Compositions and methods for the treatment of viral infections

Abstract

Compositions and methods for treating viral infections include conjugates containing an Fc monomer, an Fc domain, and a viral neuraminidase inhibitor (e.g., zanamivir, peramivir, or an analog thereof) linked to an Fc-binding peptide, albumin protein, or albumin-binding peptide. In particular, the conjugates can be used to treat viral infections, such as influenza virus infections.

Description

[Technical Field]

[0001] background There is a significant and urgent medical need for new antiviral treatments for influenza. The influenza virus, the causative agent of influenza, is responsible for 3 to 5 million cases of severe illness and approximately 500,000 deaths worldwide each year. While most people fully recover from influenza within about one to two weeks, others develop life-threatening complications, such as pneumonia. Thus, influenza can be fatal, especially for the young, the elderly, or those with chronic illnesses. People with weakened or compromised immune systems, such as those with advanced HIV infection or transplant patients whose immune systems are medically suppressed to prevent transplant organ rejection, are at higher risk for influenza-related complications. Pregnant women and young children are also at increased risk for complications.

[0002] The development of antiviral treatments for influenza continues to be a challenge. Several influenza antiviral drugs have been approved for use in the clinic, and these drugs play an important role in modulating disease severity and halting pandemics while preparing vaccines. However, drug-resistant strains have emerged against the most commonly used inhibitors.

[0003] Influenza antiviral drugs generally target proteins displayed on the surface of influenza virus particles. The influenza virus envelope contains two immunodominant glycoproteins, hemagglutinin and neuraminidase, which play essential roles in viral infection and spread. Hemagglutinin interacts with surface sialic acid to bind the virus to the host cell, thereby initiating entry. Neuraminidase is an exoglycosidase enzyme that cleaves sialic acid (terminal neuraminic acid residues) from glycan structures on the surface of infected host cells, liberating progeny viruses and allowing them to spread from the host cell to surrounding uninfected cells. Therefore, inhibition of neuraminidase serves as a pharmacological target for antiviral drugs. Viral neuraminidase inhibitors used to reduce viral spread have been identified and include oseltamivir (Tamiflu™), zanamivir (Relenza™), and peramivir (Rapivab™).

[0004] However, influenza in transplant recipients is still characterized by prolonged viral shedding, increasing the potential for 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, such conjugates contain a monomer or dimer of a moiety that inhibits influenza virus neuraminidase (e.g., zanamivir, peramivir, or an analog thereof) conjugated to an Fc monomer, an Fc domain, an Fc-binding peptide, an albumin protein, or an albumin protein-binding peptide. The neuraminidase inhibitor (e.g., zanamivir, peramivir, or an analog thereof) in the conjugate targets neuraminidase on the surface of viral particles. The Fc monomer or Fc domain in the complex binds to FcγR (e.g., FcRn, FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and FcγRIIIb) on immune cells, e.g., neutrophils, activating phagocytosis and effector functions, e.g., antibody-dependent cellular cytotoxicity (ADCC), leading to engulfment and destruction of viral particles by immune cells, further enhancing the antiviral activity of the complex. Albumin or albumin-binding peptides can extend the half-life of the complex, e.g., by binding of albumin to the recycling fetal Fc receptor. Such compositions are useful in methods of inhibiting viral growth and treating viral infections, e.g., those caused by influenza A, influenza B, and influenza C viruses.

[0006] In a first aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: A conjugate represented by any one of formulas (DI), (MI), (1) or (2): [ka] [wherein each A1 and each A2 independently represent a group represented by formula (AI) to (A-XII): [ka] is selected from one of the following: R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; and Y is [ka] is selected from R6 is [ka] is selected from R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; R8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; n is 1 or 2, each E comprises an Fc domain monomer, an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide; L is a linker covalently linking E and each Y of each A or each of A and A; T is an integer from 1 to 20, Each wavy line in formula (DI), (MI), (1) or (2) represents a covalent bond between L and each E. or a pharmaceutically acceptable salt thereof.

[0007] 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 protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide.

[0008] 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), and the Fc domain monomers dimerize to form an Fc domain; L is a linker covalently binding each E and each Y, or each of A1 and / or A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and each wavy line in formula (DI), (MI), (1), or (2) represents an L covalently linked to each E (e.g., by a covalent bond or a linker), or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L or each A1-L-A2 can be independently selected (e.g., can be independently selected from any of the A1-L or A1-L-A2 structures described herein).

[0009] In preferred embodiments of any of the aspects 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 complex having two Fc domain monomers (e.g., a complex of formula (1), formula (2), formula (DI) when n is equal to 2, or formula (MI) when n is equal to 2), the Fc domain monomers dimerize to form an Fc domain.

[0010] In another aspect, the present invention provides a conjugate represented by formula (DI): [ka] wherein each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of SEQ ID NOs: 1-138), L in each A1-L-A2 is a linker covalently linked to the sulfur atom of a hinge cysteine ​​in E and to each of A1 and A2, n is 1 or 2 (e.g., when n is 2, two Fc domain monomers dimerize to form an Fc domain), T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E represents that each A1-L-A2 is covalently linked (e.g., by a covalent bond or a linker) to the sulfur atom of a hinge cysteine ​​in E), or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0011] In another aspect, the present invention provides a conjugate represented by formula (DI): [ka] wherein each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of SEQ ID NOs: 1-138), L in each A1-L-A2 is a linker covalently attached to a nitrogen atom of a surface-exposed lysine in E and to each of A1 and A2, n is 1 or 2 (e.g., when n is 2, two Fc domain monomers dimerize to form an Fc domain), T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E represents that each A1-L-A2 is covalently attached (e.g., by a covalent bond or a linker) to a nitrogen atom of a surface-exposed lysine in E); or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein). In some embodiments, each of A1 and A2 can independently be selected from any one of formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1 and A2 can independently be selected from formula (AI).

[0012] In another aspect, the present invention provides a conjugate of formula (MI): [ka] wherein each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of SEQ ID NOs: 1-138), L in each L-A1 is a linker covalently linked to the sulfur atom of a hinge cysteine ​​in E and to A1, n is 1 or 2 (e.g., when n is 2, two Fc domain monomers dimerize to form an Fc domain), T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E represents that each L-A1 is covalently linked (e.g., by a covalent bond or a linker) to the sulfur atom of a hinge cysteine ​​in E; or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any structure represented by formula (AI) through (A-XII). In some embodiments, each A1 can be independently selected from any one of formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each A1 can be independently selected from formula (AI).

[0013] In another aspect, the present invention provides a conjugate of formula (MI): [ka] wherein each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of SEQ ID NOs: 1-138), L in each L-A1 is a linker covalently attached to the nitrogen atom of a surface-exposed lysine in E and to A1, n is 1 or 2 (e.g., when n is 2, two Fc domain monomers dimerize to form an Fc domain), T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E represents that each L-A1 is covalently attached (e.g., by a covalent bond or linker) to the nitrogen atom of a surface-exposed lysine in E); or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any structure represented by formula (AI) through (A-XII). In some embodiments, each A1 can be independently selected from any one of formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each A1 can be independently selected from formula (AI).

[0014] In one aspect, the present disclosure provides a conjugate represented by formula (1): [ka] wherein each A1 and each A2 is independently selected from any one of formulas (AI) to (A-XII), each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138), L in each A1-L-A2 is a linker covalently bonded to the sulfur atoms of the hinge cysteines in each E and to each of A1 and A2, T is an integer of 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 connecting the two E represent that each A1-L-A2 is covalently bonded (e.g., by a covalent bond or a linker) to a pair of sulfur atoms of the two hinge cysteines in the two E's); or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein). In some embodiments, each of A1 and A2 can independently be selected from any one of formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each A1A2 can independently be selected from formula (AI).

[0015] In another aspect, the present disclosure provides a conjugate represented by formula (1): [ka] wherein each A1 and each A2 is independently selected from any one of formulas (AI) to (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 to 138), L in each A1-L-A2 is a linker covalently bonded to the sulfur atoms of the hinge cysteines in each E and to each of A1 and A2, T is an integer of 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 connecting the two E's represent that each A1-L-A2 is covalently bonded (e.g., by a covalent bond or a linker) to a pair of sulfur atoms of the two hinge cysteines in the two E's; or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0016] In another aspect, the present disclosure provides a conjugate represented by formula (1): [ka] wherein each A1 and each A2 is independently selected from any one of formulas (A-VI) to (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 to 138), L in each A1-L-A2 is a linker covalently bonded to the sulfur atoms of the hinge cysteines in each E and to each of A1 and A2, T is an integer of 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 connecting the two E's represent that each A1-L-A2 is covalently bonded (e.g., by a covalent bond or a linker) to a pair of sulfur atoms of the two hinge cysteines in the two E's. or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0017] In another aspect, the present invention provides a conjugate represented by formula (2): [ka] wherein each A1 is independently selected from any one of formulas (AI) to (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 to 138), L in each L-A1 is a linker covalently bonded to a sulfur atom in a hinge cysteine ​​in E and to A1, T is an integer of 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 linked to the two sulfur atoms represent that each L-A1 is covalently bonded (e.g., by a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in two E's), or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of formulas (AI) through (A-XII). In some embodiments, each of A1 and A2 can independently be selected from any one of formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1 and A2 can independently be selected from formula (AI).

[0018] In another aspect, the present invention provides a conjugate represented by formula (2): [ka] wherein each A1 is independently selected from any one of formulas (AI) to (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 to 138), L in each L-A1 is a linker covalently bonded to a sulfur atom in a hinge cysteine ​​in E and to A1, T is an integer of 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 linked to the two sulfur atoms represent that each L-A1 is covalently bonded (e.g., by a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in two E's; or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of formulas (AI) to (AV).

[0019] In another aspect, the present invention provides a conjugate represented by formula (2): [ka] wherein each A1 is independently selected from any one of formulas (A-VI) to (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 to 138), L in each L-A1 is a linker covalently bonded to a sulfur atom in a hinge cysteine ​​in E and to A1, T is an integer of 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 linked to the two sulfur atoms represent that each L-A1 is covalently bonded (e.g., by a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in two E's), or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of formulas (A-VI) to (A-IX).

[0020] In some embodiments of any of the above embodiments, each E comprises an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138. In some embodiments, at least one of the paired sulfur atoms is the sulfur atom corresponding to (e.g., the sulfur atom of) the hinge cysteine ​​of SEQ ID NO: 10 or SEQ ID NO: 11, i.e., Cys10, Cys13, Cys16, or Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11. In some embodiments, the paired sulfur atoms are the sulfur atoms corresponding to (e.g., the sulfur atom of) 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. In some embodiments, when T is 2, the paired sulfur atoms are 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 (e.g., the sulfur atoms corresponding thereto).

[0021] In some embodiments, the pair of sulfur atoms comprises the sulfur atom of one cysteine ​​from each E, i.e., LA together with the sulfur atom attached to it 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 pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO:10 or SEQ ID NO:11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO:10 or SEQ ID NO:11 from another E. In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO:10 or SEQ ID NO:11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO:10 or SEQ ID NO:11 from another E.

[0022] In some embodiments, when T is 2, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, when T is 2, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, when T is 2, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0023] In some embodiments, when T is 2, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, when T is 2, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0024] In some embodiments, when T is 2, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0025] In some embodiments, when T is 3, the pairs of sulfur atoms are a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, when T is 3, the pairs of sulfur atoms are a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.In some embodiments, when T is 3, the pairs of sulfur atoms are a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E. In some embodiments, when T is 3, the pairs of sulfur atoms are: a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0026] In some embodiments, when T is 3, the pairs of sulfur atoms are: a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0027] In some embodiments, the complex has the structure: [ka] wherein each of a, b, c, and d is independently 0 or 1, and when a, b, c, or d is 0, the two sulfur atoms form a disulfide bond. It has.

[0028] 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.

[0029] In some embodiments, each E is selected from the group consisting of MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4) Includes.

[0030] In some embodiments, each E is selected from the group consisting of MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 33) Includes.

[0031] In some embodiments, at least one of the paired sulfur atoms is the sulfur atom corresponding to (e.g., the sulfur atom of) the hinge cysteines, i.e., Cys10 and / or Cys13, of SEQ ID NO: 4 or SEQ ID NO: 33. In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 and Cys13 in SEQ ID NO: 4 or SEQ ID NO: 33.

[0032] In some embodiments, the pair of sulfur atoms comprises the sulfur atom of one cysteine ​​from each E, i.e., LA together with the sulfur atom attached to it 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 pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 4 or SEQ ID NO: 33 from another E. In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 4 or SEQ ID NO: 33 from another E. In some embodiments, when T is 2, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO:4 or SEQ ID NO:33 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO:4 or SEQ ID NO:33 from another E, and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO:4 or SEQ ID NO:33 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO:4 or SEQ ID NO:33 from another E.

[0033] In some embodiments, the complex has the structure: [ka] wherein each of a and b is independently 0 or 1, and 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.

[0034] In some embodiments, at least one of the paired sulfur atoms is the sulfur atom corresponding to (e.g., the sulfur atom of) the hinge cysteines, i.e., Cys10 and / or Cys13, of SEQ ID NO: 8. In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 and Cys13 in SEQ ID NO: 8.

[0035] In some embodiments, the pair of sulfur atoms includes the sulfur atoms of one cysteine ​​from each E, i.e., LA together with the sulfur atoms attached thereto forms a bridge between two Fc domains (e.g., two Fc domains comprising the sequence of SEQ ID NO: 8). In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 8 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO: 8 from another E. In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 8 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO: 8 from another E. In some embodiments, when T is 2, the pair of sulfur atoms is a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO:8 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys10 of SEQ ID NO:8 from another E, and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO:8 from one E and a sulfur atom corresponding to (e.g., its sulfur atom) Cys13 of SEQ ID NO:8 from another E.

[0036] In some embodiments, the complex has the structure: [ka] wherein each of a and b is independently 0 or 1, and 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.

[0037] In some embodiments, the complex has the structure: [ka] wherein each of a and b is independently 0 or 1, and 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.

[0038] In some embodiments, the complex has the structure: [ka] wherein each of a and b is independently 0 or 1, and 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.

[0039] In some embodiments, the complex has the structure: [ka] wherein each of a and b is independently 0 or 1, and 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.

[0040] In some embodiments of the preceding three aspects, the nitrogen atom is a nitrogen of a surface-exposed lysine, e.g., a nitrogen atom corresponding to (e.g., a nitrogen atom of) Lys35, Lys63, Lys77, Lys79, Lys106, Lys123, Lys129, Lys181, Lys203, Lys228, or Lys236 of SEQ ID NO: 10 or SEQ ID NO: 11. In some embodiments, the nitrogen atom is a nitrogen atom corresponding to (e.g., a nitrogen atom of) Lys65, Lys79, Lys108, Lys230, and / or Lys238 of SEQ ID NO: 10 or SEQ ID NO: 11.

[0041] In some embodiments, the complex has the structure: [ka] wherein each of a, b, c, d, and e is independently 0 or 1, and when a, b, c, d, or e is 0, two nitrogen atoms are NH. In some embodiments, a is 1 and b, c, d, and e are 0. In some embodiments, b is 1 and a, c, d, and e are 0. In some embodiments, c is 1 and a, b, d, and e are 0. In some embodiments, d is 1 and a, b, c, and e are 0. In some embodiments, e is 1 and a, b, c, and d are 0. In some embodiments, a and b are 1 and c, d, and e are 0. In some embodiments, a and c are 1 and b, d, and e are 0. In some embodiments, a and d are 1 and b, c, and e are 0. In some embodiments, a and e are 1 and b, c, and d are 0. In some embodiments, b and c are 1 and a, d, and e are 0. In some embodiments, b and d are 1 and a, c, and e are 0. In some embodiments, b and e are 1 and a, c, and d are 0. In some embodiments, c and d are 1 and a, b, and e are 0. In some embodiments, c and e are 1 and a, b, and d are 0. In some embodiments, d and e are 1 and a, b, and c are 0. In some embodiments, a, b, and c are 1 and d and e are 0. In some embodiments, a, b, and d are 1 and c and e are 0. In some embodiments, a, b, and e are 1 and c and d are 0. In some embodiments, a, c, and d are 1 and b and e are 0. In some embodiments, a, c, and 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.

[0042] In some embodiments of any of the complexes described herein, the complex forms a homodimer that includes an Fc domain. In some embodiments of the complexes described herein, an E homodimerizes with another E to form an Fc domain.

[0043] In another aspect, the present invention provides a conjugate represented by (DI): [ka] wherein E comprises an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 141), an albumin-binding peptide, or an Fc-binding peptide; L in each of A1-L-A2 is a linker independently covalently bonded to a sulfur atom of a surface-exposed cysteine ​​or a nitrogen atom of a surface-exposed lysine in E and to each of A1 and A2; n is 1; T is an integer of 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 represents that each of A1-L-A2 is independently covalently bonded to a sulfur atom of a solvent-exposed cysteine ​​or a nitrogen atom of a solvent-exposed lysine in E. or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein). In some embodiments, each A1A2 can be independently selected from any one of formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each A1A2 can be independently selected from formula (AI).

[0044] In the preferred embodiment above, x is 2.

[0045] In another aspect, the present invention provides a conjugate of formula (MI): [ka] wherein E comprises an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 141), an albumin-binding peptide, or an Fc-binding peptide; L in each L-A1 is independently a linker covalently bonded to A1 and a sulfur atom of a surface-exposed cysteine ​​or a nitrogen atom of a surface-exposed lysine in E; n is 1; T is an integer of 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 represents that each L-A1 is independently covalently bonded to E and a sulfur atom of a solvent-exposed cysteine ​​or a nitrogen atom of a solvent-exposed lysine. or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any structure represented by formula (AI) to (A-XII). In some embodiments, each A1 can be independently selected from any one of formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each A1 can be independently selected from formula (AI). In the above preferred embodiment, x is 2.

[0046] In some embodiments, each E comprises an albumin protein having the sequence of any one of SEQ ID NOs: 139-141.

[0047] In some embodiments, T is 1 and L-A1 is covalently bound to the sulfur atom corresponding to Cys34 of SEQ ID NO:139.

[0048] The intermediates in Table 1a can be conjugated (e.g., via a linker) to an Fc domain or Fc domain monomer by any suitable method known to one of skill in the art, including any of the methods described or exemplified herein. In some embodiments, a conjugate (e.g., a conjugate represented by any one of formulas (1), (2), (DI) to (D-XI), or (MI) to (M-XI)) comprises E, where E is an Fc domain monomer or Fc domain (e.g., an Fc domain monomer or Fc domain, each Fc domain monomer independently having a sequence set forth in any one of SEQ ID NOS: 1 to 138). In preferred embodiments, one or more nitrogen atoms of one or more surface-exposed lysine residues of E, or one or more sulfur atoms of one or more surface-exposed cysteines in E, are covalently linked to a linker (e.g., PEG2 to PEG 20 The linker conjugated to E can be functionalized to react and form a covalent bond with any of the Ints described herein (e.g., Int in Table 1a). In a preferred embodiment, E is conjugated to a linker functionalized with an azide group, and Int (e.g., Int in Table 1a) is functionalized with an alkyne group. Conjugation of the linker-azide of E with the linker-alkyne of Int (e.g., via click chemistry) forms a conjugate of the invention, e.g., a conjugate represented by formula (5). In yet another embodiment, E is conjugated to a linker functionalized with an alkyne group, and Int (e.g., Int in Table 1a) is functionalized with an azide group. Conjugation of the linker-alkyne of E with the linker-azide of Int (e.g., via click chemistry; see e.g., Figure 103) forms a conjugate of the invention, e.g., a conjugate represented by any one of formulas (1), (2), (DI)-(D-XI), or (MI)-(M-XI). [Table 1] TIFF0007667139000025.tif241170TIFF0007667139000026.tif202170TIFF0007667139000027.tif238170TIFF0007667139000028.tif230170TIFF0007667139000029.tif225170TIFF0007667139000030.tif227170TIFF0007667139000031.tif247170TIFF0007667139000032.tif216170TIFF0007667139000033.tif197170TIFF0007667139000034.tif244170TIFF0007667139000035.tif247170TIFF0007667139000036.tif219170TIFF0007667139000037.tif230170TIFF0007667139000038.tif232170TIFF0007667139000039.tif248170TIFF0007667139000040.tif241170TIFF0007667139000041.tif119170

[0049] In another aspect, the invention features conjugates of Table 1b. Each conjugate in Table 1b corresponds to a conjugate of either Formula (MI) or Formula (DI) as shown. The conjugates of Table 1b include conjugates formed by covalently reacting an Int of Table 1a with a linker, which in turn conjugates to E (e.g., an Fc domain monomer, an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide). In some embodiments, a reactive moiety of Int (e.g., an alkyne or azide group) reacts with a corresponding reactive group (e.g., an alkyne or azide group) of a linker (represented by L') that is covalently attached to E, such that an Int of Table 1a is covalently attached to E. As shown in Table 1b, L' corresponds to the remainder of L as defined in (M-1) or (DI) (e.g., L' is the linker covalently linking Int and E). For example, L' can be a triazole (formed by click chemistry reaction of Int with a linker conjugated to E) and a linker (e.g., PEG2 to PEG 20 linker), which in turn is conjugated to an amino acid side chain of E (see, for example, Figure 103).

[0050] In some embodiments, n is 1 or 2 in the conjugates of Table 1b. When n is 1, each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide. When n is 2, each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), and the Fc domain monomers dimerize to form an Fc domain.

[0051] In some embodiments of any of the conjugates in Table 1b, T is an integer between 1 and 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 further provides a population of any of the conjugates in Table 2, wherein the average value of T is between 1 and 20 (e.g., the average value of T is between 1 and 2, between 1 and 3, between 1 and 4, between 1 and 5, between 5 and 10, between 10 and 15, between 15 and 20, between 1.5 and 3.5, between 2.5 and 4.5, between 3.5 and 5.5, between 4.5 and 6.5, between 5.5 and 7.5, between 6.5 and 8.5, between 7.5 and 9.5, or between 8.5 and 10.5). In some embodiments, the average 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 5 to 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).

[0052] The wavy lines in the complexes of Table 1b represent that each L'-Int is covalently attached to an amino acid side chain in E (e.g., the nitrogen atom of a surface-exposed lysine or the sulfur atom of a surface-exposed cysteine ​​in E) or a pharmaceutically acceptable salt thereof.

[0053] [Table 2] TIFF0007667139000043.tif199170TIFF0007667139000044.tif203170TIFF0007667139000045.tif170170TIFF0007667139000046.tif211170TIFF0007667139000047.tif185170TIFF0007667139000048.tif200170TIFF0007667139000049.tif231170TIFF0007667139000050.tif219170TIFF0007667139000051.tif215170TIFF0007667139000052.tif160170TIFF0007667139000053.tif175170TIFF0007667139000054.tif175170TIFF0007667139000055.tif221170TIFF0007667139000056.tif194170TIFF0007667139000057.tif215170TIFF0007667139000058.tif170170TIFF0007667139000059.tif186170TIFF0007667139000060.tif175170TIFF0007667139000061.tif215170TIFF0007667139000062.tif226170TIFF0007667139000063.tif175170TIFF0007667139000064.tif235170TIFF0007667139000065.tif231170TIFF0007667139000066.tif210170TIFF0007667139000067.tif209170TIFF0007667139000068.tif249170TIFF0007667139000069.tif196170TIFF0007667139000070.tif202170TIFF0007667139000071.tif218170TIFF0007667139000072.tif223170

[0054] In some embodiments, each E comprises an Fc domain monomer having the 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 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 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 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 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 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 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 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 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 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 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 the amino acid sequence of SEQ ID NO: 85 or SEQ ID NO: 86.

[0055] In another aspect, the invention features a conjugate comprising: (i) a first portion A1; (ii) a second portion A2; (iii) an Fc domain monomer or an Fc domain; and (iv) a linker covalently linking A1 and A2 and to the Fc domain monomer or Fc domain; each A1 and each A2 is independently selected from any one of formulas (AI) through (A-XII). In some embodiments, each of A1 and A2 can be independently selected from any one of formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1 and A2 can be independently selected from formula (AI). In the preferred embodiment above, x is 2.

[0056] In another aspect, the invention features a conjugate comprising: (i) a first moiety, Int; (ii) an Fc domain monomer or an Fc domain; and (iv) a linker covalently linking Int and to the Fc domain monomer or Fc domain; wherein each Int is independently selected from any one of the intermediates in Table 1a.

[0057] In another aspect, the invention features a conjugate comprising: (i) a first moiety A1; (ii) a second moiety A2; (iii) an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide; and (iv) a linker covalently attached to A1 and A2 and to the albumin protein, albumin protein-binding peptide, or Fc-binding peptide; each A1 and each A2 is independently selected from any one of formulas (AI) through (A-XII). In some embodiments, each of A1 and A2 can be independently selected from any one of formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1 and A2 can be independently selected from formula (AI). In the preferred embodiment described above, x is 2.

[0058] In another aspect, the present invention provides a conjugate represented by formula (DI): [ka] wherein each A1 and each A2 is independently selected from any one of formulas (AI) to (A-XII), each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of SEQ ID NOs: 1 to 138), an albumin protein (e.g., an albumin protein having any one of SEQ ID NOs: 139 to 141), an albumin protein-binding peptide, or an Fc-binding peptide, n is 1 or 2, T is an integer of 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and L is a linker covalently bonded to each of E, A1, and A2; or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein). In some embodiments, each of A1 and A2 can be independently selected from any one of formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each of A1 and A2 can be independently selected from formula (AI).

[0059] In another aspect, the present invention provides a conjugate represented by formula (DI): [ka] wherein each A1 and each A2 is independently selected from any one of formulas (AI) to (AV), each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 141), an albumin protein-binding peptide, or an Fc-binding peptide, n is 1 or 2, T is an integer of 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and L is a linker covalently bonded to each of E, A1, and A2; or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0060] In another aspect, the present invention provides a conjugate represented by formula (DI): [ka] [wherein each A1 and each A2 is independently selected from any one of formulas (A-VI) to (A-IX), each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of SEQ ID NOs: 1 to 138), an albumin protein (e.g., an albumin protein having any one of SEQ ID NOs: 139 to 141), an albumin protein-binding peptide, or an Fc-binding peptide, n is 1 or 2, T is an integer of 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and L is a linker covalently bonded to each of E, A1, and A2], or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0061] In some embodiments, the conjugate has formula (D-II): [ka] or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the conjugate has formula (D-II-1): [ka] or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the conjugate has formula (D-II-2): [ka] or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the complex has formula (D-II-3): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0065] In some embodiments, the complex comprises: [ka] The structure is selected from:

[0066] In some embodiments, the conjugate has formula (D-II-4): [ka] or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the conjugate has formula (D-II-5): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0068] In some embodiments, the complex comprises: [ka] or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the complex comprises: [ka] TIFF0007667139000085.tif89170, or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the conjugate has formula (D-II-6): [ka] wherein R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl. or a pharmaceutically acceptable salt thereof. In some embodiments, R7 is selected from C1-C20 alkyl (e.g., methyl, ethyl, propyl, or butyl).

[0071] In some embodiments, the conjugate has formula (D-II-7): [ka] or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the conjugate has formula (D-II-8): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0073] In some embodiments, the complex has the structure [ka] or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, the complex has the structure [ka] or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the complex has the structure [ka] or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the complex has the structure [ka] TIFF0007667139000093.tif65170 or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the conjugate has formula (D-II-9): [ka] or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the conjugate has formula (D-II-10): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0079] In some embodiments, the complex has the structure [ka] or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the complex [ka] or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the conjugate has formula (D-III): [ka] or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the complex has formula (D-III-1): [ka] or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the complex has formula (D-III-2): [ka] or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the complex has formula (D-III-3): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0085] In some embodiments, the complex has formula (D-III-4): [ka] or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the complex has formula (D-III-5):

[0087] [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0088] In some embodiments, the complex has formula (D-III-6): [ka] or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the complex has formula (D-III-7): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0090] In some embodiments, the complex has formula (D-III-8): [ka] or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the complex has formula (D-III-9): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0092] In some embodiments, the conjugate has formula (D-IV): [ka] or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the conjugate has formula (D-IV-1): [ka] or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the conjugate has formula (D-IV-2): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0095] In some embodiments, the conjugate has the formula (DV): [ka] or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the conjugate has the formula (DV-1): [ka] or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the conjugate has formula (DV-2): [ka] or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the conjugate has formula (DV-3): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, or y1 and y2 are each 2, or y1 and y2 are each 3.

[0099] In some embodiments, the conjugate has formula (DV-4): [ka] or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the conjugate has the formula (DV-5): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, or y1 and y2 are each 2, or y1 and y2 are each 3.

[0101] In some embodiments, the conjugate has formula (DV-6): [ka] or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the conjugate has formula (DV-7): [ka] or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the conjugate has formula (DV-8): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, or y1 and y2 are each 2, or y1 and y2 are each 3.

[0104] In some embodiments, the conjugate has the formula (DV-9): [ka] or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the conjugate has the formula (DV-10): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, or y1 and y2 are each 2, or y1 and y2 are each 3.

[0106] In some embodiments, the conjugate has formula (D-VI): [ka] or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the conjugate has formula (D-VI-1): [ka] or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the conjugate has formula (D-VI-2): [ka] or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the conjugate has formula (D-VI-3): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, or y1 and y2 are each 2, or y1 and y2 are each 3.

[0110] In some embodiments, the conjugate has formula (D-VI-4): [ka] or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the conjugate has formula (D-VI-5): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, or y1 and y2 are each 2, or y1 and y2 are each 3.

[0112] In some embodiments, the conjugate has formula (D-VI-6): [ka] or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the conjugate has formula (D-VI-7): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, or y1 and y2 are each 2, or y1 and y2 are each 3.

[0114] In some embodiments, the conjugate has formula (D-VI-8): [ka] or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the conjugate has formula (D-VI-9): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, or y1 and y2 are each 2, or y1 and y2 are each 3.

[0116] In some embodiments, the conjugate has formula (D-VII): [ka] or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments of any of the aspects described herein, R1 is OH. In some embodiments of any of the aspects described herein, R1 is NH2. In some embodiments of any of the aspects described herein, R1 is -NHC(=NH)NH2.

[0118] In some embodiments, the conjugate has formula (D-VIII): [ka] or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the conjugate has formula (D-VIII-1): [ka] or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the complex has formula (D-VIII-2): [ka] or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the complex has formula (D-VIII-3): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0122] In some embodiments, the complex comprises: [ka] or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the complex has formula (D-VIII-4): [ka] or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the conjugate has formula (D-VIII-5): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0125] In some embodiments, the complex comprises: [ka] or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the complex has the structure [ka] or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the complex has formula (D-VIII-6): [ka] or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the complex has formula (D-VIII-7): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0129] In some embodiments, the conjugate has formula (D-VIII-8): [ka] or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the conjugate has formula (D-VIII-9): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0131] In some embodiments, the conjugate has formula (D-VIII-10): [ka] or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the complex has formula (D-VIII-11): [ka] wherein L′ is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0133] In some embodiments, the complex has formula (D-IX): [ka] or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the conjugate has formula (D-IX-1): [ka] or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the complex has formula (D-IX-2): [ka] or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the conjugate has formula (D-IX-3): [ka] or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the conjugate has formula (D-IX-4): [ka] or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the conjugate has formula (D-IX-5): [ka] or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the conjugate has formula (D-IX-6): [ka] or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the conjugate has the formula (DX): [ka] or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the conjugate has the formula (DX-1): [ka] or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the conjugate has formula (DX-2): [ka] or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the conjugate has the formula (DX-3): [ka] or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments of any of the aspects described herein, L or L′ is one or more of 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 ... 20 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, 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.

[0145] In some embodiments of any of the aspects described herein, the backbone of L or L′ is 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; 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.

[0146] In some embodiments of any of the aspects described herein, L or L' is substituted with oxo. In some embodiments, the backbone of L or L' contains 250 atoms or less. In some embodiments, L or L' can form an amide, carbamate, sulfonyl, or urea linkage. In some embodiments, L or L' is a bond. In some embodiments, L or L' is an atom.

[0147] In some embodiments of any of the aspects described herein, each L has the formula (DLI): [ka] [In the formula, L A is the formula G A1 -(Z A1 ) g1 -(Y A1 ) h1 -(Z A2 ) i1 -(Y A2 ) j1 -(Z A3 ) k1 -(Y A3 ) l1 -(Z A4 ) m1 -(YA4 ) n1 -(Z A5 )o1-G A2 and L B is the formula G B1 -(Z B1 ) g2 -(Y B1 ) h2 -(Z B2 ) i2 -(Y B2 ) j2 -(Z B3 ) k2 -(Y B3 ) l2 -(Z B4 ) m2 -(Y B4 ) n2 -(Z B5 )o2-G B2 and L C is the 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 )o3-G C2 and G A1 is a bond with Q, and G A2 is the bond with A1, and G B1 is a bond with Q), and G B2 is the bond with A2, and G C1 is a bond with Q, and G C2 is a bond 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 alkene and tetrazine), and Z A1 , Z A2 , Z A3 , ZA4 , Z A5 , Z B1 , Z B2 , Z B3 , Z B4 , Z B5 , Z C1 , Z C2 , Z C3 , Z C4 and Z C5 each is independently an 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 independently represents O, S, or NR i , P, carbonyl, thiocarbonyl, sulfonyl R is aryl, phosphate, phosphoryl, or imino; 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 and 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 g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h Each of i3, i3, j3, k3, l3, m3, n3, and o3 is independently 0 or 1, and 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 C optionally substituted C-C cycloalkylene, optionally substituted C-C heterocycloalkylene, optionally substituted C-C cycloalkenylene, optionally substituted C-C heterocycloalkenylene, optionally substituted C-C cycloalkynylene, optionally substituted C-C heterocycloalkynylene, optionally substituted C-C arylene, or optionally substituted C-C heteroarylene. It is expressed as:

[0148] In some embodiments, L C The antibody has two attachment points (e.g., two GC2 ).

[0149] In some embodiments of any of the aspects described herein, L comprises a polyethylene glycol (PEG) linker. PEG linkers include a repeating unit structure (-CH2CH2O-) n where n is an integer of 2 to 100. The polyethylene glycol linker may covalently link the neuraminidase inhibitor and E (e.g., in a conjugate of any one of formulas (MI) to (M-XI)). The polyethylene glycol linker may covalently link the first neuraminidase inhibitor and the second neuraminidase inhibitor (e.g., in a conjugate of any one of formulas (DI) to (D-XI)). The polyethylene glycol linker may covalently link the neuraminidase inhibitor dimer and E (e.g., in a conjugate of any one of formulas (DI) to (D-XI)). The polyethylene glycol linker may covalently link the neuraminidase inhibitor dimer and E (e.g., in a conjugate of any one of formulas (DI) to (D-XI)). The polyethylene glycol linker may be PEG2 to PEG 100 (e.g., PEG2, PEG3, PEG4, PEG5, PEG5-PEG 10 , PEG 10 ~PEG 20 , PEG 20 ~PEG 30 , PEG 30 ~PEG 40 , PEG 50 ~PEG 60 , PEG 60 ~PEG 70 , PEG 70 ~PEG 80 , PEG 80 ~PEG 90 , PEG 90 ~PEG 100 In some embodiments, L c contains a PEG linker, and L C is covalently bonded to each of Q and E.

[0150] In some embodiments, L is [ka] TIFF0007667139000161.tif241170TIFF0007667139000162.tif232170TIFF0007667139000163.tif234170TIFF00076671 39000164.tif226170TIFF0007667139000165.tif225170TIFF0007667139000166.tif222170TIFF0007667139000167.tif2 29170TIFF0007667139000168.tif233170TIFF0007667139000169.tif229170TIFF0007667139000170.tif209170 (wherein z1 and z2 are each independently an integer of 1 to 20, and R9 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl). is.

[0151] In some embodiments, L is [ka] TIFF0007667139000172.tif214170TIFF0007667139000173.tif227170TIFF0007667139000174.tif226170 where R *is a bond, or 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; 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.

[0152] In some embodiments, Y is [ka] and L is [ka] is.

[0153] In some embodiments, Y is [ka] and L is [ka] is.

[0154] In some embodiments, Y is [ka] and L is [ka] is.

[0155] In some embodiments, Y is [ka] and L is [ka] is.

[0156] In another aspect, the present invention provides a conjugate of formula (MI): [ka] wherein each A1 is independently selected from any one of formulas (AI) to (A-XII), each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 141), an albumin protein-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer of 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and L is a linker covalently bonded to each of E and A1; or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of formulas (AI) through (A-XII). In some embodiments, each A1 can be independently selected from any one of formulas (AI), (A-II), (A-VI), or (A-VII). In other embodiments, each A1 can be independently selected from formula (AI).

[0157] In another aspect, the present invention provides a conjugate of formula (MI): [ka] wherein each A1 is independently selected from any one of formulas (AI) to (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 to 138), an albumin protein (e.g., an albumin protein having a sequence of any one of SEQ ID NOs: 139 to 141), an albumin protein-binding peptide, or an Fc-binding peptide, n is 1 or 2, T is an integer of 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and L is a linker covalently bonded to each of E and A1; or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of formulas (AI) to (AV).

[0158] In another aspect, the present invention provides a conjugate of formula (MI): [ka] wherein each A1 is independently selected from any one of formulas (A-VI) to (A-IX), each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of SEQ ID NOs: 1 to 138), an albumin protein (e.g., an albumin protein having any one of SEQ ID NOs: 139 to 141), an albumin protein-binding peptide, or an Fc-binding peptide, n is 1 or 2, T is an integer of 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and L is a linker covalently bonded to each of E and A1; or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1 can be independently selected from any one of formulas (A-VI) to (A-IX).

[0159] In some embodiments, the conjugate has formula (M-II): [ka] or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the conjugate has formula (M-II-1): [ka] or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the conjugate has formula (M-II-2): [ka] or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the conjugate has formula (M-II-3): [ka] 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.

[0163] In some embodiments, the conjugate has formula (M-II-4): [ka] or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the conjugate has formula (M-II-5): [ka] 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.

[0165] In some embodiments, the complex has the structure [ka] or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the conjugate has formula (M-II-6): [ka] wherein R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl. or a pharmaceutically acceptable salt thereof. In some embodiments, R7 is selected from C1-C20 alkyl (e.g., methyl, ethyl, propyl, or butyl).

[0167] In some embodiments, the conjugate has formula (M-II-7): [ka] or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the conjugate has formula (M-II-8): [ka] 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.

[0169] In some embodiments, the complex has the structure [ka] It has.

[0170] In some embodiments, the conjugate has formula (M-II-9): [ka] or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the conjugate has formula (M-II-10): [ka] 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.

[0172] In some embodiments, the complex has the structure [ka] or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the conjugate has formula (M-III): [ka] or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the conjugate has formula (M-III-1): [ka] or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the conjugate has formula (M-III-2): [ka] or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the conjugate has formula (M-III-3):

[0177] [ka] 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.

[0178] In some embodiments, the conjugate has formula (M-III-4): [ka] or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the conjugate has formula (M-III-5): [ka] 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.

[0180] In some embodiments, the conjugate has formula (M-III-6): [ka] or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the conjugate has formula (M-III-7): [ka] 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.

[0182] In some embodiments, the conjugate has formula (M-III-8): [ka] or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the conjugate has formula (M-III-9): [ka] 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.

[0184] In some embodiments, the conjugate has formula (M-IV): [ka] or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the conjugate has formula (M-IV-1): [ka] or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the conjugate has formula (M-IV-2): [ka] 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.

[0187] In some embodiments, the conjugate has the formula (MV): [ka] or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the conjugate has the formula (MV-1): [ka] or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the conjugate has the formula (MV-2): [ka] or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, the conjugate has the formula (MV-3): [ka] 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.

[0191] In some embodiments, the conjugate has the formula (MV-4): [ka] or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the conjugate has the formula (MV-5): [ka] 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.

[0193] In some embodiments, the conjugate has the formula (MV-6): [ka] or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the conjugate has the formula (MV-7): [ka] or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the conjugate has the formula (MV-8): [ka] 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.

[0196] In some embodiments, the conjugate has the formula (MV-9): [ka] or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the conjugate has the formula (MV-10): [ka] 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.

[0198] In some embodiments, the conjugate has formula (M-VI): [ka] or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, the conjugate has formula (M-VI-1): [ka] or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the conjugate has formula (M-VI-2): [ka] or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the conjugate has formula (M-VI-3): [ka] 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.

[0202] In some embodiments, the conjugate has formula (M-VI-4): [ka] or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the conjugate has formula (M-VI-5): [ka] 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.

[0204] In some embodiments, the conjugate has formula (M-VI-6): [ka] or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the conjugate has formula (M-VI-7): [ka] 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.

[0206] In some embodiments, the conjugate has formula (M-VI-8): [ka] or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the conjugate has formula (M-VI-9): [ka] 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.

[0208] In some embodiments, the conjugate has formula (M-VII): [ka] or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments of any of the aspects described herein, R1 is OH. In some embodiments of any of the aspects described herein, R1 is NH2. In some embodiments of any of the aspects described herein, R1 is -NHC(=NH)NH2.

[0210] In some embodiments, the conjugate has formula (M-VIII): [ka] or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the conjugate has formula (M-VIII-1): [ka] or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the conjugate has formula (M-VIII-2): [ka] or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the conjugate has formula (M-VIII-3): [ka] 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.

[0214] In some embodiments, the conjugate has formula (M-VIII-4): [ka] or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the conjugate has formula (M-VIII-5): [ka] (wherein L′ is the remainder of L, and y1 is an integer of 1 to 20). or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the complex comprises: [ka] or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the conjugate has formula (M-VIII-6): [ka] or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the conjugate has formula (M-VIII-7): [ka] 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.

[0219] In some embodiments, the conjugate has formula (M-VIII-8): [ka] or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the conjugate has formula (M-VIII-9): [ka] 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.

[0221] In some embodiments, the conjugate has formula (M-VIII-10): [ka] or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments, the conjugate has formula (M-VIII-11): [ka] 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.

[0223] In some embodiments, the conjugate has formula (M-IX): [ka] or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the conjugate has formula (M-IX-1): [ka] or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the conjugate has formula (M-IX-2): [ka] or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the conjugate has formula (M-IX-3): [ka] or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the conjugate has formula (M-IX-4): [ka] or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the conjugate has formula (M-IX-5): [ka] or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the conjugate has formula (M-IX-6): [ka] or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the conjugate has the formula (MX): [ka] or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the conjugate has the formula (MX-1): [ka] or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the conjugate has formula (MX-2): [ka] or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the conjugate has formula (MX-3): [ka] or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments of any of the aspects described herein, L or L′ is one or more of 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 ... 20 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, 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.

[0235] In some embodiments of any of the aspects described herein, the backbone of L or L′ is 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; 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.

[0236] In some embodiments of any of the aspects described herein, L or L' is substituted with oxo. In some embodiments, the backbone of L or L' contains 250 atoms or less. In some embodiments, L or L' can form an amide, carbamate, sulfonyl, or urea linkage. In some embodiments, L or L' is a bond. In some embodiments, L or L' is an atom. In some embodiments, L' is a nitrogen atom.

[0237] In some embodiments, each L has the formula (ML-1): 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 [During the ceremony, J 1 is the bond with A1, and J 2 is a bond 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 alkene and tetrazine), and Q 1 , Q 2 , Q 3 , Q 4 and Q 5each is independently an 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; 1 , T 2 , T 3 , T 4 each independently represents O, S, or NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino, and 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 each of g, h, i, j, k, l, m, n, and o is independently 0 or 1. or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, J 2 The antibody has two attachment points (e.g., two J 2 ).

[0239] In some embodiments, L is [ka] where 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).

[0240] In some embodiments, L is [ka] [wherein d and e each independently represent an integer of 1 to 26] or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments of any of the aspects described herein, L comprises a polyethylene glycol (PEG) linker. PEG linkers include a repeating unit structure (-CH2CH2O-) n where n is an integer of 2 to 100. The polyethylene glycol linker may covalently link the neuraminidase inhibitor and E (e.g., in a conjugate of any one of formulas (MI) to (M-XI)). The polyethylene glycol linker may covalently link the first neuraminidase inhibitor and the second neuraminidase inhibitor (e.g., in a conjugate of any one of formulas (DI) to (D-XI)). The polyethylene glycol linker may covalently link the neuraminidase inhibitor dimer and E (e.g., in a conjugate of any one of formulas (DI) to (D-XI)). The polyethylene glycol linker may covalently link the neuraminidase inhibitor dimer and E (e.g., in a conjugate of any one of formulas (DI) to (D-XI)). The polyethylene glycol linker may be PEG2 to PEG 100 (e.g., PEG2, PEG3, PEG4, PEG5, PEG5-PEG10 , 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 contains a PEG linker, and L C is covalently bonded to each of Q and E.

[0242] In some embodiments of any of the aspects described herein, R1 is -NHC(=NH)NH2. In some embodiments of any of the aspects described herein, R2 is -F. In some embodiments of any of the aspects described herein, R3 is -F. In some embodiments of any of the aspects described herein, R4 is -CO2H. In some embodiments of any of the aspects described herein, R5 is -COCH3.

[0243] In some embodiments of any of the aspects described herein, L is covalently attached to the nitrogen atom of a surface-exposed lysine of E, or L is covalently attached to the sulfur atom of a surface-exposed cysteine ​​of E.

[0244] 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.

[0245] In some embodiments, n is 2, each E is an Fc domain monomer, and each E dimerizes to form an Fc domain, and the complex has the formula (DI-1):

[0246] [ka] wherein J is an Fc domain and T is an integer between 1 and 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.

[0247] In some embodiments, the complex comprises: [ka] or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, n is 2, each E is an Fc domain monomer, and each E dimerizes to form an Fc domain, and the complex has the formula (MI-1): [ka] wherein J is an Fc domain and T is an integer between 1 and 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.

[0249] In some embodiments of any of the aspects described herein, E has the sequence of any one of SEQ ID NOs: 1-138.

[0250] In some embodiments of any of the aspects described herein, E is an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide. In some embodiments, when E is an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide, n is 1.

[0251] In some embodiments, n is 1, E is an albumin protein, an albumin protein binding peptide, or an Fc binding peptide, and the conjugate has formula (DI-2): [ka] [wherein E is an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide, and T is an integer of 1 to 20] or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, n is 1, E is an albumin protein, an albumin protein binding peptide, or an Fc binding peptide, and the conjugate has the formula (MI-2): [ka] [wherein E is an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide, and T is an integer of 1 to 20] or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments of any of the aspects described herein, E is an albumin protein having the sequence of any one of SEQ ID NOs: 139-141.

[0254] In some embodiments of any of the aspects described herein, T is 1, 2, 3, 4, or 5.

[0255] In another aspect, the present invention provides a population of complexes having the structure of any of the complexes described herein (e.g., a population of complexes having the formula of any one of formulas (1)-(5), (D-I)-(D-XI), (D'-I), (M-I)-(M-XI), or (M'-I)), wherein the average value of T is 1-20 (e.g., the average value of T is 1-2, 1-3, 1-4, 1-5, 5-10, 10-15, 15-20, 1.5-3.5, 2.5-4.5, 3.5-5.5, 4.5-6.5, 5.5-7.5, 6.5-8.5, 7.5-9.5, or 8.5-10.5). 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.

[0256] In some embodiments of any of the aspects described herein, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein). In some embodiments, E can be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different A1-L-A2 moieties. In some embodiments, E can be conjugated to a first A1-L-A2 moiety and a second A1-L-A2 moiety. In some embodiments, A1 and A2 of the first A1-L-A2 moiety are independently selected from any one of formulas (A-III) through (AV), and A1 and A2 of the second A1-L-A2 moiety are independently selected from any one of formulas (AI), (A-II), (A-VI), (A-VII), (A-VIII), and (A-IX).

[0257] In some embodiments, each first A1-L-A2 moiety is specifically conjugated to a lysine residue of E (e.g., the nitrogen atom of a surface-exposed lysine residue of E), and each second A1-L-A2 moiety is specifically conjugated to a cysteine ​​residue of E (e.g., the sulfur atom of a surface-exposed cysteine ​​residue of E). In some embodiments, each first A1-L-A2 moiety is specifically conjugated to a cysteine ​​residue of E (e.g., the sulfur atom of a surface-exposed cysteine ​​residue of E), and each second A1-L-A2 moiety is specifically conjugated to a lysine residue of E (e.g., the nitrogen atom of a surface-exposed lysine residue of E).

[0258] In some embodiments, the number of first A1-L-A2 moieties conjugated to E is an integer between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the number of second A1-L-A2 moieties conjugated to E is an integer between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0259] In some embodiments of any of the aspects described herein, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L can be independently selected (e.g., independently selected from any of the A1-L structures described herein). In some embodiments, E can be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different A1-L moieties. In some embodiments, E is conjugated to a first A1-L moiety and a second A1-L moiety. In some embodiments, A1 of the first A1-L moiety is selected from any one of Formulas (A-III) through (AV), and A1 of the second A1-L moiety is selected from any one of Formulas (AI), (A-II), (A-VI), (A-VII), (A-VIII), or (A-IX).

[0260] In some embodiments, each first A1-L moiety is specifically conjugated to a lysine residue of E (e.g., the nitrogen atom of a surface-exposed lysine residue of E), and each second A1-L moiety is specifically conjugated to a cysteine ​​residue of E (e.g., the sulfur atom of a surface-exposed cysteine ​​residue of E). In some embodiments, each first A1-L moiety is specifically conjugated to a cysteine ​​residue of E (e.g., the sulfur atom of a surface-exposed cysteine ​​residue of E), and each second A1-L moiety is specifically conjugated to a lysine residue of E (e.g., the nitrogen atom of a surface-exposed lysine residue of E).

[0261] In some embodiments, the number of first A1-L moieties conjugated to E is an integer between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the number of second A1-L moieties conjugated to E is an integer between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0262] In another aspect, the present invention provides a conjugate represented by formula (D'-I): [ka] [wherein each A1 is independently selected from any one of formulae (A-III) to (AV), each A2 is independently selected from any one of formulae (AI), (A-II), (A-VI), (A-VII), (A-VIII) and (A-IX), and each E is selected from an Fc domain monomer (e.g., an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 141), an albumin protein-binding peptide (e.g., an Fc domain monomer having any one of the sequences of SEQ ID NOs: 139 to 141), an albumin protein-binding peptide (e.g., an albumin protein-binding peptide ... a peptide or an Fc-binding peptide, n is 1 or 2, T1 is an integer of 1 to 10 (e.g., T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), L1 is a linker covalently binding E to each A1, T1 is an integer of 1 to 10 (e.g., T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and L2 is a linker covalently binding E to each A2, T2 is an integer of 1 to 10 (e.g., T2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, each A1-L-A1 moiety is specifically conjugated to a lysine residue of E (e.g., the nitrogen atom of a surface-exposed lysine residue of E), and each A2-L-A2 moiety is specifically conjugated to a cysteine ​​residue of E (e.g., the sulfur atom of a surface-exposed cysteine ​​residue of E). In some embodiments, each A1-L-A1 moiety is specifically conjugated to a cysteine ​​residue of E (e.g., the sulfur atom of a surface-exposed cysteine ​​residue of E), and each A2-L-A2 moiety is specifically conjugated to a lysine residue of E (e.g., the nitrogen atom of a surface-exposed lysine residue of E).

[0264] In another aspect, the present invention provides a conjugate represented by formula (M'-I): [ka] [wherein each A1 is independently selected from (M-IX) of any one of formulas (A-III) to (AV), each A2 is independently selected from any one of formulas (AI), (A-II), (A-VI), (A-VII), (A-VIII) and (A-IX), and each E is selected from an Fc domain monomer (e.g., an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 141 ...2), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 143), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 144), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 145), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 146), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 147), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 148), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 149), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NO a protein-binding peptide or an Fc-binding peptide, n is 1 or 2, T1 is an integer of 1 to 10 (e.g., T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), L1 is a linker covalently linking E and A1, T1 is an integer of 1 to 10 (e.g., T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and L2 is a linker covalently linking E and A2, T2 is an integer of 1 to 10 (e.g., T2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, each A1-L is specifically conjugated to a lysine residue of E (e.g., the nitrogen atom of a surface-exposed lysine residue of E), and each A2-L is specifically conjugated to a cysteine ​​residue of E (e.g., the sulfur atom of a surface-exposed cysteine ​​residue of E). In some embodiments, each A1-L moiety is specifically conjugated to a cysteine ​​residue of E (e.g., the sulfur atom of a surface-exposed cysteine ​​residue of E), and each A2-L moiety is specifically conjugated to a lysine residue of E (e.g., the nitrogen atom of a surface-exposed lysine residue of E).

[0266] In another aspect, the present invention provides a pharmaceutical composition comprising any of the conjugates described herein (e.g., a conjugate of any one of Formulas (1) to (5), (DI) to (D-XI), (D'-I), (MI) to (M-XI), or (M'-I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0267] In another aspect, the present 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 one of formulas (1) to (5), (DI) to (D-XI), (D'-I), (MI) to (M-XI), or (M'-I)).

[0268] In another aspect, the present invention provides a method for prophylactically treating a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of any of the conjugates or compositions described herein (e.g., a conjugate of any one of formulas (1) to (5), (DI) to (D-XI), (D'-I), (MI) to (M-XI), or (M'-I)).

[0269] In some embodiments, the viral infection is caused by an influenza virus or a parainfluenza virus, hi some embodiments, the viral infection is an influenza A, B, or C virus, or a parainfluenza virus.

[0270] In some embodiments, the subject is immunocompromised.

[0271] In some embodiments, the subject has been diagnosed with a humoral immune deficiency, a T cell deficiency, neutropenia, asplenia, or a complement deficiency.

[0272] In some embodiments, the subject is being treated or is about to be treated with immunosuppressive therapy.

[0273] In some embodiments, the subject has been diagnosed with a disease that causes immunosuppression. In some embodiments, the disease is cancer or acquired immune deficiency syndrome. In some embodiments, the cancer is leukemia, lymphoma, or multiple myeloma.

[0274] In some embodiments, the subject has undergone or is about to undergo a hematopoietic stem cell transplant.

[0275] In some embodiments, the subject has undergone or is about to undergo an organ transplant.

[0276] In some embodiments, the subject has or is at risk of developing a secondary infection. In some embodiments, the secondary infection is a bacterial infection (e.g., methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, Pseudomonas aeruginosa, and / or Haemophilus influenzae), a viral infection, or a fungal infection. In particular embodiments, the secondary infection is MRSA. In certain embodiments, the secondary infection is S. pneumoniae. In some embodiments, the secondary infection is a respiratory infection (e.g., an infection of the respiratory tract). In some embodiments, the secondary infection is associated with (e.g., causes) pneumonia (e.g., bacterial or viral pneumonia). In some embodiments, the subject has or is at risk of developing pneumonia.

[0277] In another aspect, the disclosure features a method for preventing a subsequent infection in a subject diagnosed with influenza infection, the method including administering to the subject a conjugate or composition described herein. In some embodiments, the method includes administering to the subject conjugate 45 or a pharmaceutical composition including conjugate 45.

[0278] In some embodiments, administering a conjugate or composition of the invention to a subject diagnosed with an influenza infection reduces the likelihood of developing a secondary infection by, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, or more (e.g., compared to a subject with influenza who is not treated with the conjugate or composition). For example, administering a conjugate or composition of the invention to a subject diagnosed with an influenza infection reduces the likelihood of developing a secondary infection (e.g., MRSA, Streptococcus pneumoniae, Pseudomonas aeruginosa, and / or Haemophilus influenzae) by, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, or more. In some embodiments, the complex or composition is administered intramuscularly, intravenously, intradermally, intra-arterially, intraperitoneally, intralesionally, intracranially, intra-articularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subcutaneously, subconjunctivally, intravesicularly, transmucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, by inhalation, injection, or infusion.

[0279] 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 particular embodiments, the second therapeutic agent is pimovidir. In some embodiments, the second therapeutic agent is a viral vaccine. In some embodiments, the viral vaccine induces an immune response in the subject against influenza A, B, or C virus, or parainfluenza virus.

[0280] In some embodiments, the conjugate is administered in combination with an antiviral agent, and the antiviral agent is baloxavir. In certain embodiments, the conjugate is represented by Formula (D-II-6). In other embodiments, the conjugate is represented by Formula (D-II-7). In certain embodiments, each E comprises an Fc domain having an amino acid sequence at least 95% identical to 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 any one of SEQ ID NOs: 63, 64, 67, 68, 72, 73, 76, 77, 81, 82, 85, or 86. In certain embodiments, each E comprises an Fc domain having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 63, 64, 67, 68, 72, 73, 76, 77, 81, 82, 85, or 86. In preferred embodiments, the complex is complex 45 (eg, complex 45a or 45b) or complex 46.

[0281] In some embodiments, the conjugate and baloxavir are administered sequentially, hi other embodiments, the conjugate and baloxavir are administered simultaneously.

[0282] In one aspect, the present disclosure provides a method for treating or preventing a viral infection in a subject by administering to the subject: a) an effective amount of a conjugate or composition of 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, is suspected of having, or has been exposed to a viral infection. 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, is suspected of having, or has been exposed to a viral infection. 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, within 14 days, within 7 days, within 2 days, or within 24 hours of the conjugate. In certain embodiments, the second therapeutic agent is administered within 2 days of the conjugate. In certain embodiments, the second therapeutic agent is an antiviral agent (e.g., pimovidir, oseltamivir, zanamivir, peramivir, laninamivir, amantadine, baloxavir marboxil, baloxavir acid, rimantadine, or a pharmaceutically acceptable salt thereof). In certain embodiments, the antiviral agent is baloxavir marboxil, baloxavir acid, or a pharmaceutically acceptable salt thereof. In certain embodiments, baloxavir marboxil is administered in an amount of 20-90 mg (e.g., 25-50 mg, 45-70 mg, or 65-90 mg). In some embodiments, baloxavir marboxil is administered orally. In certain embodiments, baloxavir marboxil is administered as a single dose. In other embodiments, baloxavir marboxil is administered as more than one dose. In certain embodiments, baloxavir marboxil is administered in an amount of 20-40 mg. In other embodiments, baloxavir marboxil is administered in an amount of 30-80 mg. In some embodiments, the conjugate is represented by Formula (D-II-6). In other embodiments, the conjugate is represented by Formula (D-II-7). In some embodiments, each E has a sequence at least 95% identical to 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 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 complex is complex 45 (e.g., complex 45a or 45b) or complex 46. In certain embodiments, the conjugate is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intra-articularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subcutaneously, subconjunctivally, intravesicularly, transmucosally, intrapericardially, intraumbilically, intraocularly, orally, locally, by inhalation, injection, or 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 an influenza virus or a parainfluenza virus. In certain embodiments, the virus is an influenza A, B, or C virus, or a parainfluenza virus.

[0283] (1)~(5),(DI)~(D-XI),(D'-I),(MI)~(M-XI)またたは(M'-I)のいずれか1つ(1)、(2)、(3)(4)、(5)、(DI)、(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-III- IV-1)、(D-IV-2)、(DV)、(DV-1)、(DV-2)、(DV-3)、(DV-4)、(DV-5)、(DV-6) 、(DV-7)、(DV-8)、(DV-9)、(DV-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-VI-VI) I)、(D-VIII)、(D-VIII-1)、(D-VIII-2)、(D-VIII-3)、(D-VIII-4)、(D-VI II-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-IX) -5)、(D-IX-6)、(DX)、(DX-1)、(DX-2)、(DX-3)、(D-XI)、(D-XI-1)、(D'-I)、 (MI)、(M-II)、(M-II-1)、(M-II-2)、(M-II-3)、(M-II-4)、(M-II-5)、(M-I I-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)、(MV)、(MV-1)、(MV-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-VIII-4), (M-VIII-5), (M-VIII-6), (M-VIII-7), (M In any of the formulae described herein (e.g., any one of formulae (1) to (5), (D-I) to (D-XI), (D'-I), (M-I) to (M-XI), or (M'-I)), an Fc domain-containing construct may be used in place of the Fc domain, and an Fc domain monomer-containing construct may be used in place of the Fc domain. When n is 1 in any of the formulae described herein (e.g., any one of formulae (1) to (5), (D-I) to (D-XI), (D'-I), (M-I) to (M-XI), or (M'-I)), E is an Fc domain monomer-containing construct. In any of the formulas described herein (e.g., any one of formulas (1) to (5), (D-I) to (D-XI), (D'-I), (M-I) to (M-XI), or (M'-I)), when n is 2, E is an Fc domain-containing construct.

[0284] In one embodiment, the Fc domain-containing construct is an antibody or antibody fragment. Antibodies can include any form of immunoglobulin, heavy chain antibody, light chain antibody, LRR-based antibody, or other protein scaffold with antibody-like properties, as well as any other immunological binding moiety known in the art, such as an antibody fragment (e.g., Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, scFv, or SMIP). The subunit structures and three-dimensional configurations of various classes of antibodies are known in the art. An antibody fragment can include a binding portion derived from or containing a portion highly homologous to an antibody, such as an antigenic determining region of an antibody. Exemplary antibody fragments include Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, scFv, and SMIP.

[0285] In certain embodiments, the antibody or antibody fragment is a human, murine, camelid (e.g., llama, alpaca, or camel), goat, sheep, rabbit, chicken, guinea pig, hamster, horse, or rat antibody or antibody fragment. In specific embodiments, the antibody is an IgG, IgA, IgD, IgE, IgM, or an intrabody. In some embodiments, the antibody fragment comprises an scFv, sdAb, dAb, Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, or SMIP.

[0286] In some embodiments, the Fc domain-containing construct (eg, an antibody or antibody fragment) confers binding specificity for one or more targets (eg, antigens).

[0287] In some embodiments, one or more targets (e.g., antigens) bound by the Fc domain-containing construct (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 a viral surface antigen. In some embodiments, the antibody or antibody fragment targets hemagglutinin. Hemagglutinin-directed antibodies include monoclonal antibodies such as CR6261, CR8020, MEDI8852, MHAA4549A, and VIS410. In some embodiments, the antibody or antibody fragment is an antibody or antibody fragment that targets and broadly neutralizes influenza hemagglutinin (e.g., the 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 a viral matrix protein (e.g., matrix 2 protein). TCN032 is a monoclonal antibody directed against matrix 2 protein.

[0288] In some embodiments, the Fc domain-containing construct (e.g., an antibody or antibody fragment) comprises one or more single domain antibodies (sdAbs). In some embodiments, the Fc domain-containing construct is an antibody or antibody fragment comprising an sdAb with influenza A reactivity, such as an sdAb that binds to influenza A hemagglutinin (e.g., SD36 or SD38 as described in Laursen et al. Science. 362:598-602 (2018)). In some embodiments, the Fc domain-containing construct is an antibody or antibody fragment comprising an sdAb with influenza B reactivity, such as an sdAb that binds to influenza B hemagglutinin (e.g., SD83 or SD84 as described in Laursen et al. Science. 362:598-602 (2018)).

[0289] In some embodiments, the Fc domain-containing construct is a multi-domain antibody (MDAb) or multi-domain antibody fragment comprising two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more) sdAbs. In some embodiments, the MDAb or fragment thereof comprises one or more sdABs that bind to influenza A hemagglutinin and one or more sdAbs that bind to influenza B hemagglutinin. In some embodiments, the MDAb is JNJ-7445 (also known as MD3606), described in Laursen et al. Science. 362:598-602 (2018). Briefly, JNJ-7445 is an MDAb containing two sdAbs (SD36 and SD38) that bind to influenza A hemagglutinin and two sdAbs (SD83 and SD84) that bind to influenza B hemagglutinin, linked to an Fc domain (IgG1). The sdAbs were produced by immunizing llamas with influenza vaccine and H7 and H2 recombinant hemagglutinins.

[0290] (1) ~ (5), (DI) ~ (D-XI), (D'-I), (MI) ~ (M-XI), M-(M-XI) I) (1), (2), (3), (4), (5), (DI), (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-8) 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)、(DV)、(DV-1)、(DV-2)、(DV-3)、(DV-4)、(DV-5)、(DV-5) -6)、(DV-7)、(DV-8)、(DV-9)、(DV-10)、(D-VI)、(D-VI-1)、(D-VI-2)、(D-VI-2) 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-VII I-10)、(D-VIII-11)、(D-IX)、(D-IX-1)、(D-IX-2)、(D-IX-3)、(D-IX-4)、 (D-IX-5)、(D-IX-6)、(DX)、(DX-1)、(DX-2)、(DX-3)、(D-XI)、(D-XI-1)、( D'-I)、(MI)、(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-II I-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)、(MV)、(MV-1)、(MV-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-VIII-4 (M-IX-1), (M-IX-2), (M-IX-3), (M-IX-4), (M-IX-5), (M-IX-6), (M-VIII-7), (M-VIII-8), (M-VIII-9), (M-VIII-10), (M-VIII-11), (M-IX), (M-IX-1), (M-IX-2), (M-IX-3), (M-IX-4), (M-IX-5), (M-IX-6), (MX), (MX-1), (MX-2), (MX-3) or (M'-I)), wherein E is an antibody or antibody fragment. In a preferred embodiment, when E is an antibody or antibody fragment, n is 1. In some embodiments, the antibody or antibody fragment comprises any antibody or antibody fragment described herein, e.g., a monoclonal antibody that binds to a viral hemagglutinin (e.g., CR6261, CR8020, MEDI8852, MHAA4549A, or VIS410); an antibody or antibody fragment that targets and broadly neutralizes a viral hemagglutinin (e.g., an antibody or antibody fragment described in Wu et al., J. Mol. Biol. 429:2694-2709 (2017)); an sdAb that targets a viral hemagglutinin (e.g., SD36, SD38, SD83, or SD84); or an MDAb or fragment thereof that targets a viral hemagglutinin (e.g., JNJ-7445).

[0291] In some embodiments of any of the aspects 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.

[0292] In some embodiments of any of the aspects 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.

[0293] In some embodiments of any of the aspects 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.

[0294] In some embodiments of any of the aspects 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.

[0295] In some embodiments of any of the aspects 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.

[0296] In some embodiments of any of the aspects 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.

[0297] In some embodiments of any of the aspects 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.

[0298] In some embodiments of any of the aspects 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.

[0299] In some embodiments of any of the aspects 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.

[0300] In some embodiments of any of the aspects 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.

[0301] In some embodiments of any of the aspects 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.

[0302] In some embodiments of any of the aspects 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.

[0303] In some embodiments of any of the aspects 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.

[0304] In some embodiments of any of the aspects 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.

[0305] In some embodiments of any of the aspects 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.

[0306] In some embodiments of any of the aspects 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.

[0307] In some embodiments of any of the aspects 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.

[0308] In some embodiments of any of the aspects 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.

[0309] In some embodiments of any of the aspects 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.

[0310] In some embodiments of any of the aspects 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.

[0311] In some embodiments of any of the aspects 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.

[0312] In some embodiments of any of the aspects 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.

[0313] In some embodiments of any of the aspects 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.

[0314] In some embodiments of any of the aspects 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.

[0315] In some embodiments of any of the aspects 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.

[0316] In some embodiments of any of the aspects 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.

[0317] In some embodiments of any of the aspects 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.

[0318] In some embodiments of any of the aspects 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.

[0319] In some embodiments of any of the aspects 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.

[0320] In some embodiments of any of the aspects 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.

[0321] In some embodiments of any of the aspects 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.

[0322] In some embodiments of any of the aspects 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.

[0323] In some embodiments of any of the aspects 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.

[0324] In some embodiments of any of the aspects 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.

[0325] In some embodiments of any of the aspects 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.

[0326] In some embodiments of any of the aspects 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.

[0327] In some embodiments of any of the aspects 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.

[0328] In some embodiments of any of the aspects 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.

[0329] In some embodiments of any of the aspects 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.

[0330] In some embodiments of any of the aspects 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.

[0331] In some embodiments of any of the aspects 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.

[0332] In some embodiments of any of the aspects 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.

[0333] In some embodiments of any of the aspects 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.

[0334] In some embodiments of any of the aspects 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.

[0335] In some embodiments of any of the aspects 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.

[0336] In some embodiments of any of the aspects 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.

[0337] In some embodiments of any of the aspects 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.

[0338] In some embodiments of any of the aspects 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.

[0339] In some embodiments of any of the aspects 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.

[0340] In some embodiments of any of the aspects 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.

[0341] In some embodiments of any of the aspects 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.

[0342] In some embodiments of any of the aspects 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.

[0343] In some embodiments of any of the aspects 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.

[0344] In some embodiments of any of the aspects 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.

[0345] In some embodiments of any of the aspects 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.

[0346] In some embodiments of any of the aspects 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.

[0347] In some embodiments of any of the aspects 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.

[0348] In some embodiments of any of the aspects 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.

[0349] In some embodiments of any of the aspects 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.

[0350] In some embodiments of any of the aspects 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.

[0351] In some embodiments of any of the aspects 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.

[0352] In some embodiments of any of the aspects 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.

[0353] In some embodiments of any of the aspects 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.

[0354] In some embodiments of any of the aspects 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.

[0355] In some embodiments of any of the aspects 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.

[0356] In some embodiments of any of the aspects 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.

[0357] In some embodiments of any of the aspects 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.

[0358] In some embodiments of any of the aspects 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.

[0359] In some embodiments of any of the aspects 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.

[0360] In some embodiments of any of the aspects 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.

[0361] In some embodiments of any of the aspects 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.

[0362] In some embodiments of any of the aspects 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.

[0363] In some embodiments of any of the aspects 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.

[0364] In some embodiments of any of the aspects 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.

[0365] In some embodiments of any of the aspects 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.

[0366] In some embodiments of any of the aspects 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.

[0367] In some embodiments of any of the aspects 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.

[0368] In some embodiments of any of the aspects 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.

[0369] In some embodiments of any of the aspects 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.

[0370] In some embodiments of any of the aspects 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.

[0371] In some embodiments of any of the aspects 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.

[0372] In some embodiments of any of the aspects 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.

[0373] In some embodiments of any of the aspects 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.

[0374] In some embodiments of any of the aspects 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.

[0375] In some embodiments of any of the aspects 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.

[0376] In some embodiments of any of the aspects 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.

[0377] In some embodiments of any of the aspects 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.

[0378] In some embodiments of any of the aspects 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.

[0379] In some embodiments of any of the aspects 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.

[0380] In some embodiments of any of the aspects 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.

[0381] In some embodiments of any of the aspects 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.

[0382] In some embodiments of any of the aspects 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.

[0383] In some embodiments of any of the aspects 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.

[0384] In some embodiments of any of the aspects 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.

[0385] In some embodiments of any of the aspects 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.

[0386] In some embodiments of any of the aspects 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.

[0387] In some embodiments of any of the aspects 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.

[0388] In some embodiments of any of the aspects 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.

[0389] In some embodiments of any of the aspects 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.

[0390] In some embodiments of any of the aspects 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.

[0391] In some embodiments of any of the aspects 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.

[0392] In some embodiments of any of the aspects 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.

[0393] In some embodiments of any of the aspects 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.

[0394] In some embodiments of any of the aspects 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.

[0395] In some embodiments of any of the aspects 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.

[0396] In some embodiments of any of the aspects 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.

[0397] In some embodiments of any of the aspects 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.

[0398] In some embodiments of any of the aspects 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.

[0399] In some embodiments of any of the aspects 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.

[0400] In some embodiments of any of the aspects 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.

[0401] In some embodiments of any of the aspects 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.

[0402] In some embodiments of any of the aspects 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.

[0403] In some embodiments of any of the aspects 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.

[0404] In some embodiments of any of the aspects 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.

[0405] In some embodiments of any of the aspects 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.

[0406] In some embodiments of any of the aspects 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.

[0407] In some embodiments of any of the aspects 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.

[0408] In some embodiments of any of the aspects 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.

[0409] In some embodiments of any of the aspects 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.

[0410] In some embodiments of any of the aspects 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.

[0411] In some embodiments of any of the aspects 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.

[0412] In some embodiments of any of the aspects 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.

[0413] In some embodiments of any of the aspects 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.

[0414] In some embodiments of any of the aspects 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.

[0415] In some embodiments of any of the aspects 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.

[0416] In some embodiments of any of the aspects 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.

[0417] In some embodiments of any of the aspects 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.

[0418] In some embodiments of any of the aspects 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.

[0419] In some embodiments of any of the aspects 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.

[0420] In some embodiments of any of the aspects 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.

[0421] In some embodiments of any of the aspects 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.

[0422] In some embodiments of any of the aspects 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.

[0423] In some embodiments of any of the aspects 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.

[0424] In some embodiments of any of the aspects 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.

[0425] In some embodiments of any of the aspects 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.

[0426] In some embodiments of any of the aspects 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.

[0427] In some embodiments of any of the aspects 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.

[0428] In some embodiments of any of the aspects 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.

[0429] In some embodiments of any of the aspects 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.

[0430] In some embodiments of any of the aspects 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.

[0431] In some embodiments of any of the aspects described herein, E comprises an Fc domain monomer, and the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138) comprises a triple mutation corresponding to M252Y / S254T / T256E (YTE). As used herein, an amino acid "corresponding to" a particular amino acid residue (e.g., of a particular SEQ ID NO) should be understood to include any amino acid residue that would be understood by one of skill in the art to align with the particular residue (e.g., of a particular sequence). For example, any one of SEQ ID NOs: 1-138 may be mutated to comprise a YTE mutation.

[0432] In some embodiments of any of the aspects described herein, E comprises an Fc domain monomer, and the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138) comprises a double mutation corresponding to M428L / N434S (LS). As used herein, an amino acid "corresponding to" a particular amino acid residue (e.g., of a particular SEQ ID NO) should be understood to include any amino acid residue that would be understood by one of skill in the art to align with the particular residue (e.g., of a particular sequence). For example, any one of SEQ ID NOs: 1-138 may be mutated to comprise an LS mutation.

[0433] In some embodiments of any of the aspects described herein, E comprises an Fc domain monomer, and the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138) comprises a mutation corresponding to N434H. As used herein, an amino acid "corresponding to" a particular amino acid residue (e.g., of a particular SEQ ID NO) should be understood to include any amino acid residue that would be understood by one of skill in the art to align with the particular residue (e.g., of a particular sequence). For example, any one of SEQ ID NOs: 1-138 may be mutated to comprise an N434H mutation.

[0434] In some embodiments of any of the aspects described herein, E comprises an Fc domain monomer, and the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138) comprises a mutation corresponding to C220S. As used herein, an amino acid "corresponding to" a particular amino acid residue (e.g., of a particular SEQ ID NO) should be understood to include any amino acid residue that would be understood by one of skill in the art to align with the particular residue (e.g., of a particular sequence). For example, any one of SEQ ID NOs: 1-138 may be mutated to comprise a C220S mutation.

[0435] In some embodiments of any of the aspects described herein, an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOS: 1-95) comprises a triple mutation corresponding to V309D / Q311H / N434S (DHS). As used herein, an amino acid "corresponding to" a particular amino acid residue (e.g., of a particular SEQ ID NO) should be understood to include any amino acid residue that would be understood by one of skill in the art to align with the particular residue (e.g., of a particular sequence). For example, any one of SEQ ID NOS: 1-95 may be mutated to comprise a DHS mutation.

[0436] In some embodiments of any of the aspects described herein, E comprises an Fc domain monomer, and the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138) can be a fragment of an 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, 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, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 12 0 or more), at least 50 (e.g., 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 or more), at least 75 (e.g., 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more) contiguous amino acids in length.

[0437] In some embodiments of any of the aspects described herein (e.g., a conjugate of any one of Formulas (1)-(5), (D-I)-(D-XI), (D'-I), (M-I)-(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 in E, are covalently linked to a linker (e.g., PEG2 to PEG 20The linker conjugated to E can be functionalized to react to form a covalent bond with any A1-L or any L of A2-L-A1 described herein. In a preferred embodiment, E is conjugated to a linker functionalized with an azide group, and any L of A1-L or any A2-L-A1 is functionalized with an alkyne group. Conjugation of the linker-azide of E to the linker-alkyne of A1-L or A2-L-A1 (e.g., via click chemistry) forms a conjugate of the invention, e.g., a conjugate represented by any one of formulas (1)-(5), (D-I)-(D-XI), (D'-I), (M-I)-(M-XI), or (M'-I). In yet another embodiment, E is conjugated to a linker functionalized with an alkyne group, and any L of A1-L or any L of A2-L-A1 is functionalized with an azide group. Conjugation of the linker-alkyne of E with the linker-azide of A1-L or A2-L-A1 (e.g., via click chemistry, see e.g., Figure 103) forms a conjugate of the invention, e.g., a conjugate represented by formula (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I). In some embodiments of any of the aspects described herein, the wavy line in any one of formulas (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I) can represent a covalent bond between E and L of A1-L or A2-L-A1.

[0438] In some embodiments of any of the aspects described herein, the wavy line in any one of formulas (1)-(5), (D-I)-(D-XI), (D'-I), (M-I)-(M-XI), or (M'-I) may be a linker (e.g., PEG2-PEG 20linker) that is functionalized with a reactive moiety such that the reactive moiety forms a covalent bond with L of any A1-L or any A2-L-A1 described herein (e.g., by click chemistry between an azide-functionalized linker and an alkyne-functionalized linker, as described above, e.g., with reference to Figure 103).

[0439] In some embodiments of any of the aspects described herein, A1 and / or A2 are selected from the group consisting of the structures represented by (AI): [ka] It has.

[0440] In a preferred embodiment, A1 and / or A2 have the structure represented by (AI), wherein R1 is -NHC(=NH)NH2, R4 is -CO2H, R5 is -COCH3, and / or X is -O-. [ka] It has the structure of zanamivir represented by the formula:

[0441] In some embodiments of any of the aspects described herein, A1 and / or A2 is (A-II): [ka] It has a structure represented by the following formula:

[0442] In a preferred embodiment, A1 and / or A2 have the structure represented by (A-II), wherein R1 is -NHC(=NH)NH2, R2 is H or F, R3 is H or F, R4 is -CO2H, R5 is -COCH3, and / or X is -O-. [ka] It has a structure represented by the following formula:

[0443] In some embodiments of any of the aspects described herein, A1 and / or A2 is (A-III): [ka] It has a structure represented by the following formula:

[0444] In a preferred embodiment, A1 and / or A2 have the structure represented by (A-III), where R1 is -NHC(=NH)NH2, R4 is -CO2H, and / or R5 is -COCH3. In a preferred embodiment, A1 and / or A2 are [ka] It has the structure of peramivir represented by the formula:

[0445] In some embodiments of any of the aspects described herein, A1 and / or A2 are (A-IV): [ka] It has a structure represented by the following formula:

[0446] In a preferred embodiment, A1 and / or A2 have the structure represented by (A-IV), where R1 is -NHC(=NH)NH2, R4 is -CO2H, and / or R5 is -COCH3. In a preferred embodiment, A1 and / or A2 are [ka] It has a structure represented by the following formula:

[0447] In some embodiments of any of the aspects described herein, A1 and / or A2 are (AV):

[0448] [ka] It has a structure represented by the following formula:

[0449] In a preferred embodiment, A1 and / or A2 have the structure represented by (AV), where R1 is -NHC(=NH)NH2, R4 is -CO2H, and / or R5 is -COCH3. In a preferred embodiment, A1 and / or A2 are

[0450] [ka] It has a structure represented by the following formula:

[0451] In some embodiments of any of the aspects described herein, A1 and / or A2 are (A-VI): [ka] It has a structure represented by the following formula:

[0452] In a preferred embodiment, A1 and / or A2 have the structure represented by (A-VI), wherein R1 is -NHC(=NH)NH2, R4 is -CO2H, R5 is -COCH3, and / or X is -O-. [ka] in The compound has the structure of zanamivir represented by the formula:

[0453] In some embodiments of any of the aspects described herein, A1 and / or A2 are (A-VII): [ka] It has a structure represented by the following formula:

[0454] In a preferred embodiment, A1 and / or A2 have the structure represented by (A-VII), wherein R1 is -NHC(=NH)NH2, R2 is H or F, R3 is H or F, R4 is -CO2H, R5 is -COCH3, and / or X is -O-. [ka] It has a structure represented by the following formula:

[0455] In some embodiments of any of the aspects described herein, A1 and / or A2 are (A-VIII): [ka] It has a structure represented by the following formula:

[0456] In a preferred embodiment, A1 and / or A2 have the structure represented by (A-VIII), wherein R1 is -NHC(=NH)NH2, R5 is -COCH3, and / or X is -O-. [ka] It has a structure represented by the following formula:

[0457] In some embodiments of any of the aspects described herein, A1 and / or A2 are (A-IX): [ka] It has a structure represented by the following formula:

[0458] In a preferred embodiment, A1 and / or A2 have the structure represented by (A-IX), where R1 is -NHC(=NH)NH2, R2 is H or F, R3 is H or F, R5 is -COCH3, and / or X is -O-. [ka] It has a structure represented by the following formula:

[0459] In some embodiments of any of the aspects described herein, A1 and / or A2 are (AX): [ka] It has a structure represented by the following formula:

[0460] In a preferred embodiment, A1 and / or A2 have the structure represented by (AX), where R1 is -NHC(=NH)NH2, R3 is H, R5 is -COCH3, and / or X is -O-. [ka] It has the structure of sulfozanamivir represented by the formula:

[0461] In some embodiments of any of the aspects described herein, A1 and / or A2 are (A-XI): [ka] It has a structure represented by the following formula:

[0462] In a preferred embodiment, A1 and / or A2 have the structure represented by (A-XI), R4 is -CO2H, and / or R5 is -COCH3. In a preferred embodiment, the alkene is (E), (Z), or a racemic mixture of (E) / (Z). In a preferred embodiment, A1 and / or A2 are [ka] It has the structure of A-315675 (Abbott) represented by the formula:

[0463] In some embodiments of any of the aspects described herein, A1 and / or A2 are (A-XII): [ka] It has a structure represented by the following formula:

[0464] In a preferred embodiment, A1 and / or A2 have the structure represented by (A-XII) and R4 is -CO2H. In a preferred embodiment, A1 and / or A2 are [ka] It has the structure of A-315675 (Abbott) represented by the formula:

[0465] In some embodiments, the conjugate is Conjugate 1 or any positional isomer 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, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of Complex 1, wherein the average DAR (e.g., T) of the population of complexes 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.

[0466] In some embodiments, the complex is Complex 2 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of Complex 2, wherein the average DAR (e.g., T) of the population of complexes 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.

[0467] In some embodiments, the complex is Complex 3 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of Complex 3, wherein the average DAR (e.g., T) of the population of complexes 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.

[0468] In some embodiments, the complex is Complex 4 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of Complex 4, wherein the average DAR (e.g., T) of the population of complexes 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.

[0469] In some embodiments, the complex is Complex 5 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 5, wherein the average DAR (e.g., T) of the population of complexes 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.

[0470] In some embodiments, the complex is Complex 6 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of Complex 6, wherein the average DAR (e.g., T) of the population of complexes 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.

[0471] In some embodiments, the complex is Complex 7 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of Complex 7, wherein the average DAR (e.g., T) of the population of complexes 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.

[0472] In some embodiments, the complex is Complex 8 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of Complex 8, wherein the average DAR (e.g., T) of the population of complexes 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.

[0473] In some embodiments, the complex is Complex 9 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 9, wherein the average DAR (e.g., T) of the population of complexes 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.

[0474] In some embodiments, the conjugate is conjugate 10 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 10, wherein the average DAR (e.g., T) of the population of complexes 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.

[0475] In some embodiments, the conjugate is conjugate 11 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 11, wherein the average DAR (e.g., T) of the population of complexes 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.

[0476] In some embodiments, the conjugate is Conjugate 12 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 12, wherein the average DAR (e.g., T) of the population of complexes 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.

[0477] In some embodiments, the conjugate is Conjugate 13 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 13, wherein the average DAR (e.g., T) of the population of complexes 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.

[0478] In some embodiments, the conjugate is Conjugate 14 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 14, wherein the average DAR (e.g., T) of the population of complexes 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.

[0479] In some embodiments, the conjugate is Conjugate 15 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 15, wherein the average DAR (e.g., T) of the population of complexes 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.

[0480] In some embodiments, the conjugate is Conjugate 16 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 16, wherein the average DAR (e.g., T) of the population of complexes 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.

[0481] In some embodiments, the conjugate is Conjugate 17 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 17, wherein the average DAR (e.g., T) of the population of complexes 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.

[0482] In some embodiments, the conjugate is Conjugate 18 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 18, wherein the average DAR (e.g., T) of the population of complexes 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.

[0483] In some embodiments, the conjugate is Conjugate 19 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 19, wherein the average DAR (e.g., T) of the population of complexes 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.

[0484] In some embodiments, the conjugate is conjugate 20 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 20, wherein the average DAR (e.g., T) of the population of complexes 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.

[0485] In some embodiments, the complex is Complex 21 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 21, wherein the average DAR (e.g., T) of the population of complexes 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.

[0486] In some embodiments, the complex is Complex 22 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 22, wherein the average DAR (e.g., T) of the population of complexes 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.

[0487] In some embodiments, the conjugate is Conjugate 23 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 23, wherein the average DAR (e.g., T) of the population of complexes 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.

[0488] In some embodiments, the conjugate is Conjugate 24 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 24, wherein the average DAR (e.g., T) of the population of complexes 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.

[0489] In some embodiments, the conjugate is Conjugate 25 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of Complex 25, wherein the average DAR (e.g., T) of the population of complexes 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.

[0490] In some embodiments, the conjugate is Conjugate 26 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 26, wherein the average DAR (e.g., T) of the population of complexes 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.

[0491] In some embodiments, the conjugate is conjugate 27 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 27, wherein the average DAR (e.g., T) of the population of complexes 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.

[0492] In some embodiments, the conjugate is conjugate 28 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 28, wherein the average DAR (e.g., T) of the population of complexes 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.

[0493] In some embodiments, the conjugate is Conjugate 29 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 29, wherein the average DAR (e.g., T) of the population of complexes 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.

[0494] In some embodiments, the conjugate is conjugate 30 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 30, wherein the average DAR (e.g., T) of the population of complexes 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.

[0495] In some embodiments, the conjugate is conjugate 31 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 31, wherein the average DAR (e.g., T) of the population of complexes 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.

[0496] In some embodiments, the complex is complex 32 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 32, wherein the average DAR (e.g., T) of the population of complexes 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.

[0497] In some embodiments, the conjugate is conjugate 33 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 33, wherein the average DAR (e.g., T) of the population of complexes 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.

[0498] In some embodiments, the conjugate is conjugate 34 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 34, wherein the average DAR (e.g., T) of the population of complexes 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.

[0499] In some embodiments, the complex is Complex 35 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 35, wherein the average DAR (e.g., T) of the population of complexes 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.

[0500] In some embodiments, the conjugate is conjugate 36 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 36, wherein the average DAR (e.g., T) of the population of complexes 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.

[0501] In some embodiments, the complex is complex 37 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 37, wherein the average DAR (e.g., T) of the population of complexes 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.

[0502] In some embodiments, the conjugate is conjugate 38 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 38, wherein the average DAR (e.g., T) of the population of complexes 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.

[0503] In some embodiments, the conjugate is Conjugate 39 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 39, wherein the average DAR (e.g., T) of the population of complexes 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.

[0504] In some embodiments, the conjugate is conjugate 40 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 40, wherein the average DAR (e.g., T) of the population of complexes 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.

[0505] In some embodiments, the complex is complex 41 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 41, wherein the average DAR (e.g., T) of the population of complexes 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.

[0506] In some embodiments, the complex is complex 42 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 42, wherein the average DAR (e.g., T) of the population of complexes 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.

[0507] In some embodiments, the conjugate is conjugate 43 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 43, wherein the average DAR (e.g., T) of the population of complexes 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.

[0508] In some embodiments, the conjugate is conjugate 44 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 44, wherein the average DAR (e.g., T) of the population of complexes 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.

[0509] In some embodiments, the complex is complex 45 (e.g., complex 45a or complex 45b) or any positional isomer thereof, and the DAR (e.g., T) is 0.5 to 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 4.10, 4.11, 4.12, 4.13, 4.14, 4.15, 4.16, 4.17, 4.18, 4.19, 4.20, 4.21, 4.22, 4.23, 4.24, 4.25, 4.26, 4.27, 4.28, 4.29, 4.30, 4.31, 4.32, 4.33, 4.34, 4.35, 4.36, 4.37, 4.38, 4.39, 4.39, 4.39, 4.39, 4.39, 4.39, 4.39, 4.39, 4.39 .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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 45 (e.g., complex 45a or complex 45b), wherein the average DAR (e.g., T) of the population of complexes 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.

[0510] In some embodiments, the conjugate is conjugate 46 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 46, wherein the average DAR (e.g., T) of the population of complexes 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.

[0511] In some embodiments, the conjugate is conjugate 47 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 47, wherein the average DAR (e.g., T) of the population of complexes 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.

[0512] In some embodiments, the conjugate is conjugate 48 or any positional isomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6 , 4.7, 4.8, 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 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the invention provides a population of complexes, each complex having the structure of complex 48, wherein the average DAR (e.g., T) of the population of complexes 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.

[0513] In some embodiments of any of the aspects described herein, the invention features a conjugate represented by any one of formulas (DI), (MI), (1), or (2), or a pharmaceutically acceptable salt thereof, wherein each A and each A independently represents formula (A-XIII): [ka] is selected from one of the following: R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; and Y is [ka] is selected from R6 is [ka] is selected from R7 is H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C 15 heteroaryl, R8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; R9 is -H, halogen (e.g., Cl or F), -OR 10 , —NHC(═O)R7, optionally substituted C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; R 10 is selected from C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; n is 1 or 2, each E comprises an Fc domain monomer, an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide; L is a linker covalently linking E and each Y of each A or each of A and A; T is an integer from 1 to 20, Each wavy line in formula (DI), (MI), (1) or (2) represents a covalent bond between L and each E.

[0514] In some embodiments, each A1 and each A2 has formula (A-XIII-1): [ka] It is expressed as:

[0515] In some embodiments, each A1 and each A2 independently represents formula (A-XIII-1a) to (A-XIII-1d): [ka] is selected from one of the following.

[0516] In some embodiments, the conjugate has formula (D-XI): [ka] or a pharmaceutically acceptable salt thereof.

[0517] In some embodiments, the conjugate has formula (D-XI-1): [ka] wherein R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl. or a pharmaceutically acceptable salt thereof.

[0518] In some embodiments, the conjugate has formula (M-XI): [ka] or a pharmaceutically acceptable salt thereof.

[0519] In some embodiments, the conjugate has formula (M-XI-1): [ka] wherein R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl. or a pharmaceutically acceptable salt thereof.

[0520] definition To facilitate understanding of the present invention, certain terms are defined below. Terms defined herein have meanings commonly understood by one of ordinary skill in the art to which the present invention pertains. Terms such as "a," "an," and "the" are not intended to refer solely to a singular entity, but include general classes for which specific examples may be used for illustration. While terminology herein is used to describe particular embodiments of the present invention, such usage does not limit the invention except as defined in the claims.

[0521] The terms "neuraminidase inhibitor" or "viral neuraminidase inhibitor," as used herein, refer to a compound that reduces the activity of the enzyme influenza virus neuraminidase (e.g., from influenza A, B, or C viruses). Neuraminidase inhibitors can be identified by methods known to those of skill in the art, such as a reduction in viral replication in an influenza virus plaque reduction assay, e.g., at concentrations below 20 μM (e.g., below 10 μM, below 5 μM, below 2 μM, below 1 μM, below 500 nM, or below 100 nM). Viral neuraminidase inhibitors known to those skilled in the art include zanamivir, sulfozanamivir, peramivir, and A-315675 (Abbott) (see, e.g., Hadhazi et al. A sulfozanamivir analogue has potent anti-influenza virus activity. ChemMedChem Comm. 13:785-789 (2018) and In vitro characterization of A-315675, a highly potent inhibitor of A and B strains of influenza virus neuraminidases and influenza virus replication. Antimicrobial Agents and Chemotherapy 46(4):1014-1021 (2002)). The viral neuraminidase inhibitors of the present invention include zanamivir, sulfozanamivir, peramivir, A-315675, and analogs thereof, such as those represented by formulae (AI) to (A-XIII): [ka] wherein R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; and Y is [ka] and R6 is selected from [ka] R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; R8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; R9 is -H, halogen (e.g., Cl, F, or Br), -OR 10 , —NHC(═O)R7, optionally substituted C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; R 10 is selected from C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl. Contains viral neuraminidase inhibitors.

[0522] As used herein, the term "inhibits neuraminidase activity" refers to an IC50 of 1,000 nM or less, as measured, for example, according to the neuraminidase inhibition assay in Example 2 herein. 50 Specifically, IC 50 represents the concentration of influenza virus neuraminidase inhibitor required for 50% inhibition in vitro. In some embodiments, the IC 50 A β-glucan concentration of 100 nM or less or 10 nM or less indicates that the compound inhibits neuraminidase activity.

[0523] "Viral infection" refers to the growth of a pathogenic 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(s) is damaging to the host's body. Thus, a subject is "suffering from" a viral infection when an excessive amount of viral population is present in or on the subject's body, or when the presence of a viral population(s) is damaging to the subject's cells or other tissues.

[0524] As used herein, the term "Fc domain monomer" refers to a monomer that contains at least a hinge domain and a second and third antibody constant domain (C H 2 and C H3) or a functional fragment thereof (e.g., a fragment that is capable of (i) dimerizing with another Fc domain monomer to form an Fc domain and (ii) binding to an Fc receptor). The Fc domain monomer can be any immunoglobulin antibody isotype (e.g., IgG), including IgG, IgE, IgM, IgA, or IgD. 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 contain any portion of an immunoglobulin that can act as an antigen recognition region, such as a variable domain or a complementarity-determining region (CDR). The Fc domain monomer in the complexes described herein can contain one or more alterations (e.g., 1-10, 1-8, 1-6, or 1-4 amino acid substitutions, additions, or deletions) from the wild-type Fc domain monomer sequence that alter the interaction of the Fc domain with an Fc receptor. Examples of suitable alterations are known in the art. In some embodiments, a human Fc domain monomer (e.g., an IgG heavy chain, e.g., IgG1) comprises a region extending from any of Asn208, Glu216, Asp221, Lys222, or Cys226 to the carboxy terminus of the heavy chain at Lys447. The C-terminal Lys447 of the Fc region may be present or absent without affecting the structure or stability of the Fc region. The C-terminal Lys447 may be proteolytically cleaved upon expression of the polypeptide. In some embodiments of any of the Fc domain monomers described herein, the C-terminal Lys447 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, which do not include the C-terminal Lys corresponding to Lys447. The N-terminal N (Asn) of the Fc region (e.g., of any one of SEQ ID NOs: 60-77) may or may not be present without affecting the structure or stability of the Fc region. The N-terminal Asn may be deamidated upon expression of the polypeptide. In some embodiments of any of the Fc domain monomers 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, numbering of amino acid residues within an IgG or Fc domain monomer follows the EU numbering system for antibodies, also referred to as the Kabat EU index, as described, for example, in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0525] As used herein, the term "Fc domain" refers to a dimer of two Fc domain monomers that can bind to an Fc receptor. In a wild-type Fc domain, the two Fc domain monomers are separated by two C H They dimerize through interactions between the three antibody constant domains, and in some embodiments, one or more disulfide bonds are formed between the hinge domains of the two dimerizing Fc domain monomers. The term "covalently linked" means that the two parts of the complex are connected to each other by a covalent bond formed between two atoms in the two parts of the complex.

[0526] As used herein, the term "Fc-binding peptide" refers to a polypeptide having an amino acid sequence of 5-50 (e.g., 5-40, 5-30, 5-20, 5-15, 5-10, 10-50, 10-30, or 10-20) amino acid residues that has affinity and binding function for an Fc domain, e.g., any of the Fc domains described herein. Fc-binding peptides can be of various origins, e.g., synthetic, human, mouse, or rat. Fc-binding peptides of the invention include Fc-binding peptides engineered to contain one or more (e.g., two, three, four, or five) solvent-exposed cysteine ​​or lysine residues that can provide sites for conjugation with a compound of the invention (e.g., conjugation with a neuraminidase inhibitor monomer or dimer, including via a linker). Most preferably, the Fc-binding peptide contains a single solvent-exposed cysteine ​​or lysine, thereby allowing for site-specific conjugation of a compound of the invention. The Fc-binding peptide may contain only naturally occurring amino acid residues, or may contain one or more non-naturally occurring amino acid residues. When included, non-naturally occurring amino acid residues (e.g., side chains of non-naturally occurring amino acid residues) can be used as a point of attachment to the compounds of the present invention (e.g., neuraminidase inhibitor monomers or dimers, including via a linker). The Fc-binding peptides of the present invention may be linear or cyclic. The Fc-binding peptides of the present invention include any Fc-binding peptides known to those skilled in the art.

[0527] As used herein, the term "albumin protein" refers to a polypeptide comprising an amino acid sequence corresponding to a naturally occurring albumin protein (e.g., human serum albumin) or a variant thereof, e.g., an engineered variant of a naturally occurring albumin protein. Variants of albumin proteins include polymorphisms, fragments, e.g., domains and subdomains, and fusion proteins (e.g., albumin proteins fused at the C-terminus or N-terminus, e.g., with a polypeptide linker). Preferably, the albumin protein has the amino acid sequence of human serum albumin (HSA), or a variant or fragment thereof, most preferably a functional variant or fragment thereof. Albumin proteins of the present invention include 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. Albumin proteins of the present invention include albumin proteins engineered to contain one or more (e.g., two, three, four, or five) solvent-exposed cysteine ​​or lysine residues that can provide sites for conjugation to a compound of the present invention (e.g., conjugation to a neuraminidase inhibitor monomer or dimer, including via a linker). Most preferably, the albumin protein contains a single solvent-exposed cysteine ​​or lysine, thereby allowing for site-specific conjugation of a compound of the present invention. The albumin protein may contain only naturally occurring amino acid residues, or may contain one or more non-naturally occurring amino acid residues. When included, a non-naturally occurring amino acid residue (e.g., a side chain of a non-naturally occurring amino acid residue) may be used as a point of attachment to a compound of the present invention (e.g., a neuraminidase inhibitor monomer or dimer, including via a linker).

[0528] As used herein, the term "albumin protein-binding peptide" refers to a polypeptide having an amino acid sequence of 5 to 50 (e.g., 5 to 40, 5 to 30, 5 to 20, 5 to 15, 5 to 10, 10 to 50, 10 to 30, or 10 to 20) amino acid residues that has affinity and binding function for albumin protein, e.g., any of the albumin proteins described herein. Preferably, the albumin protein-binding peptide binds to naturally occurring serum albumin, most preferably human serum albumin. Albumin protein-binding peptides can be of various origins, e.g., synthetic, human, mouse, or rat origin. Albumin protein-binding peptides of the present invention include albumin protein-binding peptides engineered to contain one or more (e.g., two, three, four, or five) solvent-exposed cysteine ​​or lysine residues that can provide sites for conjugation with a compound of the present invention (e.g., conjugation with a neuraminidase inhibitor monomer or dimer, including via a linker). Most preferably, the albumin protein-binding peptide contains a single solvent-exposed cysteine ​​or lysine, thereby allowing for site-specific conjugation of the compounds of the present invention. The albumin protein-binding peptide may contain only naturally occurring amino acid residues, or may contain one or more non-naturally occurring amino acid residues. When included, a non-naturally occurring amino acid residue (e.g., a side chain of a non-naturally occurring amino acid residue) may be used as a point of attachment to the compounds of the present invention (e.g., neuraminidase inhibitor monomers or dimers, including via a linker). The albumin protein-binding peptides of the present invention may be linear or cyclic. The albumin protein-binding peptides of the present invention include any albumin protein-binding peptide known to those skilled in the art, examples of which are provided herein. Further exemplary albumin protein-binding peptides are set forth in U.S. Patent Application Publication No. 2005 / 0287153, which is incorporated herein by reference in its entirety.

[0529] As used herein, a "surface-exposed amino acid" or "solvent-exposed amino acid," e.g., a surface-exposed cysteine ​​or a surface-exposed lysine, refers to an amino acid that is accessible to the solvent surrounding a protein. A surface-exposed amino acid may be naturally occurring or may be an engineered variant (e.g., a substitution or insertion) of a protein. In some embodiments, a surface-exposed amino acid is an amino acid that, when substituted, does not substantially alter the three-dimensional structure of a protein.

[0530] The terms "linker," "L," and "L'," as used herein, refer to a covalent linkage or connector between two or more components in a complex (e.g., between two neuraminidase inhibitors in a complex described herein, between a neuraminidase inhibitor and an Fc domain or albumin protein in a complex described herein, and between a dimer of two neuraminidase inhibitors and an Fc domain or albumin protein in a complex described herein). In some embodiments, the complexes described herein may contain a linker having a trivalent structure (e.g., a trivalent linker). A trivalent linker has three arms, each covalently linked to a component of the complex (e.g., a first arm is conjugated to a first neuraminidase inhibitor, a second arm is conjugated to a second neuraminidase inhibitor, and a third arm is conjugated to an Fc domain or albumin protein).

[0531] Molecules that can be used as linkers contain at least two functional groups, which can be the same or different, such as two carboxylic acid groups, two amine groups, two sulfonic acid groups, a carboxylic acid group and a maleimide group, a carboxylic acid group and an alkyne group, a carboxylic acid group and an amine group, a carboxylic acid group and a sulfonic acid group, an amine group and a maleimide group, an amine group and an alkyne group, or an amine group and a sulfonic acid group. The first functional group can form a covalent linkage with a first component in the complex, and the second functional group can form a covalent linkage with a second component in the complex. In some trivalent linker embodiments, the two arms of the linker can contain two dicarboxylic acids, where the first carboxylic acid can form a covalent linkage with a first neuraminidase inhibitor in the complex, the second carboxylic acid can form a covalent linkage with a second neuraminidase inhibitor in the complex, and the third arm of the linker can be for covalent linkage with an Fc domain or albumin protein in the complex. Examples of dicarboxylic acids are described further herein. In some embodiments, molecules containing one or more maleimide groups may be used as linkers, in which case the maleimide groups can form a carbon-sulfur linkage with a cysteine ​​in a component (e.g., an Fc domain or an albumin protein) in the complex. In some embodiments, molecules containing one or more alkyne groups may be used as linkers, in which case the alkyne groups can form a 1,2,3-triazole linkage with an azide in a component (e.g., an Fc domain or an albumin protein) in the complex. In some embodiments, molecules containing one or more azide groups may be used as linkers, in which case the azide groups can form a 1,2,3-triazole linkage with an alkyne in a component (e.g., an Fc domain or an albumin protein) in the complex. In some embodiments, molecules containing one or more bissulfone groups may be used as linkers, in which case the bissulfone groups can form a linkage with an amine group in a component (e.g., an Fc domain or an albumin protein) in the complex.In some embodiments, molecules containing one or more sulfonic acid groups can be used as linkers, where the sulfonic acid groups can form sulfonamide linkages with components in the complex. In some embodiments, molecules containing one or more isocyanate groups can be used as linkers, where the isocyanate groups can form urea linkages with components in the complex. In some embodiments, molecules containing one or more haloalkyl groups can be used as linkers, where the haloalkyl groups can form covalent linkages, such as C-N and C-O linkages, with components in the complex.

[0532] In some embodiments, a linker provides space, rigidity, and / or flexibility between two or more components. In some embodiments, a linker can be a bond, e.g., a covalent bond. The term "bond" refers to a chemical bond, e.g., an amide bond, a disulfide bond, a C-O bond, a C-N bond, an N-N bond, a C-S bond, or any type of bond created by a chemical reaction, e.g., chemical conjugation. In some embodiments, a linker comprises 250 atoms or fewer. In some embodiments, a linker comprises 250 non-hydrogen atoms or fewer. In some embodiments, the backbone of a linker comprises 250 atoms or fewer. The "backbone" of a linker refers to the atoms in the linker that together form the shortest path from one portion of a complex to another portion of the complex (e.g., the shortest path connecting a first neuraminidase inhibitor and a second neuraminidase inhibitor). The atoms in the backbone of a linker are directly involved in connecting one portion of a complex to another portion of the complex (e.g., connecting a first neuraminidase inhibitor and a second neuraminidase inhibitor). For example, a hydrogen atom attached to a carbon in the backbone of a linker is not considered to be directly involved in connecting one portion of the conjugate to another portion of the conjugate.

[0533] In some embodiments, the linker can include a synthetic group, for example, derived from a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer). In some embodiments, the linker can include one or more amino acid residues, for example, D- or L-amino acid residues. In some embodiments, the linker can be residues of an amino acid sequence (e.g., 1 to 25 amino acids, 1 to 10 amino acids, 1 to 9 amino acids, 1 to 8 amino acids, 1 to 7 amino acids, 1 to 6 amino acids, 1 to 5 amino acids, 1 to 4 amino acids, 1 to 3 amino acids, 1 to 2 amino acids, or 1 amino acid sequence). In some embodiments, the linker is selected from one or more, e.g., 1 to 100, 1 to 50, 1 to 25, 1 to 10, 1 to 5, or 1 to 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 imay include 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 may be 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, cyclobutene, ethylene), 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 imay include 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.

[0534] As used herein, the terms "alkyl," "alkenyl," and "alkynyl" include straight-chain and branched-chain monovalent substituents, and combinations thereof, that, when unsubstituted, contain only C and H. If 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" group, respectively. The monovalence of an alkyl, alkenyl, or alkynyl group does not include optional substituents attached to the alkyl, alkenyl, or alkynyl group. For example, when an alkyl, alkenyl, or alkynyl group is attached to a compound, what is meant by the monovalent alkyl, alkenyl, or alkynyl group is that it is attached to a compound and does not include any additional substituents that may be present on the alkyl, alkenyl, or alkynyl group. In some embodiments, an alkyl or heteroalkyl group can contain, for example, 1 to 20, 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, the alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl group can contain, for example, 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 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.

[0535] The term "cycloalkyl," as used herein, refers to a monovalent saturated or unsaturated non-aromatic cyclic alkyl group. Cycloalkyls can have, for example, 3 to 20 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 cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. When a cycloalkyl group contains at least one carbon-carbon double bond, the cycloalkyl group can be referred to as a "cycloalkenyl" group. A cycloalkenyl can have, for example, 4 to 20 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 cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. If a cycloalkyl group contains at least one carbon-carbon triple bond, the cycloalkyl group can be referred to as a "cycloalkynyl" group. A cycloalkynyl can have, for example, 8 to 20 carbons (e.g., C8-C9, C8-C10, C8-C11, C8-C12, C8-C14, C8-C16, C8-C18, or C8-C20 cycloalkynyl). The term "cycloalkyl" also includes cyclic compounds having bridged polycyclic structures in which one or more carbons bridge two non-adjacent members of a single ring, such as bicyclo[2.2.1]heptyl and adamantane. The term "cycloalkyl" also includes bicyclic, tricyclic, and tetracyclic fused ring structures, such as decalin and spirocyclic compounds.

[0536] The term "aryl," as used herein, refers to any monocyclic or fused bicyclic or tricyclic ring system, e.g., phenyl, naphthyl, or phenanthrene, having the characteristics of aromaticity with respect to electron distribution throughout the ring system. In some embodiments, the ring system contains 5 to 15 ring atoms or 5 to 10 ring atoms. Aryl groups can have, for example, 5 to 15 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 such monocyclic or fused bicyclic ring systems containing one or more heteroatoms selected from O, S, and N, e.g., 1 to 4, 1 to 3, 1, 2, 3, or 4 heteroatoms. Heteroaryl groups can have, for example, 2 to 15 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). The inclusion of a heteroatom allows a five-membered ring to be considered aromatic, just as a six-membered ring would. Thus, typical heteroaryl systems include, for example, pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzisoxazolyl, and imidazolyl. Because tautomers are possible, groups such as phthalimide are also considered heteroaryl. In some embodiments, the aryl or heteroaryl group, optionally containing 1 to 2 nitrogen atoms, is a 5- or 6-membered aromatic ring system. In some embodiments, the aryl or heteroaryl group is optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, or imidazopyridinyl. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group can be optionally substituted with a substituent, such as an aryl substituent, for example, biphenyl.

[0537] The term "alkaryl" refers to an aryl group linked to an alkylene, alkenylene, or alkynylene group. When a compound is bound to an alkaryl group, it is usually the alkylene, alkenylene, or alkynylene portion of the alkaryl that is bound to the compound. In some embodiments, the alkaryl is a C6-C35 alkaryl (e.g., C6-C16, C6-C14, C6-C12, C6-C10, C6-C9, C6-C8, C7, or C6 alkaryl), where the number of carbons represents the total number of carbons in both the aryl and alkylene, alkenylene, or alkynylene portions of the alkaryl. Examples of alkaryl 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, alkaryl is benzyl or phenethyl. 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 group and / or may be present in the aryl portion of the alkaryl group. In optionally substituted alkaryl, substituents may be present on the alkylene, alkenylene, or alkynylene portion of the alkaryl group and / or may be present on the aryl portion of the alkaryl group.

[0538] The term “amino” as used herein refers to —N(R x )2, or -N + (R x )3, and each R in the formula x are independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x are combined to form a heterocycloalkyl. In some embodiments, the amino group is —NH 2 .

[0539] The term "alkamino" refers to an amino group, as described herein, linked to an alkylene (e.g., C1-C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene group (e.g., C2-C5 alkynylene). When a compound is linked to an alkamino group, it is often the alkylene, alkenylene, or alkynylene portion of the alkamino that is linked to the compound. The amino portion of the alkamino is linked to -N(R x )2, or -N + (R x )3, and each R in the formula x are independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x taken together form a heterocycloalkyl. In some embodiments, the amino portion of the alkamino is -NH. An example of an alkamino group is a C-C alkamino, such as a C alkamino (e.g., CHCHNH or CHCHN(CH). In a heteroalkamino group, one or more heteroatoms selected from N, O, and S, e.g., 1 to 4, 1 to 3, 1, 2, 3, or 4, can be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkamino group. In some embodiments, an alkamino group can be optionally substituted. In a substituted alkamino group, substituents can be present in the alkylene, alkenylene, or alkynylene portion of the alkamino group and / or on the amino portion of the alkamino group.

[0540] The term "alkamide," as used herein, refers to an amide group bonded to an alkylene (e.g., C1-C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene (e.g., C2-C5 alkynylene) group. When a compound is bonded to an alkamide group, the alkylene, alkenylene, or alkynylene portion of the alkamide is often bonded to the compound. The amide portion of the alkamide is —C(O)—N(R x )2, and each R in the formula xare independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x are combined to form a heterocycloalkyl. In some embodiments, the amide portion of the alkamide is —C(O)NH. The alkamide group can be —(CH)—C(O)NH or —CH—C(O)NH. In a heteroalkamide group, one or more heteroatoms selected from N, O, and S, e.g., 1 to 4, 1 to 3, 1, 2, 3, or 4, can be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkamide group. In some embodiments, the alkamide group can be optionally substituted. In a substituted alkamide group, the substituents can be present in the alkylene, alkenylene, or alkynylene portion of the alkamide group and / or on the amide portion of the alkamide group.

[0541] The terms "alkylene," "alkenylene," and "alkynylene," as used herein, refer to a divalent group having the specified size. In some embodiments, an alkylene can contain, for example, 1 to 20, 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 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, alkenylene or alkynylene can contain, for example, 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 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 include straight-chain and branched-chain forms and combinations thereof. The divalent nature of an alkylene, alkenylene, or alkynylene group does not include optional substituents attached to the alkylene, alkenylene, or alkynylene group. For example, two neuraminidase inhibitors may be linked to each other by a linker comprising alkylene, alkenylene, and / or alkynylene, or a combination thereof. Each alkylene, alkenylene, and / or alkynylene group in a linker is considered to be divalent with respect to the two bonds at 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 is considered to be divalent with respect to the bonds between it and the two alkylenes at the ends of the linker. Optional substituents on the alkenylene do not contribute to the divalency of the alkenylene. 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 the alkylene, alkenylene, or alkynylene group.Because they are divalent, they can link multiple (e.g., two) moieties of a conjugate, such as a first neuraminidase inhibitor and a second neuraminidase inhibitor. The alkylene, alkenylene, and / or alkynylene groups can be substituted with groups typically suitable as substituents for alkyl, alkenyl, and alkynyl groups described herein. For example, C=O is a C1 alkylene substituted with oxo (=O). For example, -HCR-C≡C- can be considered an optionally substituted alkynylene and is considered a divalent group even with the optional substituent R. Heteroalkylene, heteroalkenylene, and / or heteroalkynylene groups refer to alkylene, alkenylene, and / or alkynylene groups containing one or more heteroatoms, e.g., 1 to 4, 1 to 3, 1, 2, 3, or 4, such as N, O, and S. For example, a polyethylene glycol (PEG) polymer or PEG unit -(CH2)2-O- in a PEG polymer is considered a heteroalkylene containing one or more oxygen atoms.

[0542] As used herein, "combination therapy" or "administered in combination" means that a conjugate described herein (e.g., a conjugate of any one of Formulas (1)-(5), (DI)-(D-XI), (D'-I), (MI)-(M-XI), or (M'-I)) and one (or more) different agent(s) or treatment(s) are administered to a subject as part of a defined treatment regimen for a viral infection. The treatment regimen defines the dosage and periodicity of administration of each agent so that the effects of the separate agents on the subject overlap. In some embodiments, delivery of the conjugate and one or more agents is simultaneous or concurrent, 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 but are administered in a sequential manner as part of a defined dosing regimen. In some embodiments, the administration of the conjugate in combination with one or more agents or treatments is such that the alleviation of symptoms or other parameters associated with the viral infection is greater than that observed when one agent or treatment is delivered alone or in the absence of the other. The effects of the conjugate and one or more agents may be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent may be by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. For example, a conjugate described herein may be administered by intravenous injection, while a second therapeutic agent of the combination may be administered orally.

[0543] The term "cycloalkylene," as used herein, refers to a divalent cyclic group that connects two portions of a compound. For example, one carbon in a cycloalkylene group can be connected to one portion of a compound, while another carbon in the cycloalkylene group can be connected to another portion of the compound. A cycloalkylene group can include saturated or unsaturated non-aromatic ring groups. A cycloalkylene can have, for example, 3 to 20 carbons in the cycloalkylene ring portion (e.g., C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkylene). When a cycloalkylene group contains at least one carbon-carbon double bond, the cycloalkylene group can be referred to as a "cycloalkenylene" group. Cycloalkenylene can have, for example, 4 to 20 carbons in the ring 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 cycloalkenyl). If the cycloalkylene group contains at least one carbon-carbon triple bond, the cycloalkylene group can be referred to as a "cycloalkynylene" group. Cycloalkynylene can have, for example, 4 to 20 carbons in the ring 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 groups can be substituted with groups typically suitable as substituents for alkyl, alkenyl, and alkynyl groups as defined herein. Heterocycloalkylene refers to cycloalkylene groups containing one or more, e.g., 1-4, 1-3, 1, 2, 3, or 4 heteroatoms, such as N, O, and S. Examples of cycloalkylene include, but are not limited to, cyclopropylene and cyclobutylene. Tetrahydrofuran can be considered a heterocycloalkylene.

[0544] The term "arylene," as used herein, refers to a polyvalent (e.g., divalent or trivalent) aryl group that connects multiple (e.g., two or three) moieties of a compound. For example, one carbon in the arylene group can be connected to one moiety of the compound, while another carbon in the arylene group can be connected to another moiety of the compound. The arylene can have, for example, 5 to 15 carbons in the aryl portion of the arylene (e.g., C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C11, C5-C12, C5-C13, C5-C14, or C5-C15 arylene). The arylene group can be substituted with groups typically suitable as substituents for alkyl, alkenyl, and alkynyl groups described herein. Heteroarylene refers to an aromatic group containing one or more, e.g., 1 to 4, 1 to 3, 1, 2, 3, or 4 heteroatoms, such as N, O, and S. The heteroarylene group can have, for example, 2 to 15 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 heteroarylene).

[0545] The term "optionally substituted," as used herein, means having 0, 1, or more substituents, e.g., 0 to 25, 0 to 20, 0 to 10, or 0 to 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, alkamino, hydroxy, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, ureido, amidinyl, any of the above groups or moieties, and heteroforms of any of the above groups or moieties. Substituents include, but are not limited to, F, Cl, methyl, phenyl, benzyl, OR, NR, SR, SOR, SO,R, OCOR, NRCOR, NRCONR, NRCOOR, OCONR, RCO, COOR, alkyl-OOCR, SO,R, CONR, SO,NR, NRSO,NR, CN, CF, OCF, SiR, and NO, where each R is independently H, alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, or heteroaryl, and any two of the optional substituents on the same or adjacent atoms may be joined to form an optionally substituted aromatic or non-aromatic fused ring containing from 3 to 8 ring members, or any two of the optional substituents on the same atom may be joined to form an optionally substituted aromatic or non-aromatic, saturated or unsaturated ring containing from 3 to 8 ring members.

[0546] An optionally substituted group or moiety refers to a group or moiety (e.g., any one of the groups or moieties described above) in which one of its atoms (e.g., a hydrogen atom) has been optionally replaced with another substituent. For example, an optionally substituted alkyl can be an optionally substituted methyl, where the hydrogen atom of the methyl group has been replaced with, for example, OH. As another example, a substituent on a heteroalkyl or its divalent counterpart, heteroalkylene, can replace a hydrogen attached to a carbon or a heteroatom such as N. For example, a hydrogen atom in the group -R-NH-R- can be replaced with an alkamide substituent, e.g., -RN[(CHC(O)N(CH)]-R.

[0547] In most cases, optional substituents are non-interfering substituents. A "non-interfering substituent" refers to a substituent that preserves the ability of a conjugate described herein (e.g., a conjugate of any one of Formulas (1)-(5), (D-I)-(D-XI), (D'-I), (M-I)-(M-XI), or (M'-I)) to either bind to viral neuraminidase or inhibit influenza virus growth. Thus, in some embodiments, a substituent may alter the degree of such activity. However, as long as the conjugate retains the ability to bind to viral neuraminidase or inhibit viral growth, a substituent will be classified as "non-interfering." For example, a non-interfering substituent would preserve 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, e.g., an IC50 value of 500 nM or less against influenza virus neuraminidase in Example 2. Thus, a substituent may alter the degree of inhibition based on plaque reduction or influenza virus neuraminidase inhibition. However, as long as the compounds herein, e.g., compounds of Formulae (AI), (A-II), (A-III), (A-IV), (AV), (A-VI), (A-VII), (A-VIII), (A-IX), (AX), (A-XI), (A-XII), and (A-XIII), retain the ability to inhibit influenza virus neuraminidase activity, the substituents will be classified as "non-interfering." Multiple assays for determining viral plaque reduction, or the ability of any compound to inhibit influenza virus neuraminidase, are available in the art, several of which are illustrated in the Examples below.

[0548] The term "hetero," when used to describe a chemical group or moiety, means having at least one heteroatom that is not carbon or hydrogen, such as N, O, or S. Any one of the above groups or moieties can be referred to as hetero if it contains at least one heteroatom. For example, a heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl group 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 maleimide. 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 can be included in the substituents replacing hydrogen atoms in the groups or moieties described herein. For example, an optionally substituted heteroaryl group can contain one or more heteroatoms (e.g., methanol) when one of the hydrogen atoms in the heteroaryl group is replaced with a substituent (e.g., methyl).

[0549] The term "acyl," as used herein, refers to a compound having the structure: [ka] [In the formula, R Z is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, alkamino, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaryl, heteroalkaryl, or heteroalkamino. It refers to a group having the formula:

[0550] The term "halo" or "halogen," as used herein, refers to any halogen atom, such as F, Cl, Br, or I. Any one of the groups or moieties described herein may be referred to as a "halo moiety" if it contains at least one halogen atom, such as haloalkyl.

[0551] The term "hydroxyl," as used herein, refers to an --OH group.

[0552] The term "oxo," as used herein, refers to a substituent having the structure =O, in which there is a double bond between the atom and the oxygen atom.

[0553] The term "carbonyl," as used herein, refers to a compound having the structure: [ka] It refers to a group having the formula:

[0554] The term "thiocarbonyl," as used herein, refers to a compound having the structure: [ka] It refers to a group having the formula:

[0555] The term "phosphate" as used herein means a compound having the structure: [ka] represents a group having the formula:

[0556] The term "phosphoryl," as used herein, refers to a group having the structure: [ka] represents a group having the formula:

[0557] The term “sulfonyl,” as used herein, refers to a group having the structure: [ka] represents a group having the formula:

[0558] The term "imino," as used herein, refers to a compound having the structure: [ka] wherein R is an optional substituent. represents a group having the formula:

[0559] The term "N-protecting group," as used herein, refers to a group intended to protect an amino group from undesired reactions during synthetic procedures. 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, aryloyl, and carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, carboxybenzyl (CBz), 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries, such as protected or unprotected D, L, or N-protecting groups. or D,L-amino acid residues, e.g., alanine, leucine, phenylalanine; sulfonyl-containing groups, e.g., benzenesulfonyl and p-toluenesulfonyl; carbamate-forming groups, e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, carbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (BOC), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxy thiocarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; alkaryl groups such as benzyl, triphenylmethyl, and benzyloxymethyl; and silyl groups such as trimethylsilyl.

[0560] The term "amino acid," as used herein, refers to naturally occurring and non-naturally occurring amino acids.

[0561] The term "naturally occurring amino acid," as used herein, means amino acids including Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val.

[0562] The term "non-naturally occurring amino acid," as used herein, refers to 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(CH) nOmega amino acids of COOH (where n is 2-6), neutral nonpolar amino acids such as sarcosine, t-butylalanine, t-butylglycine, N-methylisoleucine, and norleucine; oxymethionine; phenylglycine; citrulline; methionine sulfoxide; cysteic acid; ornithine; diaminoalanine; 3-hydroxy-D-proline; 2,4-diaminobutyric acid; 2-aminopentanoic acid; 2-aminooctanoic acid, 2-carboxypiperazine; piperazine-2-carboxylic acid, 2-amino-4-phenylbutanoic acid; 3-(2-naphthyl)alanine, and hydroxyproline. Other amino acids include α-aminobutyric acid, α-amino-α-methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, aminonorbornyl-carboxylate, L-cyclohexylalanine, cyclopentylalanine, LN-methylleucine, LN-methylmethionine, LN-methylnorvaline, LN-methylphenylalanine, LN-methylproline, LN-methylserine, LN-methyltryptophan, D-ornithine, LN-methylethylglycine, L-norleucine, α-methyl-aminoisobutyrate, α-methylcyclohexylalanine, D-α-methylalanine, D-α-methylarginine, D-α-methylasparagine, D-α-methylaspartate, D-α-methylcysteine, D-α-methylglutamine, D-α-methylhistidine, D -α-methylisoleucine, D-α-methylleucine, D-α-methyllysine, D-α-methylmethionine, D-α-methylornithine, D-α-methylphenylalanine, D-α-methylproline, D-α-methylserine, DN-methylserine, D-α-methylthreonine, D-α-methyltryptophan, D-α-methyltyrosine, D-α-methylvaline, DN-methylalanine, DN-methylarginine, DN-methylasparagine, DN-methylaspartate, DN-methylcysteine, DN-methylglutamine, DN-methylglutamate, DN-methylhistidine, DN-methylisoleucine, DN-methylleucine, DN-methyllysine, N-methylcyclohexylalanine, DN-methylornithine, N-methylglycine, N-methylaminoisobutyrate,N-(1-methylpropyl)glycine, N-(2-methylpropyl)glycine, DN-methyltryptophan, DN-methyltyrosine, DN-methylvaline, γ-aminobutyric acid, Lt-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)carbamylmethylglycine, 1-carboxy-1-(2,2-diphenyl-ethylamino)cyclopropane, 4-hydroxyproline, ornithine, 2-aminobenzoyl (anthraniloyl), D-cyclohexylalanine, 4-phenyl-phenylalanine, L-citrulline, α-cyclohexylglycine, L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4-carboxylic acid, L-homotyrosine, L-2-furylalanine, L-histidine (3-methyl), N-(3-guanidinopropyl)glycine, O-methyl-L-tyrosine, O-glycan-serine, meta-tyrosine, nor-tyrosine, LN,N',N"-trimethyllysine, homolysine, norlysine, N-glycan 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 Carboxylic acid, (2S,4S)-4-amino-1-benzoyl-pyrrolidine-2-carboxylic acid, t-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-methyl Glutamic acid, LN-methylhistidine, LN-methylisoleucine, LN-methyllysine, LN-methylnorleucine, LN-methylornithine, LN-methylthreonine, LN-methyltyrosine, LN-methylvaline, LN-methyl-t-butylglycine, L-norvaline, α-methyl-γ-aminobutyrate, 4,4'-biphenylalanine, α-methylcyclopentylalanine, α-methyl-α-naphthylalanine, α-methylpenicillamine, N-(4-aminobutyl)glycine, N-(2-aminoethyl)glycine, N-(3-amino Propyl)glycine, N-amino-α-methylbutyrate, α-naphthylalanine, N-benzylglycine, N-(2-carbamylethyl)glycine, N-(carbamylmethyl)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-cycloundecylglycine,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-methylasparagine, L-α-methyl-t-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, L N-methyl-homophenylalanine, N-(N-(3,3-diphenylpropyl)carbamylmethylglycine, 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 (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-glycan-threonine, ortho-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, (2 (S,4R)-4-hydroxypiperidine-2-carboxylic acid, octahydroindole-2-carboxylic acid, (2S,4R) and (2S,4R)-4-(2-naphthyl)pyrrolidine-2-carboxylic acid, nipecotic acid, (2S,4R) and (2S,4S)-4-(4-phenylbenzyl)pyrrolidine-2-carboxylic acid, (3S)-1-pyrrolidine-3-carboxylic acid, (2S,4S)-4-tritylmercapto-pyrrolidine-2-carboxylic acid, (2S,4S)-4-mercaptoproline, t-butylglycine, N,N-bis(3-aminopropyl)glycine, 1-amino-cyclohexane-1-carboxylic acid, N-mercaptoethylglycine, and selenocysteine. In some embodiments, the amino acid residue can 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. In particular, it is contemplated that in some embodiments, the terminal amino group in an amino acid may be an amide group or a carbamate group.

[0563] As used herein, the term "percent identity" refers to the percentage of amino acid residues in a candidate sequence, e.g., an FcIgG, or fragment thereof, that are identical to those in a reference sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity (i.e., gaps can be introduced into one or both of the candidate and reference sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). Alignment for purposes of determining percent identity can be accomplished by various methods in the art, for example, using publicly available computer software, such as BLAST, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment across the full length of the sequences being compared. In some embodiments, the percent amino acid sequence identity of a given candidate sequence (which may alternatively be expressed as a given candidate sequence having or comprising a particular percent amino acid sequence identity to, with, or compared to a given reference sequence) to, with, or against a given reference sequence is as follows: 100 x (fraction A / B) where A is the number of amino acid residues evaluated as identical in the alignment of the candidate and reference sequences, and 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...

Claims

1. A complex having the formula (D-II-6): 【Chemistry 1】 [During the ceremony, each E is an Fc domain monomer; n is 1 or 2; T is an integer from 1 to 20, L is a linker, R ７ is selected from C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; The wavy line represents that L is covalently linked to E. The complex represented by or a pharma- ceutically acceptable salt thereof.

2. R ７ 2. The complex of claim 1, wherein is selected from C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl.

3. R ７ 3. The complex of claim 2, wherein is selected from methyl, ethyl, propyl, or butyl.

4. The complex has the formula (D-II-7): 【Chemistry 2】 The complex according to claim 3, which is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

5. The complex has the formula (D-II-8): 【Chemistry 3】 [Wherein L' is the remainder of L, y １ and y ２ are each independently an integer of 1 to 20. The complex according to claim 4, which is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

6. The complex is 【Chemistry 4】 6. The complex of claim 5 having the structure: or a pharma- ceutically acceptable salt thereof.

7. The complex is 【Chemistry 5】 7. The complex of claim 6 having the structure: or a pharma- ceutically acceptable salt thereof.

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

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

10. wherein n is 2, each E is an Fc domain monomer, and each E dimerizes to form an Fc domain, and the complex has the structure: 【Chemistry 6】 wherein E is an Fc domain; T is an integer from 1 to 20, L is a linker, R ７ is selected from C1-C20 alkyl, and The wavy line represents that L is covalently linked to E. The complex according to claim 1, wherein the complex is represented by the formula:

11. The complex is 【Chemistry 7】 11. The complex of claim 10 having the structure: or a pharma- ceutically acceptable salt thereof.

12. 12. The conjugate of claim 11, wherein each E comprises an amino acid sequence that is at least 95% identical to any one of SEQ ID NOs: 1-138.

13. 13. The complex of claim 12, wherein each E comprises the amino acid sequence of any 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.

14. The complex of claim 12, wherein each E comprises the amino acid sequence of SEQ ID NO:

67.

15. The complex of claim 12, wherein each E comprises the amino acid sequence of SEQ ID NO:

76.

16. 13. The conjugate of claim 12, wherein T is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

17. 13. The population of complexes of claim 12, wherein the average value of T is 1-10, 5-10, 1-5, 3-7, or 3.5-5.

5.

18. 18. The population of complexes of claim 17, wherein the average T is about 4.

5.

19. A conjugate according to claim 16, or a pharma- ceutically acceptable salt thereof; and Pharmaceutically acceptable excipients 13. A pharmaceutical composition comprising:

20. 20. Use of a conjugate, population of conjugates or pharmaceutical composition according to any one of claims 1 to 19 in the manufacture of a medicament for use in a method of treating a subject having or suspected of having a viral infection.

21. 20. Use of a conjugate, population of conjugates or pharmaceutical composition according to any one of claims 1 to 19 in the manufacture of a medicament for use in a method for the prophylactic treatment of a viral infection in a subject in need thereof.

22. 22. The use according to claim 20 or claim 21, wherein the viral infection is caused by an influenza or parainfluenza virus.

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