 Yes-COCH 3 and / or X is -O-. In a preferred embodiment, A 1 and / or A 2 Having a structure described by:

[0927]

[0928] In some embodiments of any aspect described herein, A 1 and / or A 2 Having the structure described by (A-VIII):

[0929]

[0930] In a preferred embodiment, wherein A 1 and / or A 2 Having the structure described by (A-VIII): R 1 Yes -NHC(=NH)NH 2 , R 5 Yes-COCH 3 and / or X is -O-. In a preferred embodiment, A 1 and / or A 2 Having a structure described by:

[0931]

[0932] In some embodiments of any aspect described herein, A 1 and / or A 2 Having the structure described by (A-IX):

[0933]

[0934] In a preferred embodiment, wherein A 1 and / or A 2 Having the structure described by (A-IX): R1 Yes -NHC(=NH)NH 2 , R 2 H or F, R 3 H or F, R 5 Yes-COCH 3 and / or X is -O-. In a preferred embodiment, A 1 and / or A 2 Having a structure described by:

[0935]

[0936] In some embodiments of any aspect described herein, A 1 and / or A 2 With the structure described by (AX):

[0937]

[0938] In a preferred embodiment, wherein A 1 and / or A 2 Having the structure described by (AX): R 1 Yes -NHC(=NH)NH 2 , R 3 Yes H, R 5 Yes-COCH 3 and / or X is -O-. In a preferred embodiment, A 1 and / or A 2 has the structure of sulfonamivir described by:

[0939]

[0940] In some embodiments of any aspect described herein, A 1 and / or A 2 Having the structure described by (A-XI):

[0941]

[0942] In a preferred embodiment, wherein A 1 and / or A 2 Having the structure described by (A-XI): R 4 Yes-CO 2 H and / or R 5 Yes-COCH 3 In a preferred embodiment, the olefin is (E), (Z) or a racemic mixture of (E) / (Z). In a preferred embodiment, A 1 and / or A 2Has the structure of A-315675 (Abbott) described by:

[0943]

[0944] In some embodiments of any aspect described herein, A 1 and / or A 2 Having the structure described by (A-XII):

[0945]

[0946] In a preferred embodiment, wherein A 1 and / or A 2 Having the structure described by (A-XII): R 4 Yes-CO 2 H. In a preferred embodiment, A 1 and / or A 2 Has the structure of A-315675 (Abbott) described by:

[0947]

[0948] 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.

[0949] 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, such as 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, 5. .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 2 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.

[0950] 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, such as 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, 5. .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.

[0951] 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, such as 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, 5. .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 4 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 5 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, such as 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, 5. .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 5 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.

[0953] 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, such as 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, 5. .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.

[0954] 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, such as 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, 5. .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.

[0955] 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, such as 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, 5. .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 8, 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 9 or any regioisomer thereof and the DAR (e.g., T) is between 0.5 and 10.0, such as 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, 5. .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.

[0957] 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, such as 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, 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 Conjugate 10 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.

[0958] 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, such as 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.

[0959] 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, such as 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.

[0960] 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, such as 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.

[0961] 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, such as 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.

[0962] 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.

[0963] 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, such as 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.

[0964] 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, such as 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 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.

[0965] 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, such as 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.

[0966] 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, such as 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.

[0967] 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, such as 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.

[0968] 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, such as 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.

[0969] 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.

[0970] 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, such as 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.

[0971] 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.

[0972] 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, such as 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.

[0973] 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, such as 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.

[0974] 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, such as 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 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.

[0975] 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, such as 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 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.

[0976] 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, such as 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.

[0977] 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, such as 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 conjugate 30 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.

[0978] 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, such as 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.

[0979] 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, such as 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 conjugate 32 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.

[0980] 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, such as 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 conjugate 33 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.

[0981] 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, such as 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.

[0982] 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, such as 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.

[0983] 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, such as 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 conjugate 36 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.

[0984] 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, such as 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 conjugate 37 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.

[0985] 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, such as 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.

[0986] 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, such as 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.

[0987] 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, such as 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 conjugate 40 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.

[0988] 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, such as 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 conjugate 41 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.

[0989] 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 conjugate 42 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.

[0990] 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, such as 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 conjugate 43 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.

[0991] 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, such as 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.

[0992] 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, such as 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 a 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.

[0993] 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 conjugate 46 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.

[0994] 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, such as 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.

[0995] 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.

[0996] 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 A 1 And each A 2 Independently selected from any one of formula (A-XIII):

[0997]

[0998] Where R 1 Selected from -OH, -NH 2 、-NHC(=NH)NH 2 and -NHC(=NH)NHR 6 ; R 4 Selected from -CO 2 H, -P(=O)(OH)2 、-SO 3 H; R 5 Selected from -COCH 3 , -COCF 3 、-SO 2 CH 3 ; X is selected from -O- and -S-; Y is selected from

[0999]

[1000]

[1001] R 6 Selected from

[1002] R 7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl;

[1003] R 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl and C2-C15 heteroaryl;

[1004] R 9 is selected from -H, halogen (e.g., Cl or F), -OR 10 、-NHC(=O)R 7 , optionally substituted C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl;

[1005] R 10 is selected from C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl;

[1006] n is 1 or 2;

[1007] Each E comprises an Fc domain monomer, albumin, an albumin binding peptide, or an Fc binding peptide;

[1008] L is covalently attached to E and to each A 1 or each A 1 and A 2 The connector of each Y;

[1009] T is an integer from 1 to 20, and

[1010] Each wavy line in formula (DI), (MI), (1) or (2) indicates that L is covalently attached to each E;

[1011] or a pharmaceutically acceptable salt thereof.

[1012] In some embodiments, each A 1 And each A 2 Described by formula (A-XIII-1):

[1013]

[1014] In some embodiments, each A 1 And each A 2 Independently selected from any one of the following: Formula (A-XIII-1a)-(A-XIII-1d)

[1015]

[1016] In some embodiments, the conjugate is described by: Formula (D-XI)

[1017]

[1018] or a pharmaceutically acceptable salt thereof.

[1019] In some embodiments, the conjugate is described by: Formula (D-XI-1)

[1020]

[1021]

[1022] Where R 7 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.

[1023] In some embodiments, the conjugate is described by: Formula (M-XI)

[1024]

[1025] or a pharmaceutically acceptable salt thereof.

[1026] In some embodiments, the conjugate is described by: Formula (M-XI-1)

[1027]

[1028] Where R 7 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.

[1029] definition

[1030] To facilitate understanding of the present invention, a number of terms are defined below. The terms defined herein have meanings as commonly understood by those of ordinary skill in the art to which the present invention relates. Terms such as "a," "an," and "the" are not intended to refer only to a single entity, but include general categories to which specific examples that may be used for illustration belong. The terms are used herein to describe specific embodiments of the present invention, but their use does not limit the present invention unless summarized in the claims.

[1031] 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., 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. Chem Med Chem 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)). 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):

[1032]

[1033] Where R 1 Selected from -OH, -NH 2 、-NHC(=NH)NH 2 and -NHC(=NH)NHR 6 ; R 2and R 3 are each independently selected from -H, -OH, -F, -Cl and -Br; R 4 Selected from -CO 2 H, -P(=O)(OH) 2 、-SO 3 H; R 5 Selected from -COCH 3 , -COCF 3 、-SO 2 CH 3 ; X is selected from -O- and -S-; Y is selected from

[1034]

[1035]

[1036] R 6 Selected from

[1037] R 7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; and R 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl and C2-C15 heteroaryl; R 9 is selected from -H, halogen (e.g., Cl, F or Br), -OR 10 、-NHC(=O)R 7 , 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.

[1038] 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, an IC of less than or equal to 100 nM or less than or equal to 10 nM according to a neuraminidase inhibition assay 50 Compounds that inhibit neuraminidase activity are indicated.

[1039] "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.

[1040] 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 a functional fragment thereof (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 may be any immunoglobulin antibody isotype, including IgG, IgE, IgM, IgA or IgD (e.g., IgG). In addition, the Fc domain monomer may be an IgG subtype (e.g., IgG1, IgG2a, IgG2b, IgG3 or IgG4) (e.g., IgG1). The Fc domain monomer does not include any portion of an 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 the C-terminal Lys corresponding to Lys447. The N-terminal N (Asn) of the Fc region (e.g., any 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 of SEQ ID NOs: 60-77 that do 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, which is also referred to as the Kabat EU index, as described in, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[1041] 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 connected 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.

[1042] 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.

[1043] 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, which has affinity for an Fc domain (such as any Fc domain described herein) and has the function of binding to the Fc domain. The Fc binding peptide 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, which may provide a site for conjugation to a compound of the present invention (e.g., conjugated to a neuraminidase inhibitor monomer or dimer, including with the aid of a linker). Most preferably, the Fc binding peptide will contain a single solvent exposed cysteine ​​or lysine, thus enabling site-specific conjugation of the compound of the present invention. The Fc binding peptide may include only naturally occurring amino acid residues, or may include one or more non-naturally occurring amino acid residues. When included, the non-naturally occurring amino acid residues (e.g., the side chains of non-naturally occurring amino acid residues) can be used as attachment points for the compounds of the invention (e.g., neuraminidase inhibitor monomers or dimers, including with the aid of a linker). The Fc binding peptides of the invention may be linear or cyclic. The Fc binding peptides of the invention include any Fc binding peptide known to those skilled in the art.

[1044] 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 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, 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 will contain a single solvent exposed cysteine ​​or lysine, thus enabling site-specific conjugation of a compound of the invention. The 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) may serve as an attachment point for a compound of the invention (e.g., a neuraminidase inhibitor monomer or dimer, including via a linker).

[1045] 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, which has an affinity for and has the function of binding to 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 invention include albumin binding peptides 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, thus 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., the side chains of non-naturally occurring amino acid residues) may be used as attachment points for the compounds of the invention (e.g., neuraminidase inhibitor monomers or dimers, including with the aid of a linker). 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.

[1046] As used herein, a "surface exposed amino acid" or "solvent exposed amino acid" such as a surface exposed cysteine ​​or a surface exposed lysine refers to an amino acid that is accessible to the solvent surrounding the protein. The surface exposed amino acid may be naturally occurring, or an engineered variant (e.g., substitution or insertion) of the protein. In some embodiments, a surface exposed amino acid is an amino acid that, when substituted, does not substantially change the three-dimensional structure of the protein.

[1047] As used herein, the terms "linker", "L" and "L'" refer to a covalent connection between two or more components in 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, wherein each arm is covalently linked 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).

[1048] 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 connection with the first component in the conjugate and the second functional group can form a covalent connection 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 connection with the first neuraminidase inhibitor in the conjugate and the second carboxylic acid can form a covalent connection with the second neuraminidase inhibitor in the conjugate and the third arm of the linker can form a covalent connection 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 connection 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 connection 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 connection 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 connection 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 connection 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.

[1049] In some embodiments, the joint provides space, rigidity and / or flexibility between two or more components. In some embodiments, the joint 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 NN bond, a CS bond, or any type of bond produced by a chemical reaction (e.g., chemical conjugation). In some embodiments, the joint comprises no more than 250 atoms. In some embodiments, the joint comprises no more than 250 non-hydrogen atoms. In some embodiments, the skeleton of the joint comprises no more than 250 atoms. The "skeleton" of the joint refers to the atoms in the joint, which together form the shortest path from a 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 joint directly participate in connecting a part of the conjugate to another part of the conjugate (e.g., connecting the first neuraminidase inhibitor and the second neuraminidase inhibitor). For example, the hydrogen atoms of the carbons in the skeleton attached to the joint are not considered to be directly involved in connecting a part of the conjugate to another part of the conjugate.

[1050] In some embodiments, the linker may comprise a synthetic group derived from, for example, a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer). In some embodiments, the linker may comprise one or more amino acid residues, such as D- or L-amino acid residues. In some embodiments, the linker may 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 the alkyl radical 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.

[1051] As used herein, the terms "alkyl," "alkenyl," and "alkynyl" include straight and branched monovalent substituents, and combinations thereof, containing 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 the 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, the alkyl or heteroalkyl 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 alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl 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). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-propenyl, and 3-butynyl.

[1052] As used herein, the term "cycloalkyl" refers to a monovalent saturated or unsaturated non-aromatic cyclic alkyl. Cycloalkyl may have, for example, three to twenty carbons (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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. When cycloalkyl includes at least one carbon-carbon double bond, the cycloalkyl may be referred to as "cycloalkenyl". Cycloalkenyl may have, for example, four to twenty carbons (e.g., C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18 or C4-C20 cycloalkenyl). Exemplary cycloalkenyls 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 carbons (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 (e.g., bicyclo[2.2.1.]heptyl and adamantane) with bridged polycyclic structures, in which one or more carbons 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.

[1053] 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. The aryl group can have, for example, five to fifteen carbons (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 the monocyclic or fused bicyclic ring system 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 carbons (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, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furanyl, 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 can be optionally substituted with a substituent such as an aryl substituent (e.g., biphenyl).

[1054] 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), wherein the carbon number indicates the total number of carbons in the aryl portion of the alkaryl group and the alkylene, alkenylene, or alkynylene portion. 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 a benzyl or phenethyl group. In heteroalkaryl, one or more heteroatoms selected from N, O and S may be present in the alkylene, alkenylene or alkynylene portion of the alkaryl and / or may be present in the aryl portion of the alkaryl. In optionally substituted alkaryl, substituents may be present on the alkylene, alkenylene or alkynylene portion of the alkaryl and / or may be present on the aryl portion of the alkaryl.

[1055] As used herein, the term "amino" refers to -N(R x ) 2 or –N + (R x ) 3 , where R x are each independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x In some embodiments, the amino group is -NH 2 .

[1056] 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 group), an alkenylene group (e.g., C2-C5 alkenylene group), or an alkynylene group (e.g., C2-C5 alkenylene group). 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 are each independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x In some embodiments, the amino group of the alkylamino group is -NH 2 Examples of alkylamino groups are C1-C5 alkylamino groups, such as C2 alkylamino groups (e.g., CH2 CH 2 NH 2 or CH 2 CH 2 N(CH 3 ) 2 ). In the heteroalkylamino 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 heteroalkylamino group. In some embodiments, the alkylamino group may be optionally substituted. In a substituted alkylamino group, substituents may be present on the alkylene, alkenylene, or alkynylene portion of the alkylamino group and / or may be present on the amino portion of the alkylamino group.

[1057] As used herein, the term "alkanoamide" refers to an amide group that is attached to an alkylene (e.g., C1-C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene (e.g., C2-C5 alkenylene). Generally, if a compound is attached to an alkanoamide group, then 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 are each independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x In some embodiments, the amide portion of the alkaneamide is -C(O)NH 2 The alkanoyl group can be -(CH 2 ) 2 -C(O)NH 2 or -CH 2 -C(O)NH 2 In the heteroalkanoyl, 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. In some embodiments, the alkanoyl may be optionally substituted. In a substituted alkanoyl, substituents may be present on the alkylene, alkenylene, or alkynylene portion of the alkanoyl and / or may be present on the amide portion of the alkanoyl.

[1058] As used herein, the terms "alkylene," "alkenylene," and "alkynylene" refer to divalent groups of 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 straight and branched 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 may be attached to each other by means of 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 on either end of the alkylene, alkenylene, and / or alkynylene group. For example, if a linker includes -(optionally substituted alkylene)-(optionally substituted alkenylene)-(optionally substituted alkylene)-, the alkenylene group is considered divalent with respect to its attachments to two alkylene groups at the ends of the linker. Optional substituents on an 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 ends of the group and does not include optional substituents that may be present in an alkylene, alkenylene, or alkynylene group. Because it is divalent, it allows multiple (e.g., two) moieties of a conjugate (e.g., a first neuraminidase inhibitor and a second neuraminidase inhibitor) to be linked together. Alkylene, alkenylene and / or alkynylene groups may be substituted with groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein. For example, C=O is a C1 alkylene group substituted with oxo (=O). For example, -HCR-C≡C- may be considered an optionally substituted alkynylene group and is considered a divalent group even though it has an 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 -(CH 2 ) 2 -O- is considered a heteroalkylene group containing one or more oxygen atoms.

[1059] 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 viral infection. The treatment regimen determines the dosage and period 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 greater reduction in symptoms or other parameters associated with viral infection than would be observed if only one agent or treatment 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 routes, intravenous routes, intramuscular routes, and absorption directly through mucosal tissues. The therapeutic agents can be administered by the same route or by different routes. For example, the conjugates described herein can be administered by intravenous injection, while the second therapeutic agent of the combination can be administered orally.

[1060] As used herein, the term "cycloalkylene" refers to a divalent cyclic group that connects two parts of a compound together. For example, a 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 carbons 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 the cycloalkylene includes at least one carbon-carbon triple bond, the cycloalkylene can be referred to as "cycloalkynylene". Cycloalkynylene can have, for example, four to twenty carbons in the cyclic portion of the cycloalkynylene (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 may be substituted with groups typically suitable as substituents for alkyl, alkenyl, and alkynyl groups as set forth herein. Heterocycloalkylene refers to a cycloalkylene group 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.

[1061] As used herein, the term "arylene" refers to a polyvalent (e.g., divalent or trivalent) aryl group that connects multiple (e.g., two or three) parts of a compound together. For example, one carbon in an arylene group may be connected to a portion of the compound, and another carbon in the arylene group may be connected to another portion of the compound. An arylene group may have, for example, five to fifteen carbons (e.g., C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C11, C5-C12, C5-C13, C5-C14, or C5-C15 arylene groups) in the aryl portion of the arylene group. An arylene group may be substituted with a group that is typically suitable as a substituent for an alkyl, alkenyl, and alkynyl group as set forth herein. A heteroarylene group refers to an aromatic group comprising 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).

[1062] 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, hydroxyl, 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, NR 2 ,SR,SOR,SO 2 R, OCOR, NRCOR, NRCONR 2 、NRCOOR、OCONR 2 、RCO、COOR、alkyl-OOCR、SO 3 R.CONR 2 、SO 2 NR 2 、NRSO 2 NR 2 , CN, CF 3 、OCF 3 、SiR 3 and NO 2, 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.

[1063] 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 a group -R-NH-R- may be replaced by an alkaneamide substituent, such as -RN[(CH 2 C(O)N(CH 3 ) 2 ]-R. In general, the optional substituents are non-interfering substituents. "Non-interfering substituents" refer to substituents that retain the ability of the conjugates described herein (e.g., conjugates of any of formulas (1)-(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 substituents 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 substituents will be classified as "non-interfering". For example, non-interfering substituents will retain the ability of the compound to provide antiviral efficacy based on an IC50 value of 10 μM or less in a viral plaque reduction assay (such as an IC50 value for influenza virus neuraminidase based on less than 500 nM in Example 2). Thus, based on plaque reduction or influenza virus neuraminidase inhibition, the substituents may alter the extent of inhibition. However, as long as the compounds described 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 would be classified as "non-interfering." A variety of assays for determining viral plaque reduction or the ability of any compound to inhibit influenza virus neuraminidase are available in the art and some are exemplified in the Examples below.

[1064] The term "hetero" when used to describe a chemical group or moiety refers to 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 a maleimido group. For example, a heteroaryl group 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).

[1065] 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.

[1066] 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 may be referred to as a "halo moiety", such as a haloalkyl group.

[1067] As used herein, the term "hydroxy" refers to an -OH group.

[1068] As used herein, the term "oxo" refers to a substituent having the structure =0, wherein a double bond exists between the atom and the oxygen atom.

[1069] As used herein, the term "carbonyl" refers to a group having the following structure:

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

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

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

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

[1074] As used herein, the term "imino" refers to a group having the following structure: wherein R is an optional substituent.

[1075] As used herein, the term "N-protecting group" means those groups 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, 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 auxiliary agents 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, isopropoxycarbonyl, 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.

[1076] As used herein, the term "amino acid" means naturally occurring amino acids and non-naturally occurring amino acids.

[1077] 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.

[1078] 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 NH 2 (CH 2 ) nω amino acids of COOH, wherein n is 2-6, neutral nonpolar 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. The 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- DN-methyl valine, DN-methyl alanine, DN-methyl arginine, DN-methyl asparagine, DN-methyl aspartate, DN-methyl cysteine, DN-methyl glutamine, DN-methyl glutamate, DN-methyl histidine, DN-methyl isoleucine, DN-methyl leucine, DN-methyl lysine, N-methyl cyclohexyl alanine, DN-methyl ornithine, N-methyl glycine, N-methyl amino isobutyrate, N-(1-methylpropyl) glycine, N-(2-methylpropyl) glycine, DN-methyl tryptophan, 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-furanylalanine, L-histidine (3-methyl), N-(3-guanidinopropyl)glycine, O-methyl-L-tyrosine, O-polysaccharide-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-cyclodecyl 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 alanine (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, symmetric 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, piperidinecarboxylic acid, (2S,4R) and (2S,4S)-4-(4-phenylbenzyl)pyrrolidine-2-carboxylic acid, (3S)-1-pyrrolidine-3-carboxylic acid, (2S,4S)-4-tritylthio-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 the amino acid may be an amide group or a carbamate group.

[1079] 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 may be introduced in one or both of the candidate and reference sequences for optimal alignment and non-homologous sequences may 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. One 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 percentage amino acid sequence identity of a given candidate sequence relative to, with, or for a given reference sequence (which may alternatively be expressed as a given candidate sequence having or including a certain percentage amino acid sequence identity relative to, with, or for a given reference sequence) is calculated as follows:

[1080] 100×(score of A / B)

[1081] 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.

[1082] When aligned for maximum correspondence as described above, two polynucleotide or polypeptide sequences are said to be "identical" if the sequence of nucleotides or amino acids in the sequences is the same. 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 adjacent positions, about 20 adjacent positions, about 25 adjacent positions or more (e.g., about 30 to about 75 adjacent positions or about 40 to about 50 adjacent positions), wherein the two sequences can be compared after the sequence and a reference sequence of the same number of adjacent positions are optimally aligned.

[1083] 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 an influenza infection) in a subject. In some embodiments, the therapeutic treatment can slow the progression of the viral infection, improve the prognosis of the subject, and / or eliminate the infection. In some embodiments, the therapeutic treatment of a viral infection in a subject can alleviate or improve one or more symptoms or conditions associated with the viral infection, weaken the viral level, 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.

[1084] 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.

[1085] 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.

[1086] 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 an 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 preventive 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 (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI) or (M'-I)) for treating 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 when the conjugate is not administered.

[1087] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical or pharmaceutical preparation 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 make the active ingredient suitable for administration. The pharmaceutical compositions of the present disclosure include 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).

[1088] 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 capable of suspending or dissolving an 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 drug stability for the conjugates described herein. The nature of the carrier varies with 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.

[1089] As used herein, the term "pharmaceutically acceptable salt" means a salt of 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)) that is suitable for use in the methods described herein without undue toxicity, irritation, and / or allergic response, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Pharmaceutical Salts: Properties, Selection, and Use (eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. Such salts may be prepared in situ during the final isolation and purification of the conjugates described herein, or separately by reacting the free base with a suitable organic acid.

[1090] The term "drug:antibody ratio" or "DAR" refers to the average number of small molecule drug moieties conjugated to an antibody, Fc domain, or albumin described herein (e.g., the average number of small molecule drug monomers or dimers). In some embodiments described herein, DAR is represented by "T" (e.g., in formulas (1)-(5), (DI)-(D-XI), (D'-...

Claims

1. A conjugate, the conjugate is described by the following: Formula (D-II-6) wherein each E is an Fc domain monomer; n is 1 or 2; T is an integer from 1 to 20; R7 is a C1-C20 alkyl group; The wavy line indicates that L is covalently attached to E; L is a linker as shown in the following structure: or a pharmaceutically acceptable salt thereof.

2. The conjugate of claim 1, wherein the conjugate has the following structure: or a pharmaceutically acceptable salt thereof.

3. The conjugate of claim 1, wherein the wavy line indicates that L is covalently attached to the nitrogen atom of the solvent-exposed lysine of E.

4. The conjugate of claim 1, wherein the wavy line indicates that L is covalently attached to the sulfur atom of the solvent-exposed cysteine ​​of E.

5. The conjugate of claim 1, wherein n is 2, each E is an Fc domain monomer, each E dimerizes to form an Fc domain, and the conjugate is described by the following structure: Wherein E is the Fc domain; T is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

6. The conjugate of any one of claims 1-5, wherein each E comprises the amino acid sequence of any one of SEQ ID NOs: 1-138.

7. The conjugate of any one of claims 1-5, wherein each E comprises the amino acid sequence of any one of the following: 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.

8. The conjugate of any one of claims 1-5, wherein each E comprises the amino acid sequence 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 or SEQ ID NO:

77.

9. The conjugate of any one of claims 1-5, wherein each E comprises the amino acid sequence of SEQ ID NO:

67.

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

11. A population of conjugates as described in any one of claims 1-5, wherein the average value of T is 1 to 10, 5 to 10, 1 to 5, 3 to 7 or 3.5 to 5.

5.

12. A population of conjugates as described in claim 11, wherein the average value of T is about 4.

5.

13. A pharmaceutical composition comprising the conjugate according to any one of claims 1 to 10 or a group of conjugates according to claim 11 or 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. Use of a conjugate according to any one of claims 1 to 10, a population of conjugates according to claim 11 or 12, or a pharmaceutical composition according to claim 13 in the preparation of a medicament for treating a subject suffering from or suspected of suffering from a viral infection or for the prophylactic treatment of a viral infection in a subject in need thereof.

15. The use according to claim 14, wherein the viral infection is caused by influenza virus or parainfluenza virus.

Images