Compositions and methods for treating viral infections

Abstract

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

Description

[0001] This application is a divisional application of the invention patent application filed on September 6, 2019, with application number 201980072811.3 and invention title "Composition and Method for Treating Viral Infections". Background Technology

[0002] The need for novel antiviral treatments for influenza is significant and particularly crucial in the medical field. The influenza virus (the pathogen of influenza) causes three to five million serious illnesses each year and approximately 500,000 deaths worldwide. While most people fully recover from influenza within about one to two weeks, others develop life-threatening complications such as pneumonia. Therefore, influenza can be fatal, especially for young people, the elderly, or those with chronic illnesses. People with weakened or compromised immune systems, such as those with advanced HIV infection or transplant recipients (whose immune systems are medically suppressed to prevent organ rejection), are at greater risk of influenza-related complications. Pregnant women and young children are also at high risk of complications.

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

[0004] Influenza antiviral agents primarily target proteins present on the surface of influenza virus particles. The influenza virus envelope contains two immunodominant glycoproteins, hemagglutinin and neuraminidase, which play crucial roles in viral infection and spread. Hemagglutinin facilitates viral attachment to host cells, particularly initiating entry, through its interaction with surface sialic acid. Neuraminidase, an exoglycosidase, cleaves sialic acid (terminal neuraminidase residues) from glycan structures on the surface of infected host cells, releasing progeny viruses and allowing the virus to spread from the host cell to uninfected surrounding cells. Inhibition of neuraminidase thus serves as a pharmacological target for antiviral drugs. Viral neuraminidase inhibitors for reducing viral spread have been identified, including oseltamivir (Tamiflu). TM Zanamivir (Relenza) TM ) and peramivir (Rapivab) TM ).

[0005] However, influenza in transplant recipients is characterized by prolonged viral shedding, which increases the likelihood of developing drug-resistant strains. New and more effective treatments for influenza are needed. Summary of the Invention

[0006] The present invention relates to conjugates, compositions and methods for inhibiting viral growth, and methods for treating viral infections. In particular, the conjugates contain monomers or dimers of a moiety that inhibits influenza virus neuraminidase (e.g., zanamivir, peramivir, or analogs thereof) conjugated to an Fc monomer, Fc domain, Fc binding peptide, albumin, or albumin binding peptide. The neuraminidase inhibitor (e.g., zanamivir, peramivir, or analogs thereof) in the conjugates targets the neuraminidase on the surface of the virion. The Fc monomer or Fc domain in the conjugates binds to FcyRs (e.g., FcRn, FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and FcyRIIIb) on immune cells (e.g., neutrophils) to activate phagocytosis and effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), thus engulfing and destroying the virion by the immune cells and further enhancing the anti-viral activity of the conjugates. The albumin or albumin binding peptide can, for example, extend the half-life of the conjugates by conjugating albumin to the recycling neonatal Fc receptor. The compositions are suitable for use in methods of inhibiting viral growth and methods of treating viral infections, such as those caused by influenza A, influenza B, and influenza C viruses.

[0007] In one aspect, the present invention provides a conjugate described by formula (1):

[0008]

[0009] wherein each A1and each A2is independently selected from any one of formulae (A-I) - (A-XII):

[0010]

[0011] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0012]

[0013] R6is selected from

[0014] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68); L in each A1-L-A2is a linker covalently attached to the sulfur atom of the hinge cysteine in each E and to the linker of each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two wavy lines connecting the two E indicate that each A1-L-A2is covalently attached (e.g., by means of a covalent bond or linker) to a pair of sulfur atoms of two hinge cysteines in the two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0015] In another aspect, the application provides a conjugate described by formula (1):

[0016]

[0017] wherein each A1and each A2is independently selected from any one of formulae (A-I)-(A-V):

[0018]

[0019] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0020]

[0021] R6is selected from

[0022] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68); L in each A1-L-A2is a linker covalently attached to the sulfur atom of the hinge cysteine in each E and to the linker of each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two wavy lines connecting the two E indicate that each A1-L-A2is covalently attached (e.g., by means of a covalent bond or linker) to a pair of sulfur atoms of two hinge cysteines in two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0023] In another aspect, the application provides a conjugate described by formula (1):

[0024]

[0025] wherein each A1and each A2is independently selected from any one of formulae (A-VI)-(A-IX):

[0026]

[0027] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0028]

[0029] R6is selected from

[0030] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68); L in each A1-L-A2is a linker covalently attached to the sulfur atom of the hinge cysteine in each E and to the linker of each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two wavy lines connecting the two E indicate that each A1-L-A2is covalently attached (e.g., by means of a covalent bond or linker) to a pair of sulfur atoms of two hinge cysteines in the two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0031] In another aspect, the application provides a conjugate described by formula (2):

[0032]

[0033] wherein each A1is independently selected from any one of formulae (A-I)-(A-XII):

[0034]

[0035] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0036]

[0037] R6is selected from

[0038] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68); L in each L-A1is a linker covalently attached to a sulfur atom of a hinge cysteine in E and attached to A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two wavy lines connecting to two sulfur atoms indicate that each L-A1is covalently (e.g., by means of a covalent bond or linker) attached to a pair of sulfur atoms of two hinge cysteines in two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1may be independently selected from any one of formulae (A-I)-(A-XII).

[0039] In another aspect, the present application provides a conjugate described by formula (2):

[0040]

[0041] wherein each A1is independently selected from any one of formulae (A-I)-(A-V):

[0042]

[0043] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0044]

[0045] R6is selected from

[0046] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68); L in each L-A1is a linker covalently attached to a sulfur atom of a hinge cysteine in E and attached to A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two wavy lines connecting to two sulfur atoms indicate that each L-A1is covalently attached (e.g., by way of a covalent bond or linker) to a pair of sulfur atoms of two hinge cysteines in two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1may be independently selected from any one of formulae (A-I)-(A-V).

[0047] In another aspect, the present application provides a conjugate described by formula (2):

[0048]

[0049] wherein each A1is independently selected from any one of formulae (A-VI)-(A-IX):

[0050]

[0051] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0052]

[0053] R6is selected from

[0054] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68); L in each L-A1is a linker covalently attached to a sulfur atom of a hinge cysteine in E and attached to A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two wavy lines connecting to two sulfur atoms indicate that each L-A1is covalently attached (e.g., by means of a covalent bond or linker) to a pair of sulfur atoms of two hinge cysteines in two E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1may be independently selected from any one of formulas (A-VI)-(A-IX).

[0055] In some embodiments of any of the foregoing embodiments, each E comprises an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68.

[0056] In some embodiments, each E comprises the sequence

[0057] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH (SEQ ID NO: 10).

[0058] In some embodiments, each E comprises the sequence

[0059] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11).

[0060] In some embodiments, at least one of the pair of sulfur atoms is a hinge cysteine of SEQ ID NO: 10 or SEQ ID NO: 11, i.e., the sulfur atom of Cys 10, Cys 13, Cys 16, or Cys 18 of SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., the sulfur atom thereof). In some embodiments, the pair of sulfur atoms is the sulfur atom of Cys 10 and Cys 13 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys 10 and Cys 16 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys 30 and Cys 18 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys 13 and Cys 36 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys 13 and Cys 38 in SEQ ID NO: 10 or SEQ ID NO: 11, and / or Cys 36 and Cys 38 in SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., the sulfur atom thereof).

[0061] In some embodiments, when T is 2, the pair of sulfur atoms is Cys 10 and Cys 13 in SEQ ID NO: 10 or SEQ ID NO: 11 or Cys 36 and Cys 38 in SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., the sulfur atom thereof).

[0062] In some embodiments, the pair of sulfur atoms comprises one sulfur atom from a cysteine of each E, i.e., L-A together with its attached sulfur atom 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 the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from the other E. In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from the other E. In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from the other E. In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from the other E.

[0063] In some embodiments, when T is 2, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) 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 the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) 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 the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0064] In some embodiments, when T is 2, the pair of sulfur atoms is the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) 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 the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0065] In some embodiments, when T is 2, the pair of sulfur atoms is the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

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

[0067] In some embodiments, when T is 3, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0068] In some embodiments, the conjugate has the structure:

[0069]

[0070] wherein a, b, c, and d are each independently 0 or 1 and wherein when a, b, c, or d is 0, the two sulfur atoms form a disulfide bond.

[0071] 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.

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

[0073] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4).

[0074] In some embodiments, each E comprises the sequence

[0075] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 33).

[0076] In some embodiments, at least one of the pair of sulfur atoms is the sulfur atom corresponding to the hinge cysteines of SEQ ID NO: 4 or SEQ ID NO: 33, i.e., Cys10 and / or Cys13 (e.g., the sulfur atom thereof). In some embodiments, the pair of sulfur atoms is the pair of sulfur atoms corresponding to Cys10 and Cys13 (e.g., the sulfur atom thereof) in SEQ ID NO: 4 or SEQ ID NO: 33.

[0077] In some embodiments, the pair of sulfur atoms comprises one sulfur atom from a cysteine of each E, i.e., L-A together with its attached sulfur atom 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 the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from the other E. In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from the other E. In some embodiments, when T is 2, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from the other E, and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from the other E.

[0078] In some embodiments, the conjugate has the structure:

[0079]

[0080] wherein a and b are each independently 0 or 1 and wherein when a or b is 0, the two sulfur atoms form a disulfide bond. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0081] In some embodiments, each E comprises the sequence

[0082] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH (SEQ ID NO: 8).

[0083] In some embodiments, at least one of the pairs of sulfur atoms is a sulfur atom corresponding to the hinge cysteines of SEQ ID NO: 8, i.e., Cys10 and / or Cys13 (e.g., the sulfur atom thereof). In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to Cys10 and Cys13 (e.g., the sulfur atom thereof) in SEQ ID NO: 8.

[0084] In some embodiments, the pair of sulfur atoms includes one sulfur atom from a cysteine of each E, i.e., L-A together with the sulfur atom to which it is attached forms a bridge between two Fc domains (e.g., two Fc domains comprising the sequence of SEQ ID NO: 8). In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from the other E. In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from the other E. In some embodiments, when T is 2, the pair of sulfur atoms is a sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from the other E, and a sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from the other E.

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

[0086]

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

[0088] In another aspect, the present application also provides a population of conjugates described in any of the foregoing aspects, wherein the average of T is 1 to 20 (e.g., the average of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20). In some embodiments, the average of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0089] In another aspect, the present application provides a conjugate described by formula (3):

[0090]

[0091] wherein each A1and each A2is independently selected from any one of formulae (A-I) - (A-VII):

[0092]

[0093] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0094]

[0095]

[0096] R6is selected from

[0097] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each A1-L-A2is a linker covalently attached to the sulfur atom of a hinge cysteine in E and to each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2is covalently (e.g., by means of a covalent bond or linker) attached 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-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0098] In another aspect, the present application provides a conjugate described by formula (3):

[0099]

[0100] wherein each A1and each A2is independently selected from any one of formulae (A-I)-(A-V):

[0101]

[0102] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0103]

[0104] R6is selected from

[0105] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each A1-L-A2is a linker covalently attached to the sulfur atom of a hinge cysteine in E and to each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2is covalently attached (e.g., by means of a covalent bond or 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-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0106] In another aspect, the present application provides a conjugate described by formula (3):

[0107]

[0108] wherein each A1and each A2is independently selected from any one of formulae (A-VI)-(A-IX):

[0109]

[0110] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0111]

[0112] R6is selected from

[0113] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each A1-L-A2is a linker covalently attached to the sulfur atom of a hinge cysteine in E and to each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2is covalently attached (e.g., by means of a covalent bond or 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-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0114] In some embodiments, each E comprises an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68.

[0115] In some embodiments, each E comprises the sequence

[0116] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH (SEQ ID NO: 10).

[0117] In some embodiments, each E comprises the sequence

[0118] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11).

[0119] In some embodiments, at least one of the pair of sulfur atoms is a hinge cysteine of SEQ ID NO: 10 or SEQ ID NO: 11, i.e., the sulfur atom of Cys 10, Cys 13, Cys 16, or Cys 18 of SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., the sulfur atom thereof). In some embodiments, the pair of sulfur atoms is the sulfur atom of Cys 10 and Cys 13 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys 10 and Cys 16 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys 30 and Cys 18 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys 13 and Cys 36 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys 13 and Cys 38 in SEQ ID NO: 10 or SEQ ID NO: 11, and / or Cys 36 and Cys 38 in SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., the sulfur atom thereof).

[0120] In some embodiments, when T is 2, the pair of sulfur atoms is the sulfur atom of Cys 10 and Cys 13 in SEQ ID NO: 10 or SEQ ID NO: 11 and Cys 36 and Cys 38 in SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., the sulfur atom thereof).

[0121] In some embodiments, the pair of sulfur atoms comprises one sulfur atom from a cysteine of each E, i.e., L-A together with its attached sulfur atom 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 the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from the other E. In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from the other E. In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from the other E. In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from the other E.

[0122] In some embodiments, when T is 2, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) 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 the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) 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 the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0123] In some embodiments, when T is 2, the pair of sulfur atoms is the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) 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 the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0124] In some embodiments, when T is 2, the pair of sulfur atoms is the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E, and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0125] In some embodiments, when T is 3, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11; the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11; and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11. In some embodiments, when T is 3, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11; the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11; and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11.In some embodiments, when T is 3, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11; the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11; and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11. In some embodiments, when T is 3, the pair of sulfur atoms is the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11; the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys18 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11; and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) from one E of SEQ ID NO: 10 or SEQ ID NO: 11 and the sulfur atom corresponding to Cys16 (e.g., the sulfur atom thereof) from another E of SEQ ID NO: 10 or SEQ ID NO: 11.

[0126] In some embodiments, when T is 3, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.

[0127] In some embodiments, the conjugate has the structure:

[0128]

[0129] wherein a, b, c, and d are each independently 0 or 1 and wherein when a, b, c, or d is 0, the two sulfur atoms form a disulfide bond.

[0130] 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.

[0131] In some embodiments, each E comprises the sequence

[0132] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4).

[0133] In some embodiments, each E comprises the sequence

[0134] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 33).

[0135] In some embodiments, at least one of the pair of sulfur atoms is the sulfur atom corresponding to the hinge cysteines of SEQ ID NO: 4 or SEQ ID NO: 33, i.e., Cys10 and / or Cys13 (e.g., the sulfur atom thereof). In some embodiments, the pair of sulfur atoms is the pair of sulfur atoms corresponding to Cys10 and Cys13 (e.g., the sulfur atom thereof) in SEQ ID NO: 4 or SEQ ID NO: 33.

[0136] In some embodiments, the pair of sulfur atoms comprises one sulfur atom from a cysteine of each E, i.e., L-A together with its attached sulfur atom 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 the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from the other E. In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from the other E. In some embodiments, when T is 2, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from the other E, and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) of SEQ ID NO: 4 or SEQ ID NO: 33 from the other E.

[0137] In some embodiments, the conjugate has the structure:

[0138]

[0139] wherein a and b are each independently 0 or 1 and wherein when a or b is 0, the two sulfur atoms form a disulfide bond. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0140] In some embodiments, each E comprises the sequence

[0141] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH (SEQ ID NO: 8).

[0142] In some embodiments, at least one of the pairs of sulfur atoms is a sulfur atom corresponding to the hinge cysteines of SEQ ID NO: 8, i.e., Cys10 and / or Cys13 (e.g., the sulfur atom thereof). In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to Cys10 and Cys13 (e.g., the sulfur atom thereof) in SEQ ID NO: 8.

[0143] In some embodiments, the pair of sulfur atoms includes one sulfur atom from a cysteine of each E, i.e., L-A together with the sulfur atom to which it is attached forms a bridge between two Fc domains (e.g., two Fc domains comprising the sequence of SEQ ID NO: 8). In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from the other E. In some embodiments, the pair of sulfur atoms is a sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from the other E. In some embodiments, when T is 2, the pair of sulfur atoms is a sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from the other E, and a sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from one E and a sulfur atom corresponding to Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 8 from the other E.

[0144] In some embodiments, the conjugate has the structure:

[0145]

[0146] wherein a and b are each independently 0 or 1 and wherein when a or b is 0, the two sulfur atoms form a disulfide bond. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0147] In another aspect, the present application provides a conjugate described by formula (4):

[0148]

[0149] wherein each A1is independently selected from any one of formulae (A-I) - (A-XII):

[0150]

[0151] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0152]

[0153] R6is selected from

[0154] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each L-A1is a linker covalently attached to the sulfur atom of a hinge cysteine in E and attached to A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and the wavy line connected to E indicates that each L-A1is covalently attached (e.g., by way of a covalent bond or 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 A1may be independently selected from any one of formulae (A-I)-(A-XII).

[0155] In another aspect, the present application provides a conjugate described by formula (4):

[0156]

[0157] wherein each A1is independently selected from any one of formulae (A-I)-(A-V):

[0158]

[0159] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0160]

[0161] R6is selected from

[0162] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each L-A1is a linker covalently attached to the sulfur atom of a hinge cysteine in E and attached to A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and the wavy line connected to E indicates that each L-A1is covalently attached (e.g., by way of a covalent bond or 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 A1may be independently selected from any one of formulae (A-I)-(A-V).

[0163] In another aspect, the present application provides a conjugate described by formula (4):

[0164]

[0165] wherein each A1is independently selected from any one of formulae (A-VI)-(A-IX):

[0166]

[0167] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0168]

[0169] R6is selected from

[0170] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each L-A1is a linker covalently attached to the sulfur atom of a hinge cysteine in E and attached to A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and the wavy line connected to E indicates that each L-A1is covalently attached (e.g., by way of a covalent bond or 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 A1may be independently selected from any one of formulas (A-VI)-(A-IX).

[0171] In some embodiments, each E comprises an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68.

[0172] In some embodiments, each E comprises the sequence

[0173] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4).

[0174] In some embodiments, each E comprises the sequence

[0175] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWWSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK (SEQ ID NO: 33).

[0176] In some embodiments, at least one of the sulfur atoms is the sulfur atom corresponding to the hinge cysteine, i.e., Cys10 and / or Cys13 (e.g., the sulfur atom thereof) of SEQ ID NO: 4 or SEQ ID NO: 33. In some embodiments, the sulfur atom is the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) in SEQ ID NO: 4 or SEQ ID NO: 33. In some embodiments, the sulfur atom corresponding to Cys10 (e.g., the sulfur atom thereof) in SEQ ID NO: 4 or SEQ ID NO: 33.

[0177] In some embodiments, the conjugate has the structure:

[0178]

[0179] wherein a and b are each independently 0 or 1 and wherein when a or b is 0, the sulfur atom is a thiol. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0180] In another aspect, the application provides a population of conjugates, wherein the average of T is 1 to 20 (e.g., the average of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20). In some embodiments, the average of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0181] In another aspect, the application provides a conjugate described by formula (3):

[0182]

[0183] wherein each A1and each A2is independently selected from any one of formulae (A-I) - (A-XII): MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWWSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK (SEQ ID NO: 33).

[0184]

[0185] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0186]

[0187] R6is selected from

[0188] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each A1-L-A2is a linker covalently attached to a nitrogen atom of a surface-exposed lysine in E and to each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2is covalently attached (e.g., by means of a covalent bond or 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-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0189] In another aspect, the present application provides a conjugate described by formula (3):

[0190]

[0191] wherein each A1and each A2is independently selected from any one of formulae (A-I)-(A-V):

[0192]

[0193] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0194]

[0195] R6is selected from

[0196] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each A1-L-A2is a linker covalently attached to a nitrogen atom of a surface-exposed lysine in E and to each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2is covalently attached (e.g., by means of a covalent bond or 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-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0197] In another aspect, the present application provides a conjugate described by formula (3):

[0198]

[0199] wherein each A1and each A2is independently selected from any one of formulae (A-VI)-(A-IX):

[0200]

[0201] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0202]

[0203] R6is selected from

[0204] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each A1-L-A2is a linker covalently attached to a nitrogen atom of a surface-exposed lysine in E and to each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2is covalently attached (e.g., by means of a covalent bond or 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-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0205] In another aspect, the application provides a conjugate described by formula (4):

[0206]

[0207] wherein each A1is independently selected from any one of formulae (A-I)-(A-XII):

[0208]

[0209] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0210]

[0211] R6is selected from

[0212] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each L-A1is a linker covalently attached to a nitrogen atom of a surface-exposed lysine in E and attached to A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), the wavy line connected to E indicates that each L-A1is covalently attached (e.g., by means of a covalent bond or a linker) to a nitrogen atom of a surface-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A can be independently selected from any one of formulae (A-I)-(A-XII).

[0213] In another aspect, the application provides a conjugate described by formula (4):

[0214]

[0215] wherein each A1is independently selected from any one of formulae (A-I)-(A-V):

[0216]

[0217] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0218]

[0219] R6is selected from

[0220] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each L-A1is a linker covalently attached to a nitrogen atom of a surface-exposed lysine in E and attached to A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), the wavy line connected to E indicates that each L-A1is covalently attached (e.g., by means of a covalent bond or a linker) to a nitrogen atom of a surface-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1may be independently selected from any one of formulae (A-I)-(A-V).

[0221] In another aspect, the present application provides a conjugate described by formula (4):

[0222]

[0223] wherein each A1is independently selected from any one of formulae (A-VI)-(A-IX):

[0224]

[0225] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0226]

[0227] R6is selected from

[0228] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each L-A1is a linker covalently attached to a nitrogen atom of a surface-exposed lysine in E and to A; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), the wavy line connected to E indicates that each L-A1is covalently attached (e.g., by means of a covalent bond or a linker) to a nitrogen atom of a surface-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1may be independently selected from any one of formulae (A-VI)-(A-IX).

[0229] In another aspect, the present application provides a conjugate described by formula (5):

[0230]

[0231] wherein each Int is independently selected from any of the intermediates of Table 1; E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68); L in each L-Int is a linker covalently attached to a nitrogen atom of a surface-exposed lysine in E and to Int; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), the wavy line connected to E indicates that each L-Int is covalently attached (e.g., by means of a covalent bond or linker) to a nitrogen atom of a surface-exposed lysine or a sulfur atom of a surface-exposed cysteine in E, or a pharmaceutically acceptable salt thereof. 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 Int can be independently selected from any of the intermediates of Table 1.

[0232] The intermediates of Table 1 can be conjugated to an Fc domain or Fc domain monomer (e.g., by means of a linker) by any suitable method known to one of skill in the art, including any of the methods described or exemplified herein. In some embodiments, the conjugate (e.g., the conjugate described by formula (5)) comprises E, wherein E is an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having the sequence of any one of SEQ ID NOs: 1-68). In preferred embodiments, one or more nitrogen atoms of one or more surface-exposed lysine residues of E or one or more sulfur atoms of one or more surface-exposed cysteines in E are covalently conjugated to a linker (e.g., a PEG2-PEG 20 The linker conjugated to E can be functionalized such that it can react to form a covalent bond with any of the Ints described herein (e.g., the Ints of Table 1). In preferred embodiments, E is conjugated to an azide-functionalized linker and the Int (e.g., the Int of Table 1) is alkynyl-functionalized. The linker-azide of E and the linker-alkyne of the Int conjugate (e.g., by click chemistry) to form a conjugate of the application, e.g., the conjugate described by formula (5). In other embodiments, E is conjugated to an alkynyl-functionalized linker and the Int (e.g., the Int of Table 1) is azide-functionalized. The linker-alkyne of E and the linker-azide of the Int conjugate (e.g., by click chemistry) to form a conjugate of the application, e.g., the conjugate described by formula (5).

[0233] Table 1: Intermediates

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253] In some embodiments, each E comprises an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68.

[0254] In some embodiments, E comprises the sequence

[0255] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4).

[0256] In some embodiments, each E comprises the sequence

[0257] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 33).

[0258] In some embodiments, E comprises the sequence

[0259] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH (SEQ ID NO: 10)

[0260] In some embodiments, each E comprises the sequence

[0261] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11).

[0262] In some embodiments of the foregoing three aspects, the nitrogen atom is the nitrogen of a surface-exposed lysine, e.g., a nitrogen atom corresponding to Lys35, Lys63, Lys77, Lys79, Lys106, Lys123, Lys129, Lys181, Lys203, Lys228, or Lys236 of SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., the nitrogen atom thereof). In some embodiments, the nitrogen atom is a nitrogen atom corresponding to Lys65, Lys79, Lys108, Lys230, and / or Lys238 of SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., the nitrogen atom thereof).

[0263] In some embodiments, the conjugate has the structure:

[0264]

[0265] wherein each of a, b, c, d, and e is independently 0 or 1 and wherein when a, b, c, d, or e is 0, the two nitrogen atoms are NH2. In some embodiments, a is 1 and b, c, d, and e are 0. In some embodiments, b is 1 and a, c, d, and e are 0. In some embodiments, c is 1 and a, b, d, and e are 0. In some embodiments, d is 1 and a, b, c, and e are 0. In some embodiments, e is 1 and a, b, c, and d are 0. In some embodiments, a and b are 1 and c, d, and e are 0. In some embodiments, a and c are 1 and b, d, and e are 0. In some embodiments, a and d are 1 and b, c, and e are 0. In some embodiments, a and e are 1 and b, c, and d are 0. In some embodiments, b and c are 1 and a, d, and e are 0. In some embodiments, b and d are 1 and a, c, and e are 0. In some embodiments, b and e are 1 and a, c, and d are 0. In some embodiments, c and d are 1 and a, b, and e are 0. In some embodiments, c and e are 1 and a, b, and d are 0. In some embodiments, d and e are 1 and a, b, and c are 0. In some embodiments, a, b, and c are 1 and d and e are 0. In some embodiments, a, b, and d are 1 and c and e are 0. In some embodiments, a, b, and e are 1 and c and d are 0. In some embodiments, a, c, and d are 1 and b and e are 0. In some embodiments, a, c, and 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.

[0266] In another aspect, the application provides a population of conjugates described in any of the foregoing aspects, wherein the average of T is 1 to 20 (e.g., the average of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20). In some embodiments, the average of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0267] In some embodiments of the conjugates described herein, the conjugate forms a homodimer comprising an Fc domain.

[0268] In some embodiments of the conjugates described herein, E dimerizes with another E to form an Fc domain.

[0269] In another aspect, the application provides a conjugate described by formula (3):

[0270]

[0271] wherein each A1and each A2is independently selected from any one of formulae (A-I)-(A-XII):

[0272]

[0273] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0274]

[0275] R6is selected from

[0276] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin binding peptide, or an Fc binding peptide; L in each A1-L-A2is independently covalently attached to a sulfur atom of a surface-exposed cysteine or a nitrogen atom of a surface-exposed lysine in E and to a linker of each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2is independently covalently attached (e.g., by way of a bond or a linker) 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-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0277] In another aspect, the present application provides a conjugate described by formula (3):

[0278]

[0279] wherein each A1and each A2is independently selected from any one of formulae (A-I)-(A-V):

[0280]

[0281] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0282]

[0283] R6is selected from

[0284] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; L in each A1-L-A2is independently covalently attached to a sulfur atom of a surface-exposed cysteine or a nitrogen atom of a surface-exposed lysine in E and to a linker of each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2is independently covalently attached (e.g., by way of a bond or a linker) 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-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0285] In another aspect, the present application provides a conjugate described by formula (3):

[0286]

[0287] wherein each A1and each A2is independently selected from any one of formulae (A-VI)-(A-IX):

[0288]

[0289] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0290]

[0291] R6is selected from

[0292] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; L in each A1-L-A2is independently covalently attached to a sulfur atom of a surface-exposed cysteine or a nitrogen atom of a surface-exposed lysine in E and to a linker of each of A1and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2is independently covalently attached (e.g., by way of a bond or a linker) 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-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0293] In another aspect, the application provides a conjugate described by formula (4):

[0294]

[0295] wherein each A1is independently selected from any one of formulae (A-I)-(A-XII):

[0296]

[0297] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0298]

[0299] R6is selected from

[0300] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; L in each L-A1is independently covalently attached to a sulfur atom of a surface-exposed cysteine or a nitrogen atom of a surface-exposed lysine in E and to a linker of A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and the wavy line connected to E indicates that each L-A1is independently covalently attached (e.g., by way of a bond or a linker) 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 A can be independently selected from any one of formulae (A-I)-(A-XII).

[0301] In another aspect, the application provides a conjugate described by formula (4):

[0302]

[0303] wherein each A1is independently selected from any one of formulae (A-I)-(A-V):

[0304]

[0305] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0306]

[0307] R6is selected from

[0308] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; L in each L-A1is independently covalently attached to a sulfur atom of a surface-exposed cysteine or a nitrogen atom of a surface-exposed lysine in E and to a linker of A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and the wavy line connected to E indicates that each L-A is independently covalently attached (e.g., by way of a bond or a linker) 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 A1may be independently selected from any one of formulae (A-I)-(A-V).

[0309] In another aspect, the application provides a conjugate described by formula (4):

[0310]

[0311] wherein each A1is independently selected from any one of formulae (A-VI)-(A-IX):

[0312]

[0313] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0314]

[0315] R6is selected from

[0316] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; E comprises an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; L in each L-A1is independently covalently attached to a sulfur atom of a surface-exposed cysteine or a nitrogen atom of a surface-exposed lysine in E and to a linker of A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and the wavy line connected to E indicates that each L-A1is independently covalently attached (e.g., by way of a bond or a linker) 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 A can be independently selected from any one of formulae (A-VI)-(A-IX).

[0317] In another aspect, the present application provides a conjugate described by formula (5):

[0318]

[0319] wherein each Int is independently selected from any of the intermediates of Table 1; E comprises an albumin (e.g., an albumin having the sequence of any of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; L in each L-Int is independently covalently attached to a sulfur atom of a surface-exposed cysteine or a nitrogen atom of a surface-exposed lysine in E and to a linker of Int; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and the wavy line connected to E indicates that each L-Int is independently covalently attached to a sulfur atom of a solvent-exposed cysteine or a nitrogen atom of a solvent-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each Int can be independently selected from any of the intermediates of Table 1.

[0320] The intermediates of Table 1 can be conjugated to an albumin, an albumin-binding peptide, or an Fc-binding peptide (e.g., by means of a linker) by any suitable method known to one of skill in the art, including any of the methods described or exemplified herein. In some embodiments, the conjugate (e.g., a conjugate described by formula (5)) comprises E, wherein E is an albumin (e.g., an albumin having the sequence of any of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide. In preferred embodiments, one or more nitrogen atoms of one or more surface-exposed lysine residues of E or one or more sulfur atoms of one or more surface-exposed cysteines in E are covalently conjugated to a linker (e.g., a PEG2-PEG 20 The linker conjugated to E can be functionalized such that it can react to form a covalent bond with any of the Ints described herein (e.g., Ints of Table 1). In preferred embodiments, E is conjugated to an azido-functionalized linker and the Int (e.g., an Int of Table 1) is alkynyl-functionalized. The linker-azido of E and the linker-alkyne of the Int conjugate (e.g., by click chemistry) to form a conjugate of the application, e.g., a conjugate described by formula (5). In other embodiments, E is conjugated to an alkynyl-functionalized linker and the Int (e.g., an Int of Table 1) is azido-functionalized. The linker-alkyne of E and the linker-azido of the Int conjugate (e.g., by click chemistry) to form a conjugate of the application, e.g., a conjugate described by formula (5).

[0321] In some embodiments, each E comprises an albumin having the sequence of any of SEQ ID NOs: 69-71.

[0322] In some embodiments, T is 1 and L-A is covalently attached to the sulfur atom corresponding to Cys34 of SEQ ID NO: 69.

[0323] In another aspect, the application provides a population of conjugates described in any of the foregoing aspects, wherein the average value of T is 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20). In some embodiments, the average value of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0324] In another aspect, the application provides a conjugate comprising (i) a first moiety A1; (ii) a second moiety A2; (iii) an Fc domain monomer or an Fc domain; and (iv) a linker covalently attached to A1 and A2 and to the Fc domain monomer or the Fc domain; wherein each A1 and each A2 is independently selected from any one of formulae (A-I) - (A-XII):

[0325]

[0326] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0327]

[0328]

[0329] R6is selected from

[0330] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl, or a pharmaceutically acceptable salt thereof.

[0331] In another aspect, the present application provides a conjugate comprising (i) a first moiety A1; (ii) a second moiety A2; (iii) a Fc domain monomer or a Fc domain; and (iv) a linker covalently attached to A1 and A2 and to the Fc domain monomer or the Fc domain; wherein each A1 and each A2 is independently selected from any one of Formulae (A-I)-(A-V):

[0332]

[0333] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0334]

[0335] R6is selected from

[0336] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl, or a pharmaceutically acceptable salt thereof.

[0337] In another aspect, the present application provides a conjugate comprising (i) a first moiety A1; (ii) a second moiety A2; (iii) a Fc domain monomer or a Fc domain; and (iv) a linker covalently attached to A1 and A2 and to the Fc domain monomer or the Fc domain; wherein each A1 and each A2 is independently selected from any one of Formulae (A-VI)-(A-IX):

[0338]

[0339] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0340]

[0341] R6is selected from

[0342] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl and C2-C15heteroaryl; and R8is selected from C3-C20heterocycloalkyl, C5-C15aryl and C2-C15heteroaryl, or a pharmaceutically acceptable salt thereof.

[0343] In another aspect, the present application provides a conjugate comprising (i) a first moiety Int; (ii) an Fc domain monomer or an Fc domain; and (iv) a linker covalently attached to Int and to the Fc domain monomer or the Fc domain; wherein each Int is independently selected from any of the intermediates of Table 1.

[0344] In another aspect, the present application provides a conjugate comprising (i) a first moiety A1; (ii) a second moiety A2; (iii) an albumin, albumin binding peptide or Fc binding peptide; and (iv) a linker covalently attached to A1and A2and to the albumin, the albumin binding peptide or the Fc binding peptide; wherein each A1and each A2is independently selected from any of Formulae (A-I) - (A-XII):

[0345]

[0346] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0347]

[0348] R6is selected from

[0349] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl and C2-C15heteroaryl; and R8is selected from C3-C20heterocycloalkyl, C5-C15aryl and C2-C15heteroaryl, or a pharmaceutically acceptable salt thereof.

[0350] In another aspect, the present application provides a conjugate comprising (i) a first moiety A1; (ii) a second moiety A2; (iii) an albumin, albumin binding peptide, or Fc binding peptide; and (iv) a linker covalently attached to A1 and A2 and to the albumin, the albumin binding peptide, or the Fc binding peptide; wherein each A1 and each A2 is independently selected from any one of Formulae (A-I)-(A-V):

[0351]

[0352] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0353]

[0354]

[0355] R6is selected from

[0356] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl, or a pharmaceutically acceptable salt thereof.

[0357] In another aspect, the present application provides a conjugate comprising (i) a first moiety A1; (ii) a second moiety A2; (iii) an albumin, albumin binding peptide, or Fc binding peptide; and (iv) a linker covalently attached to A1 and A2 and to the albumin, the albumin binding peptide, or the Fc binding peptide; wherein each A1 and each A2 is independently selected from any one of Formulae (A-VI)-(A-IX):

[0358]

[0359] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0360]

[0361] R6is selected from the group consisting of

[0362] R7is selected from the group consisting of H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; R8is selected from the group consisting of C3-C20 heterocycloalkyl, C5-C15 aryl and C2-C15 heteroaryl, or a pharmaceutically acceptable salt thereof.

[0363] In another aspect, the present application provides a conjugate described by formula (D-I):

[0364]

[0365] wherein each A1and each A2is independently selected from any one of formulae (A-I) - (A-XII):

[0366]

[0367] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0368]

[0369] R6is selected from the group consisting of

[0370] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and L is a linker covalently attached to each of E, A1, and A2, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0371] In another aspect, the present application provides a conjugate described by formula (D-I):

[0372]

[0373] wherein each A1and each A2is independently selected from any one of formulae (A-I)-(A-V):

[0374]

[0375] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0376]

[0377] R6is selected from

[0378] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and L is a linker covalently attached to each of E, A1, and A2, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0379] In another aspect, the present application provides a conjugate described by formula (D-I):

[0380]

[0381] wherein each A1and each A2is independently selected from any one of formulae (A-VI)-(A-IX):

[0382]

[0383] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0384]

[0385] R6is selected from

[0386] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and L is a linker covalently attached to each of E, A1, and A2, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2may be independently selected (e.g., independently selected from any one of the A1-L-A2structures described herein).

[0387] In some embodiments, the conjugate is described by formula (D-II):

[0388]

[0389] or a pharmaceutically acceptable salt thereof.

[0390] In some embodiments, the conjugate is described by formula (D-II-1):

[0391]

[0392] or a pharmaceutically acceptable salt thereof.

[0393] In some embodiments, the conjugate is described by formula (D-II-2):

[0394]

[0395] or a pharmaceutically acceptable salt thereof.

[0396] In some embodiments, the conjugate is described by formula (D-II-3):

[0397]

[0398] wherein L' is the remainder of L, and each y1and y2is independently an integer from 1-20 (e.g., each y1and y2is 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.

[0399] In some embodiments, the conjugate has a structure selected from:

[0400]

[0401]

[0402] In some embodiments, the conjugate is described by formula (D-II-4):

[0403]

[0404] or a pharmaceutically acceptable salt thereof.

[0405] In some embodiments, the conjugate is described by formula (D-II-5):

[0406]

[0407]

[0408] wherein L' is the remainder of L, and each y1and y2is independently an integer from 1-20 (e.g., each y1and y2is 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.

[0409] In some embodiments, the conjugate has a structure selected from:

[0410]

[0411] or a pharmaceutically acceptable salt thereof.

[0412] In some embodiments, the conjugate has a structure selected from:

[0413]

[0414]

[0415] or a pharmaceutically acceptable salt thereof.

[0416] In some embodiments, the conjugate is described by formula (D-II-6):

[0417]

[0418] wherein R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; or a pharmaceutically acceptable salt thereof.

[0419] In some embodiments, the conjugate is described by formula (D-II-7):

[0420]

[0421] or a pharmaceutically acceptable salt thereof.

[0422] In some embodiments, the conjugate is described by formula (D-II-8):

[0423]

[0424] wherein L’ is the remainder of L, and y1and y2are each independently an integer from 1-20 (e.g., y1and y2are 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.

[0425] In some embodiments, the conjugate has the structure

[0426]

[0427] or a pharmaceutically acceptable salt thereof.

[0428] In some embodiments, the conjugate has the structure

[0429]

[0430] or a pharmaceutically acceptable salt thereof.

[0431] In some embodiments, the conjugate has the structure

[0432]

[0433] or a pharmaceutically acceptable salt thereof.

[0434] In some embodiments, the conjugate is described by formula (D-II-9):

[0435]

[0436] or a pharmaceutically acceptable salt thereof.

[0437] In some embodiments, the conjugate is described by formula (D-II-10):

[0438]

[0439] wherein L’ is the remainder of L, and y1and y2are each independently an integer from 1-20 (e.g., y1and y2are 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.

[0440] In some embodiments, the conjugate has the structure:

[0441]

[0442] or a pharmaceutically acceptable salt thereof.

[0443] In some embodiments, the conjugate has the structure:

[0444]

[0445] or a pharmaceutically acceptable salt thereof.

[0446] In some embodiments, the conjugate is described by formula (D-III):

[0447]

[0448] or a pharmaceutically acceptable salt thereof.

[0449] In some embodiments, the conjugate is described by formula (D-III-1):

[0450]

[0451] or a pharmaceutically acceptable salt thereof.

[0452] In some embodiments, the conjugate is described by formula (D-III-2):

[0453]

[0454] or a pharmaceutically acceptable salt thereof.

[0455] In some embodiments, the conjugate is described by formula (D-III-3):

[0456]

[0457] wherein L' is the remainder of L, and each y1and y2is independently an integer from 1-20 (e.g., each y1and y2is 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.

[0458] In some embodiments, the conjugate is described by formula (D-III-4):

[0459]

[0460] or a pharmaceutically acceptable salt thereof.

[0461] In some embodiments, the conjugate is described by formula (D-III-5):

[0462]

[0463] wherein L' is the remainder of L, and each y1and y2is independently an integer from 1-20 (e.g., each y1and y2is 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.

[0464] In some embodiments, the conjugate is described by formula (D-III-6):

[0465]

[0466] or a pharmaceutically acceptable salt thereof.

[0467] In some embodiments, the conjugate is described by formula (D-III-7):

[0468]

[0469]

[0470] wherein L' is the remainder of L, and each y1and y2is independently an integer from 1-20 (e.g., each y1and y2is 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.

[0471] In some embodiments, the conjugate is described by formula (D-III-8):

[0472]

[0473] or a pharmaceutically acceptable salt thereof.

[0474] In some embodiments, the conjugate is described by formula (D-III-9):

[0475]

[0476] wherein L’ is the remainder of L, and each y1 and y2 is independently an integer from 1-20 (e.g., each y1 and y2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L’ is a nitrogen atom.

[0477] In some embodiments, the conjugate is described by formula (D-IV):

[0478]

[0479] or a pharmaceutically acceptable salt thereof.

[0480] In some embodiments, the conjugate is described by formula (D-IV-1):

[0481]

[0482] or a pharmaceutically acceptable salt thereof.

[0483] In some embodiments, the conjugate is described by formula (D-IV-2):

[0484]

[0485] wherein L’ is the remainder of L, and each y1 and y2 is independently an integer from 1-20 (e.g., each y1 and y2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L’ is a nitrogen atom. In some embodiments, the conjugate is described by formula (D-V):

[0486]

[0487] or a pharmaceutically acceptable salt thereof.

[0488] In some embodiments, the conjugate is described by formula (D-V-1):

[0489]

[0490] or a pharmaceutically acceptable salt thereof.

[0491] In some embodiments, the conjugate is described by formula (D-V-2):

[0492]

[0493] or a pharmaceutically acceptable salt thereof.

[0494] In some embodiments, the conjugate is described by formula (D-V-3):

[0495]

[0496] wherein L’ is the remainder of L, and y1and y2are each independently an integer from 1-20 (e.g., y1and y2are 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, y1and y2are each 1, y1and y2are each 2, or y1and y2are each 3.

[0497] In some embodiments, the conjugate is described by formula (D-V-4):

[0498]

[0499] or a pharmaceutically acceptable salt thereof.

[0500] In some embodiments, the conjugate is described by formula (D-V-5):

[0501]

[0502] wherein L’ is the remainder of L, and y1and y2are each independently an integer from 1-20 (e.g., y1and y2are 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, y1and y2are each 1, y1and y2are each 2, or y1and y2are each 3.

[0503] In some embodiments, the conjugate is described by formula (D-V-6):

[0504]

[0505] or a pharmaceutically acceptable salt thereof.

[0506] In some embodiments, the conjugate is described by formula (D-V-7):

[0507]

[0508] or a pharmaceutically acceptable salt thereof.

[0509] In some embodiments, the conjugate is described by formula (D-V-8):

[0510]

[0511] where L’ is the remainder of L, and y1and y2are each independently an integer from 1-20 (e.g., y1and y2are 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, y1and y2are each 1, y1and y2are each 2, or y1and y2are each 3.

[0512] In some embodiments, the conjugate is described by formula (D-V-9):

[0513]

[0514] or a pharmaceutically acceptable salt thereof.

[0515] In some embodiments, the conjugate is described by formula (D-V-10):

[0516]

[0517] where L’ is the remainder of L, and y1and y2are each independently an integer from 1-20 (e.g., y1and y2are 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, y1and y2are each 1, y1and y2are each 2, or y1and y2are each 3.

[0518] In some embodiments, the conjugate is described by formula (D-VI):

[0519]

[0520] or a pharmaceutically acceptable salt thereof.

[0521] In some embodiments, the conjugate is described by formula (D-VI-1):

[0522]

[0523] or a pharmaceutically acceptable salt thereof.

[0524] In some embodiments, the conjugate is described by formula (D-VI-2):

[0525]

[0526] or a pharmaceutically acceptable salt thereof.

[0527] In some embodiments, the conjugate is described by formula (D-VI-3):

[0528]

[0529] wherein L’ is the remainder of L, and y1and y2are each independently an integer from 1-20 (e.g., y1and y2are 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, y1and y2are each 1, y1and y2are each 2, or y1and y2are each 3.

[0530] In some embodiments, the conjugate is described by formula (D-VI-4):

[0531]

[0532] or a pharmaceutically acceptable salt thereof.

[0533] In some embodiments, the conjugate is described by formula (D-VI-5):

[0534]

[0535] wherein L’ is the remainder of L, and y1and y2are each independently an integer from 1-20 (e.g., y1and y2are 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, y1and y2are each 1, y1and y2are each 2, or y1and y2are each 3.

[0536] In some embodiments, the conjugate is described by formula (D-VI-6):

[0537]

[0538] or a pharmaceutically acceptable salt thereof.

[0539] In some embodiments, the conjugate is described by formula (D-VI-7):

[0540]

[0541] wherein L’ is the remainder of L, and y1and y2are each independently an integer from 1-20 (e.g., y1and y2are 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, y1and y2are each 1, y1and y2are each 2, or y1and y2are each 3.

[0542] In some embodiments, the conjugate is described by formula (D-VI-8):

[0543]

[0544] or a pharmaceutically acceptable salt thereof.

[0545] In some embodiments, the conjugate is described by formula (D-VI-9):

[0546]

[0547] wherein L’ is the remainder of L, and y1and y2are each independently an integer from 1-20 (e.g., y1and y2are 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, y1and y2are each 1, y1and y2are each 2, or y1and y2are each 3.

[0548] In some embodiments, the conjugate is described by formula (D-VII):

[0549]

[0550] or a pharmaceutically acceptable salt thereof.

[0551] In some embodiments of any aspect described herein, R1is OH. In some embodiments of any aspect described herein, R1is NH2. In some embodiments of any aspect described herein, R1is -NHC(=NH)NH2.

[0552] In some embodiments, the conjugate is described by formula (D-VIII):

[0553]

[0554] or a pharmaceutically acceptable salt thereof.

[0555] In some embodiments, the conjugate is described by formula (D-VIII-1):

[0556]

[0557] or a pharmaceutically acceptable salt thereof.

[0558] In some embodiments, the conjugate is described by formula (D-VIII-2):

[0559]

[0560] or a pharmaceutically acceptable salt thereof.

[0561] In some embodiments, the conjugate is described by formula (D-VIII-3):

[0562]

[0563] wherein L’ is the remainder of L, and each y1 and y2 is independently an integer from 1-20 (e.g., each y1 and y2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L’ is a nitrogen atom.

[0564] In some embodiments, the conjugate has a structure selected from:

[0565]

[0566] or a pharmaceutically acceptable salt thereof.

[0567] In some embodiments, the conjugate is described by formula (D-VIII-4):

[0568]

[0569] or a pharmaceutically acceptable salt thereof.

[0570] In some embodiments, the conjugate is described by formula (D-VIII-5):

[0571]

[0572] wherein L' is the remainder of L, and each y1and y2is independently an integer from 1-20 (e.g., each y1and y2is 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.

[0573] In some embodiments, the conjugate has a structure selected from:

[0574]

[0575] or a pharmaceutically acceptable salt thereof.

[0576] In some embodiments, the conjugate is described by the structure:

[0577]

[0578] or a pharmaceutically acceptable salt thereof.

[0579] In some embodiments, the conjugate is described by formula (D-VIII-6):

[0580]

[0581] or a pharmaceutically acceptable salt thereof.

[0582] In some embodiments, the conjugate is described by formula (D-VIII-7):

[0583]

[0584] wherein L' is the remainder of L, and each y1and y2is independently an integer from 1-20 (e.g., each y1and y2is 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.

[0585] In some embodiments, the conjugate is described by formula (D-VIII-8):

[0586]

[0587] or a pharmaceutically acceptable salt thereof.

[0588] In some embodiments, the conjugate is described by formula (D-VIII-9):

[0589]

[0590] wherein L’ is the remainder of L, and each y1 and y2 is independently an integer from 1-20 (e.g., each y1 and y2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L’ is a nitrogen atom.

[0591] In some embodiments, the conjugate is described by formula (D-VIII-10):

[0592]

[0593]

[0594] or a pharmaceutically acceptable salt thereof.

[0595] In some embodiments, the conjugate is described by formula (D-VIII-11):

[0596]

[0597] wherein L’ is the remainder of L, and each y1 and y2 is independently an integer from 1-20 (e.g., each y1 and y2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L’ is a nitrogen atom.

[0598] In some embodiments, the conjugate is described by formula (D-IX):

[0599]

[0600]

[0601] or a pharmaceutically acceptable salt thereof.

[0602] In some embodiments, the conjugate is described by formula (D-IX-1):

[0603]

[0604] or a pharmaceutically acceptable salt thereof.

[0605] In some embodiments, the conjugate is described by formula (D-IX-2):

[0606]

[0607] or a pharmaceutically acceptable salt thereof.

[0608] In some embodiments, the conjugate is described by formula (D-IX-3):

[0609]

[0610] or a pharmaceutically acceptable salt thereof.

[0611] In some embodiments, the conjugate is described by formula (D-IX-4):

[0612]

[0613] or a pharmaceutically acceptable salt thereof.

[0614] In some embodiments, the conjugate is described by formula (D-IX-5):

[0615]

[0616] or a pharmaceutically acceptable salt thereof.

[0617] In some embodiments, the conjugate is described by formula (D-IX-6):

[0618]

[0619] or a pharmaceutically acceptable salt thereof.

[0620] In some embodiments, the conjugate is described by formula (D-X):

[0621]

[0622] or a pharmaceutically acceptable salt thereof.

[0623] In some embodiments, the conjugate is described by formula (D-X-1):

[0624]

[0625] or a pharmaceutically acceptable salt thereof.

[0626] In some embodiments, the conjugate is described by formula (D-X-2):

[0627]

[0628] or a pharmaceutically acceptable salt thereof.

[0629] In some embodiments, the conjugate is described by formula (D-X-3):

[0630]

[0631] or a pharmaceutically acceptable salt thereof.

[0632] In some embodiments of any of the aspects described herein, L or L' comprises one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphato, phosphoryl, or imino, wherein R i is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0633] In some embodiments of any of the aspects described herein, the backbone of L or L' consists of one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphato, phosphoryl, or imino, wherein R iH, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20alkynyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C3-C20cycloalkyl, optionally substituted C3-C20heterocycloalkyl, optionally substituted C4-C20cycloalkenyl, optionally substituted C4-C20heterocycloalkenyl, optionally substituted C8-C20cycloalkynyl, optionally substituted C8-C20heterocycloalkynyl, optionally substituted C5-C15aryl, or optionally substituted C2-C15heteroaryl.

[0634] In some embodiments of any aspect described herein, L or L’ is substituted with an oxo. In some embodiments, the backbone of L or L’ comprises no more than 250 atoms. In some embodiments, L or L’ is capable of forming an amide, carbamate, sulfonyl, or urea linkage. In some embodiments, L or L’ is a bond. In some embodiments, L or L’ is an atom.

[0635] In some embodiments of any aspect described herein, each L is described by formula (D-L-I):

[0636]

[0637] wherein L A by formula G A1 -(Z A1 ) g1 -(Y A1 ) h1 -(Z A2 ) i1 -(Y A2 ) j1 -(Z A3 ) k1 -(Y A3 ) l1 -(Z A4 ) m1 -(Y A4 ) n1 -(Z A5 )o1-G A2 described; L B by formula G B1 -(Z B1 ) g2 -(Y B1 ) h2 -(Z B2 ) i2 -(Y B2 ) j2 -(Z B3 ) k2 -(Y B3 )l2 -(Z B4 ) m2 -(Y B4 ) n2 -(Z B5 )o2-G B2 Description; L C from Formula G C1 -(Z C1 ) g3 -(Y C1 ) h3 -(Z C2 ) i3 -(Y C2 ) j3 -(Z C3 ) k3 -(Y C3 ) l3 -(Z C4 ) m3 -(Y C4 ) n3 -(Z C5 )o3-G C2 Description; G A1 is a bond to Q; G A2 is a bond to A1; G B1 is a bond to Q) ; G B2 is a bond to A2; G C1 is a bond to Q; 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); Z A1 , Z A2 , Z A3 , Z A4 , Z A5 , Z B1 , Z B2 , Z B3 , Z B4 , Z B5 , Z C1 , Z C2 , Z C3 , Z C4 , and Z C5Each of these is independently a optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkylene, optionally substituted C2-C20 ynylene, optionally substituted C2-C20 heteroalkylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heteroalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heteroalkylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heteroalkylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene; Y A1 Y A2 Y A3 Y A4 Y B1 Y B2 Y B 3 Y B4 Y C1 Y C2 Y C3 and Y C4 Each of them is independently O, S, NR i P, carbonyl, thiocarbonyl, sulfonyl, phosphate ester, phosphoryl, or imino; R iH, 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; each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, and o3 is independently 0 or 1; Q is a nitrogen atom, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene.

[0638] In some embodiments, L C may have two points of attachment to the Fc domain, Fc binding peptide, albumin, or albumin binding peptide (e.g., two G C2 ).

[0639] In some embodiments of any of the aspects described herein, L comprises a polyethylene glycol (PEG) linker. The PEG linker comprises a linker having the repeating unit structure (-CH2CH2O-) n , wherein n is an integer from 2 to 100. The polyethylene glycol linker can covalently join a neuraminidase inhibitor and E (e.g., in a conjugate of any of formulae (M-I)-(M-X)). The polyethylene glycol linker can covalently join a first neuraminidase inhibitor and a second neuraminidase inhibitor (e.g., in a conjugate of any of formulae (D-I)-(D-X)). The polyethylene glycol linker can covalently join a neuraminidase inhibitor dimer and E (e.g., in a conjugate of any of formulae (D-I)-(D-X)). The polyethylene glycol linker can be selected from any of PEG2 to PEG 100 , for example, PEG2, PEG3, PEG4, PEG5, PEG5-PEG 10 , PEG10 -PEG 20 , PEG 20 -PEG 30 , PEG 30 -PEG 40 , PEG 50 -PEG 60 , PEG 60 -PEG 70 , PEG 70 -PEG 80 , PEG 80 -PEG 90 , PEG 90 -PEG 100 In some embodiments, L comprises a PEG linker, wherein L is covalently attached to each of Q and E. c C In some embodiments, L is

[0640] In some embodiments, L is

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652] wherein z1and z2are each independently an integer from 1 to 20; and R9is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl.

[0653] In some embodiments, L is

[0654]

[0655] ​

[0656]

[0657]

[0658]

[0659] wherein R* is a bond or comprises 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 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, phosphoester, and imino. 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.

[0660] In some embodiments, Y is: (-NH(C=O)O-) and L is:

[0661] In some embodiments, Y is: (-NH(C=O)O-) and L is:

[0662] In some embodiments, Y is: (-NH(C=O)O-) and L is:

[0663] In some embodiments, Y is: (-O-) and L is:

[0664] In another aspect, the application provides a conjugate described by formula (M-I):

[0665]

[0666] wherein each A1is independently selected from any one of formulae (A-I)-(A-XII):

[0667]

[0668] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0669]

[0670] R6is selected from

[0671] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and L is a linker covalently attached to each of E and A1, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1may be independently selected from any one of formulae (A-I)-(A-XII).

[0672] In another aspect, the application provides a conjugate described by formula (M-I):

[0673]

[0674] wherein each A1is independently selected from any one of formulae (A-I)-(A-V):

[0675]

[0676] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0677]

[0678] R6is selected from

[0679] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and L is a linker covalently attached to each of E and A1, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1may be independently selected from any one of formulae (A-I)-(A-V).

[0680] In another aspect, the present application provides a conjugate described by formula (M-I):

[0681]

[0682] wherein each A1is independently selected from any one of formulae (A-VI)-(A-IX):

[0683]

[0684] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0685]

[0686] R6is selected from

[0687]

[0688] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and L is a linker covalently attached to each of E and A1, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1may be independently selected from any one of formulae (A-VI)-(A-IX).

[0689] In some embodiments, the conjugate is described by formula (M-II):

[0690]

[0691] or a pharmaceutically acceptable salt thereof.

[0692] In some embodiments, the conjugate is described by formula (M-II-1):

[0693]

[0694] or a pharmaceutically acceptable salt thereof.

[0695] In some embodiments, the conjugate is described by formula (M-II-2):

[0696]

[0697] or a pharmaceutically acceptable salt thereof.

[0698] In some embodiments, the conjugate is described by formula (M-II-3):

[0699]

[0700] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0701] In some embodiments, the conjugate is described by formula (M-II-4):

[0702]

[0703] or a pharmaceutically acceptable salt thereof.

[0704] In some embodiments, the conjugate is described by formula (M-II-5):

[0705]

[0706] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0707] In some embodiments, the conjugate has the structure

[0708]

[0709] or a pharmaceutically acceptable salt thereof.

[0710] In some embodiments, the conjugate is described by formula (M-II-6):

[0711]

[0712] 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.

[0713] In some embodiments, the conjugate is described by formula (M-II-7):

[0714]

[0715] or a pharmaceutically acceptable salt thereof.

[0716] In some embodiments, the conjugate is described by formula (M-II-8):

[0717]

[0718] where L' is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0719] In some embodiments, the conjugate has the structure

[0720]

[0721] In some embodiments, the conjugate is described by formula (M-II-9):

[0722]

[0723] or a pharmaceutically acceptable salt thereof.

[0724] In some embodiments, the conjugate is described by formula (M-II-10):

[0725]

[0726] where L' is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0727] In some embodiments, the conjugate has the structure

[0728]

[0729] or a pharmaceutically acceptable salt thereof.

[0730] In some embodiments, the conjugate is described by formula (M-III):

[0731]

[0732] or a pharmaceutically acceptable salt thereof.

[0733] In some embodiments, the conjugate is described by formula (M-III-1):

[0734]

[0735] or a pharmaceutically acceptable salt thereof.

[0736] In some embodiments, the conjugate is described by formula (M-III-2):

[0737]

[0738] or a pharmaceutically acceptable salt thereof.

[0739] In some embodiments, the conjugate is described by formula (M-III-3):

[0740]

[0741] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0742] In some embodiments, the conjugate is described by formula (M-III-4):

[0743]

[0744] or a pharmaceutically acceptable salt thereof.

[0745] In some embodiments, the conjugate is described by formula (M-III-5):

[0746]

[0747] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0748] In some embodiments, the conjugate is described by formula (M-III-6):

[0749]

[0750] or a pharmaceutically acceptable salt thereof.

[0751] In some embodiments, the conjugate is described by formula (M-III-7):

[0752]

[0753] wherein L' is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0754] In some embodiments, the conjugate is described by formula (M-III-8):

[0755]

[0756]

[0757] or a pharmaceutically acceptable salt thereof.

[0758] In some embodiments, the conjugate is described by formula (M-III-9):

[0759]

[0760] wherein L' is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0761] In some embodiments, the conjugate is described by formula (M-IV):

[0762]

[0763] or a pharmaceutically acceptable salt thereof.

[0764] In some embodiments, the conjugate is described by formula (M-IV-1):

[0765]

[0766] or a pharmaceutically acceptable salt thereof.

[0767] In some embodiments, the conjugate is described by formula (M-IV-2):

[0768]

[0769] wherein L' is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0770] In some embodiments, the conjugate is described by formula (M-V):

[0771]

[0772] or a pharmaceutically acceptable salt thereof.

[0773] In some embodiments, the conjugate is described by formula (M-V-1):

[0774]

[0775] or a pharmaceutically acceptable salt thereof.

[0776] In some embodiments, the conjugate is described by formula (M-V-2):

[0777]

[0778] or a pharmaceutically acceptable salt thereof.

[0779] In some embodiments, the conjugate is described by formula (M-V-3):

[0780]

[0781] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0782] In some embodiments, the conjugate is described by formula (M-V-4):

[0783]

[0784] or a pharmaceutically acceptable salt thereof.

[0785] In some embodiments, the conjugate is described by formula (M-V-5):

[0786]

[0787] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0788] In some embodiments, the conjugate is described by formula (M-V-6):

[0789]

[0790] or a pharmaceutically acceptable salt thereof.

[0791] In some embodiments, the conjugate is described by formula (M-V-7):

[0792]

[0793] or a pharmaceutically acceptable salt thereof.

[0794] In some embodiments, the conjugate is described by formula (M-V-8):

[0795]

[0796] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0797] In some embodiments, the conjugate is described by formula (M-V-9):

[0798]

[0799] or a pharmaceutically acceptable salt thereof.

[0800] In some embodiments, the conjugate is described by formula (M-V-10):

[0801]

[0802] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0803] In some embodiments, the conjugate is described by formula (M-VI):

[0804]

[0805] or a pharmaceutically acceptable salt thereof.

[0806] In some embodiments, the conjugate is described by formula (M-VI-1):

[0807]

[0808] or a pharmaceutically acceptable salt thereof.

[0809] In some embodiments, the conjugate is described by formula (M-VI-2):

[0810]

[0811] or a pharmaceutically acceptable salt thereof.

[0812] In some embodiments, the conjugate is described by formula (M-VI-3):

[0813]

[0814] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0815] In some embodiments, the conjugate is described by formula (M-VI-4):

[0816]

[0817] or a pharmaceutically acceptable salt thereof.

[0818] In some embodiments, the conjugate is described by formula (M-VI-5):

[0819]

[0820] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0821] In some embodiments, the conjugate is described by formula (M-VI-6):

[0822]

[0823] or a pharmaceutically acceptable salt thereof.

[0824] In some embodiments, the conjugate is described by formula (M-VI-7):

[0825]

[0826] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0827] In some embodiments, the conjugate is described by formula (M-VI-8):

[0828]

[0829] or a pharmaceutically acceptable salt thereof.

[0830] In some embodiments, the conjugate is described by formula (M-VI-9):

[0831]

[0832]

[0833] wherein L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0834] In some embodiments, the conjugate is described by formula (M-VII):

[0835]

[0836] or a pharmaceutically acceptable salt thereof.

[0837] In some embodiments of any aspect described herein, R1is OH. In some embodiments of any aspect described herein, R1is NH2. In some embodiments of any aspect described herein, R1is -NHC(=NH)NH2.

[0838] In some embodiments, the conjugate is described by formula (M-VIII):

[0839]

[0840] or a pharmaceutically acceptable salt thereof.

[0841] In some embodiments, the conjugate is described by formula (M-VIII-1):

[0842]

[0843] or a pharmaceutically acceptable salt thereof.

[0844] In some embodiments, the conjugate is described by formula (M-VIII-2):

[0845]

[0846] or a pharmaceutically acceptable salt thereof.

[0847] In some embodiments, the conjugate is described by formula (M-VIII-3):

[0848]

[0849] wherein L' is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0850] In some embodiments, the conjugate is described by formula (M-VIII-4):

[0851]

[0852] or a pharmaceutically acceptable salt thereof.

[0853] In some embodiments, the conjugate is described by formula (M-VIII-5):

[0854]

[0855] wherein L' is the remainder of L, and y1 is an integer from 1-20, or a pharmaceutically acceptable salt thereof.

[0856] In some embodiments, the conjugate has the structure

[0857]

[0858] or a pharmaceutically acceptable salt thereof.

[0859] In some embodiments, the conjugate is described by formula (M-VIII-6):

[0860]

[0861] or a pharmaceutically acceptable salt thereof.

[0862] In some embodiments, the conjugate is described by formula (M-VIII-7):

[0863]

[0864] wherein L' is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0865] In some embodiments, the conjugate is described by formula (M-VIII-8):

[0866]

[0867] or a pharmaceutically acceptable salt thereof.

[0868] In some embodiments, the conjugate is described by formula (M-VIII-9):

[0869]

[0870] where L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0871] In some embodiments, the conjugate is described by formula (M-VIII-10):

[0872]

[0873] or a pharmaceutically acceptable salt thereof.

[0874] In some embodiments, the conjugate is described by formula (M-VIII-11):

[0875]

[0876] where L’ is the remainder of L, and y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0877] In some embodiments, the conjugate is described by formula (M-IX):

[0878]

[0879] or a pharmaceutically acceptable salt thereof.

[0880] In some embodiments, the conjugate is described by formula (M-IX-1):

[0881]

[0882] or a pharmaceutically acceptable salt thereof.

[0883] In some embodiments, the conjugate is described by formula (M-IX-2):

[0884]

[0885] or a pharmaceutically acceptable salt thereof.

[0886] In some embodiments, the conjugate is described by formula (M-IX-3):

[0887]

[0888] or a pharmaceutically acceptable salt thereof.

[0889] In some embodiments, the conjugate is described by formula (M-IX-4):

[0890]

[0891] or a pharmaceutically acceptable salt thereof.

[0892] In some embodiments, the conjugate is described by formula (M-IX-5):

[0893]

[0894] or a pharmaceutically acceptable salt thereof.

[0895] In some embodiments, the conjugate is described by formula (M-IX-6):

[0896]

[0897] or a pharmaceutically acceptable salt thereof.

[0898] In some embodiments, the conjugate is described by formula (M-X):

[0899]

[0900] or a pharmaceutically acceptable salt thereof.

[0901] In some embodiments, the conjugate is described by formula (M-X-1):

[0902]

[0903] or a pharmaceutically acceptable salt thereof.

[0904] In some embodiments, the conjugate is described by formula (M-X-2):

[0905]

[0906] or a pharmaceutically acceptable salt thereof.

[0907] In some embodiments, the conjugate is described by formula (M-X-3):

[0908]

[0909] or a pharmaceutically acceptable salt thereof.

[0910] In some embodiments of any of the aspects described herein, L or L’ comprises one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphato, phosphoryl, or imino, wherein R i is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0911] In some embodiments of any of the aspects described herein, the backbone of L or L’ consists of one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphato, phosphoryl, or imino, wherein R iH, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20alkynyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C3-C20cycloalkyl, optionally substituted C3-C20heterocycloalkyl, optionally substituted C4-C20cycloalkenyl, optionally substituted C4-C20heterocycloalkenyl, optionally substituted C8-C20cycloalkynyl, optionally substituted C8-C20heterocycloalkynyl, optionally substituted C5-C15aryl, or optionally substituted C2-C15heteroaryl.

[0912] In some embodiments of any aspect described herein, L or L’ is substituted with an oxo. In some embodiments, the backbone of L or L’ comprises no more than 250 atoms. In some embodiments, L or L’ is capable of forming an amide, carbamate, sulfonyl, or urea linkage. In some embodiments, L or L’ is a bond. In some embodiments, L or L’ is an atom. In some embodiments, L’ is a nitrogen atom.

[0913] In some embodiments, each L is described by formula (M-L-1):

[0914] 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

[0915] wherein: J 1 is a bond to A1; 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); Q 1 , Q 2 , Q 3 , Q 4 , and Q 5each of which is independently optionally substituted C1-C20alkylene, optionally substituted C1-C20heteroalkylene, optionally substituted C2-C20alkenylene, optionally substituted C2-C20heteroalkenylene, optionally substituted C2-C20alkynylene, optionally substituted C2-C20heteroalkynylene, optionally substituted C3-C20cycloalkylene, optionally substituted C3-C20heterocycloalkylene, optionally substituted C4-C20cycloalkenylene, optionally substituted C4-C20heterocycloalkenylene, optionally substituted C8-C20cycloalkynylene, optionally substituted C8-C20heterocycloalkynylene, optionally substituted C5-C15arylene, or optionally substituted C2-C15heteroarylene; T 1 , T 2 , T 3 , T 4 each of which is independently O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphato, phosphoryl, or imino; R i is H, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C2-C20alkenyl, optionally substituted C2-C20heteroalkenyl, optionally substituted C2-C20alkynyl, optionally substituted C2-C20heteroalkynyl, optionally substituted C3-C20cycloalkyl, optionally substituted C3-C20heterocycloalkyl, optionally substituted C4-C20cycloalkenyl, optionally substituted C4-C20heterocycloalkenyl, optionally substituted C8-C20cycloalkynyl, optionally substituted C8-C20heterocycloalkynyl, optionally substituted C5-C15aryl, or optionally substituted C2-C15heteroaryl; and g, h, i, j, k, l, m, n, and o are each independently 0 or 1; or a pharmaceutically acceptable salt thereof.

[0916] In some embodiments, J 2 may have two points of attachment to the Fc domain, Fc binding peptide, albumin, or albumin binding peptide (e.g., two J 2 ).

[0917] In some embodiments, L is

[0918]

[0919] wherein d is an integer from 1 to 20 (e.g., d is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).

[0920] In some embodiments, L is

[0921]

[0922]

[0923] wherein d and e are each independently an integer from 1 to 26; or a pharmaceutically acceptable salt thereof.

[0924] In some embodiments of any of the aspects described herein, L comprises a polyethylene glycol (PEG) linker. PEG linkers include linkers having the repeating unit structure (-CH2CH2O-) n , wherein n is an integer from 2 to 100. The polyethylene glycol linker can covalently join a neuraminidase inhibitor and E (e.g., in a conjugate of any of Formulas (M-I)-(M-X)). The polyethylene glycol linker can covalently join a first neuraminidase inhibitor and a second neuraminidase inhibitor (e.g., in a conjugate of any of Formulas (D-I)-(D-X)). The polyethylene glycol linker can covalently join a neuraminidase inhibitor dimer and E (e.g., in a conjugate of any of Formulas (D-I)-(D-X)). The polyethylene glycol linker can be selected from any of PEG2to 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 comprises a PEG linker, wherein L C is covalently attached to each of Q and E.

[0925] In some embodiments of any of the aspects described herein, R1is -NHC(=NH)NH2. In some embodiments of any of the aspects described herein, R2is -F. In some embodiments of any of the aspects described herein, R3is -F. In some embodiments of any of the aspects described herein, R4is -CO2H. In some embodiments of any of the aspects described herein, R5is -COCH3.

[0926] In some embodiments of any of the aspects described herein, L is covalently attached to a nitrogen atom of a surface-exposed lysine of E or L is covalently attached to a sulfur atom of a surface-exposed cysteine of E.

[0927] 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.

[0928] In some embodiments, n is 2, each E is an Fc domain monomer, each E dimerizes to form an Fc domain, and the conjugate is described by formula (D-I-1):

[0929]

[0930] where J is an Fc domain; and T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0931] In some embodiments, n is 2, each E is an Fc domain monomer, each E dimerizes to form an Fc domain, and the conjugate is described by formula (M-I-1):

[0932]

[0933] where J is an Fc domain; and T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.

[0934] In some embodiments of any of the aspects described herein, E has the sequence of any one of SEQ ID NOs: 1-68.

[0935] In some embodiments of any of the aspects described herein, E is an albumin, an albumin binding peptide, or an Fc binding peptide. In some embodiments where E is an albumin, an albumin binding peptide, or an Fc binding peptide, n is 1.

[0936] In some embodiments, n is 1, E is an albumin, an albumin binding peptide, or an Fc binding peptide and the conjugate is described by formula (D-I-2):

[0937]

[0938] where E is an albumin, an albumin binding peptide, or an Fc binding peptide; and T is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

[0939] In some embodiments, n is 1, E is an albumin, an albumin binding peptide, or an Fc binding peptide and the conjugate is described by formula (M-I-2):

[0940]

[0941] wherein E is albumin, an albumin-binding peptide, or an Fc-binding peptide; and T is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

[0942] In some embodiments of any of the aspects described herein, E is albumin having the sequence of any one of SEQ ID NOs: 69-71.

[0943] In some embodiments of any of the aspects described herein, T is 1, 2, 3, 4, or 5.

[0944] In another aspect, the present application provides a population of conjugates having the structure of any of the conjugates described herein (e.g., a population of conjugates having the structure of any one of Formulas (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I)), wherein the average value of T is from 1 to 20 (e.g., the average value of T is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20). In some embodiments, the average value of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0945] 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 one 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 than 10 different A1-L-A2 moieties. In some embodiments, E is conjugated to a first A1-L-A2 moiety and a second A1-L-A2 moiety. In some embodiments, A1 and A2 of the first A1-L-A2 moiety are independently selected from any one of Formulas (A-III)-(A-V):

[0946]

[0947] and A1 and A2 of the second A1-L-A2 moiety are independently selected from any one of Formulas (A-I), (A-II), (A-VI), (A-VII), (A-VIII), and (A-IX):

[0948]

[0949] In some embodiments, each of the first A1-L-A2 moieties is specifically conjugated to a lysine residue (e.g., a nitrogen atom of a surface-exposed lysine residue) of E, and each of the second A1-L-A2 moieties is specifically conjugated to a cysteine residue (e.g., a sulfur atom of a surface-exposed cysteine residue) of E. In some embodiments, each of the first A1-L-A2 moieties is specifically conjugated to a cysteine residue (e.g., a sulfur atom of a surface-exposed cysteine residue) of E, and each of the second A1-L-A2 moieties is specifically conjugated to a lysine residue (e.g., a nitrogen atom of a surface-exposed lysine residue) of E.

[0950] In some embodiments, the number of first A1-L-A2 moieties conjugated to E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the number of second A1-L-A2 moieties conjugated to E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0951] 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 than 10 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 of formulae (A-III)-(A-V):

[0952]

[0953] and A1 of the second A1-L moiety is selected from any of formulae (A-I), (A-II), (A-VI), (A-VII), (A-VIII), or (A-IX):

[0954]

[0955] In some embodiments, each of the first A1-L moieties is specifically conjugated to a lysine residue (e.g., a nitrogen atom of a surface-exposed lysine residue) of E, and each of the second A1-L moieties is specifically conjugated to a cysteine residue (e.g., a sulfur atom of a surface-exposed cysteine residue) of E. In some embodiments, each of the first A1-L moieties is specifically conjugated to a cysteine residue (e.g., a sulfur atom of a surface-exposed cysteine residue) of E, and each of the second A1-L moieties is specifically conjugated to a lysine residue (e.g., a nitrogen atom of a surface-exposed lysine residue) of E.

[0956] In some embodiments, the number of first A1-L moieties conjugated to E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the number of second A1-L moieties conjugated to E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0957] In another aspect, the present application provides a conjugate described by formula (D'-I):

[0958]

[0959] wherein each A1is independently selected from any one of formulae (A-III)-(A-V):

[0960]

[0961] wherein each A2is independently selected from any one of formulae (A-I), (A-II), (A-VI), (A-VII), (A-VIII), and (A-IX):

[0962]

[0963] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0964]

[0965] R6is selected from

[0966] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; n is 1 or 2; T1is an integer from 1 to 10 (e.g., T1is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L1is a linker covalently conjugated to E and each A1; T1is an integer from 1 to 10 (e.g., T1is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L2is a linker covalently conjugated to E and each A2; T2is an integer from 1 to 10 (e.g., T2is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), or a pharmaceutically acceptable salt thereof.

[0967] In some embodiments, each A1-L-A1is specifically conjugated to a lysine residue (e.g., a nitrogen atom of a surface-exposed lysine residue) of E, and each A2-L-A2is specifically conjugated to a cysteine residue (e.g., a sulfur atom of a surface-exposed cysteine residue) of E. In some embodiments, each A1-L-A1moiety is specifically conjugated to a cysteine residue (e.g., a sulfur atom of a surface-exposed cysteine residue) of E, and each A2-L-A2moiety is specifically conjugated to a lysine residue (e.g., a nitrogen atom of a surface-exposed lysine residue) of E.

[0968] In another aspect, the application provides a conjugate described by formula (M’-I):

[0969]

[0970] wherein each A1is independently selected from any one of formulas (A-III)-(A-V) (M-IX):

[0971]

[0972] wherein each A2is independently selected from any one of formulas (A-I), (A-II), (A-VI), (A-VII), (A-VIII), and (A-IX):

[0973]

[0974] wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[0975]

[0976] R6is selected from

[0977] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68), an albumin (e.g., an albumin having the sequence of any one of SEQ ID NOs: 69-71), an albumin-binding peptide, or an Fc-binding peptide; n is 1 or 2; T1is an integer from 1 to 10 (e.g., T1is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L1is a linker covalently conjugated to E and A1; T1is an integer from 1 to 10 (e.g., T1is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L2is a linker covalently conjugated to E and A2; T2is an integer from 1 to 10 (e.g., T2is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), or a pharmaceutically acceptable salt thereof.

[0978] In some embodiments, each A1-L is specifically conjugated to a lysine residue (e.g., a nitrogen atom of a surface-exposed lysine residue) of E, and each A2-L is specifically conjugated to a cysteine residue (e.g., a sulfur atom of a surface-exposed cysteine residue) of E. In some embodiments, each A1-L moiety is specifically conjugated to a cysteine residue (e.g., a sulfur atom of a surface-exposed cysteine residue) of E, and each A2-L moiety is specifically conjugated to a lysine residue (e.g., a nitrogen atom of a surface-exposed lysine residue) of E.

[0979] In another aspect, the application provides a pharmaceutical composition comprising any conjugate described herein (e.g., a conjugate of any one of formulae (1)-(5), (D-I)-(D-X), (D’-I), (M-I)-(M-X), or (M’-I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0980] In another aspect, the application provides a method for treating a subject having a viral infection or suspected of having a viral infection, the method comprising administering to the subject an effective amount of any of the conjugates or compositions described herein (e.g., a conjugate of any of formulae (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I)).

[0981] In another aspect, the application provides a method for prophylactically treating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the conjugates or compositions described herein (e.g., a conjugate of any of formulae (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I)).

[0982] In some embodiments, the viral infection is caused by an influenza virus or a parainfluenza virus. In some embodiments, the viral infection is an influenza A, B, or C virus or a parainfluenza virus.

[0983] In some embodiments, the subject is immunocompromised.

[0984] In some embodiments, the subject has been diagnosed with a humoral immunodeficiency, a T cell deficiency, neutropenia, asplenia, or a complement deficiency.

[0985] In some embodiments, the subject is being treated or is about to be treated with an immunosuppressive therapy.

[0986] In some embodiments, the subject has been diagnosed with a disease that causes immunosuppression. In some embodiments, the disease is a cancer or an acquired immunodeficiency syndrome. In some embodiments, the cancer is a leukemia, a lymphoma, or a multiple myeloma.

[0987] In some embodiments, the subject has been or is about to be subjected to a hematopoietic stem cell transplant.

[0988] In some embodiments, wherein the subject has been or is about to be subjected to an organ transplant.

[0989] In some embodiments, the conjugate or composition is administered intramuscularly, intravenously, intradermally, intra-arterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, transdermally, intratumorally, peritoneally, subcutaneously, subconjunctival, intracapsularly, mucosally, intrapericardially, intraumbilically, ocularly, orally, topically, by inhalation, by injection, or by infusion.

[0990] 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 oseltamivir, zanamivir, peramivir, laninamivir, amantadine, or rimantadine. In some embodiments, the second therapeutic agent is a viral vaccine. In some embodiments, the viral vaccine elicits an immune response in the subject against influenza A, influenza B, or influenza C virus, or parainfluenza virus.

[0991] In some embodiments, in any one of formulas (1)-(5), (D-I)-(D-X), (D’-I), (M-I)-(M-X), or (M’-I) (e.g., formula (1), (2), (3), (4), (5), (D-I), (D-II), (D-II-1), (D-II-2), (D-II-3), (D-II-4), (D-II-5), (D-II-6), (D-II-7), (D-II-8), (D-II-9), (D-II-10), (D-III), (D-III-1), (D-III-2), (D-III-3), (D-III-4), (D-III-5), (D-III-6), (D-III-7), (D-III-8), (D-III-9), (D-IV), (D-IV-1), (D-IV-2), (D-V), (D-V-1), (D-V-2), (D-V-3), (D-V-4), (D-V-5), (D-V-6), (D-V-7), (D-V-8), (D-V-9), (D-V-10), (D-VI), (D-VI-1), (D-VI-2), (D-VI-3), (D-VI-4), (D-VI-5), (D-VI-6), (D-VI-7), (D-VI-8), (D-VI-9), (D-VII), (D-VIII), (D-VIII-1), (D-VIII-2), (D-VIII-3), (D-VIII-4), (D-VIII-5), (D-VIII-6), (D-VIII-7), (D-VIII-8), (D-VIII-9), (D-VIII-10), (D-VIII-11), (D-IX), (D-IX-1), (D-IX-2), (D-IX-3), (D-IX-4), (D-IX-5), (D-IX-6), (D-X), (D-X-1), (D-X-2), (D-X-3), (D’-I), (M-I), (M-II), (M-II-1), (M-II-2), (M-II-3), (M-II-4), (M-II-5), (M-II-6), (M-II-7), (M-II-8), (M-II-9), (M-II-10), (M-III), (M-III-1), (M-III-2), (M-III-3), (M-III-4), (M-III-5), (M-III-6), (M-III-7), (M-III-8), (M-III-9), (M-IV), (M-IV-1), (M-IV-2), (M-V), (M-V-1), (M-V-2), (M-V-3), (M-V-4), (M-V-5),In any of the formulas described herein (e.g., any of formulas (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I)), when n is 1, E is an Fc domain-containing composition. In any of the formulas described herein (e.g., any of formulas (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I)), when n is 2, E is an Fc domain-containing composition.

[0992] In certain embodiments, the Fc domain-containing composition 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 immunobinding moiety known in the art, including antibody fragments (e.g., Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, scFv, or SMIP). The subunit structures and three-dimensional configurations of different classes of antibodies are known in the art. Antibody fragments can include binding moieties that include portions derived from or having significant homology to antibodies, 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.

[0993] In particular embodiments, the antibody or antibody fragment is a human, mouse, camelid (e.g., llama, alpaca, or camel), goat, sheep, rabbit, chicken, guinea pig, hamster, horse, or rat antibody or antibody fragment. In particular embodiments, the antibody is an IgG, IgA, IgD, IgE, IgM, or endosome. In certain embodiments, the antibody fragment includes a scFv, sdAb, dAb, Fab, Fab’, Fab’2, F(ab’)2, Fd, Fv, Feb, or SMIP.

[0994] In some embodiments, the Fc domain-comprising composition (e.g., antibody or antibody fragment) confers binding specificity to one or more targets (e.g., antigens).

[0995] In some embodiments, the one or more targets (e.g., antigens) bound by the Fc domain-comprising composition (e.g., antibody or antibody fragment) is a viral (e.g., influenza) protein, such as a 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-targeting antibodies include monoclonal antibodies, such as CR6261, CR8020, MEDI8852, MHAA4549A, and VIS410. In some embodiments, the antibody or antibody fragment is a broadly neutralizing antibody or antibody fragment targeting influenza hemagglutinin (e.g., an antibody or antibody fragment described in Wu et al., J. Mol. Biol. 429:2694-2709 (2017)). In some embodiments, the antibody or antibody fragment targets a viral matrix protein (e.g., a matrix 2 protein). TCN032 is a matrix 2 protein-targeting monoclonal antibody.

[0996] In some embodiments, the Fc domain-comprising composition (e.g., antibody or antibody fragment) includes one or more single domain antibodies (sdAb). In some embodiments, the Fc domain-comprising composition is an antibody or antibody fragment that includes a sdAb with influenza A reactivity, such as a sdAb that conjugates to hemagglutinin of influenza A (e.g., SD36 or SD38, described in Laursen et al., Science. 362:598-602 (2018)). In some embodiments, the Fc domain-comprising composition is an antibody or antibody fragment that includes a sdAb with influenza B reactivity, such as a sdAb that conjugates to hemagglutinin of influenza B (e.g., SD83 or SD84, described in Laursen et al., Science. 362:598-602 (2018)).

[0997] In some embodiments, the Fc-domain-containing composition 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 conjugated to hemagglutinin of influenza A and one or more sdAbs conjugated to hemagglutinin of influenza B. In some embodiments, the MDAb is JNJ-7445 (also known as MD3606), which is described in Laursen et al., Science. 362:598-602 (2018). In simple terms, JNJ-7445 is an MDAb comprising two sdAbs (SD36 and SD38) binding to influenza A hemagglutinin and two sdAbs (SD83 and SD84) binding to influenza B hemagglutinin, wherein the sdAbs are linked to the Fc domain (IgG1). These sdAbs are produced by immunizing llamas with influenza vaccine and H7 and H2 recombinant hemagglutinins.

[0998] In another aspect, the present invention includes any one of the formulas (1)-(5), (D-I)-(D-X), (D’-I), (M-I)-(M-X) or (M’-I) (e.g., formula (1), (2), (3), (4), (5), (D-I), (D-II), (D-II-1), (D-II-2), (D-II-3), (D-II-4), (D-II-5), (D-II-6), (D-II-7), (D-II-8), (D-II-9), (D-II-10), (D-III), (D-III-1), (D-III-2), (D-III-3), (D-III-4), (D-III-5), (D-III-6), (D-III-7), (D-III-8), (D-III-9), (D-IV), (D-IV-1), (D-IV-2), (D-V), (D-V-1), (D-V-2), (D-V-3), (D-V-4), (D-V-5), (D-V-6), (D-V-7), (D-V-8), (D-V-9), (D-V-10), (D-VI), (D-VI-1), (D-VI-2), (D-VI-3), (D-VI-4), (D-VI-5), (D-VI-6), (D-VI-7), (D-VI-8), (D-VI-9), (D-VII), (D-VIII), (D-VIII-1), (D-VIII-2), (D-VIII-3), (D-VIII-4), (D-VIII-5), (D-VIII-6), (D-VIII-7), (D-VIII-8), (D-VIII-9), (D-VIII-10), (D-VIII-11), (D-IX), (D-IX-1), (D-IX-2), (D-IX-3), (D-IX-4), (D-IX-5), (D-IX-6), (D-X), (D-X-1), (D-X-2), (D-X-3), (D’-I), (M-I), (M-II), (M-II-1), (M-II-2), (M-II-3), (M-II-4), (M-II-5), (M-II-6), (M-II-7), (M-II-8), (M-II-9), (M-II-10), (M-III), (M-III-1), (M-III-2), (M-III-3), (M-III-4), (M-III-5), (M-III-6), (M-III-7), (M-III-8), (M-III-9), (M-IV), (M-IV-1), (M-IV-2), (M-V), (M-V-1), (M-V-2), (M-V-3), (M-V-4), (M-V-5),the conjugates described in any of (M-V-6), (M-V-7), (M-V-8), (M-V-9), (M-V-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-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), (M-X), (M-X-1), (M-X-2), (M-X-3), or (M'-I), wherein E is an antibody or antibody fragment. In preferred embodiments wherein E is an antibody or antibody fragment, n is 1. In some embodiments, the antibody or antibody fragment comprises any of the antibodies or antibody fragments described herein, such as a monoclonal antibody conjugated to a viral hemagglutinin (e.g., CR6261, CR8020, MEDI8852, MHAA4549A, or VIS410); a broadly neutralizing antibody or antibody fragment targeting viral hemagglutinin (e.g., an antibody or antibody fragment described in Wu et al., J. Mol. Biol. 429: 2694-2709 (2017)); an sdAb targeting viral hemagglutinin (e.g., SD36, SD38, SD83, or SD84); or an MDAb or fragment thereof targeting viral hemagglutinin (e.g., JNJ-7445).

[0999] 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.

[1000] 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.

[1001] 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.

[1002] 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.

[1003] 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.

[1004] 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.

[1005] 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.

[1006] 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.

[1007] 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.

[1008] 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.

[1009] 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.

[1010] 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.

[1011] 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.

[1012] 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.

[1013] 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.

[1014] 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.

[1015] 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.

[1016] 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.

[1017] 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.

[1018] 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.

[1019] 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.

[1020] 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.

[1021] 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.

[1022] 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.

[1023] 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.

[1024] 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.

[1025] 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.

[1026] 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.

[1027] 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.

[1028] 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.

[1029] 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.

[1030] 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.

[1031] 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.

[1032] 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.

[1033] 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.

[1034] 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.

[1035] 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.

[1036] 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.

[1037] 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.

[1038] 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.

[1039] 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.

[1040] 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.

[1041] 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.

[1042] 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.

[1043] 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.

[1044] 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.

[1045] 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.

[1046] 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.

[1047] 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.

[1048] 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.

[1049] 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.

[1050] 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.

[1051] 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.

[1052] 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.

[1053] 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.

[1054] 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.

[1055] 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.

[1056] 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.

[1057] 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.

[1058] 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.

[1059] 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.

[1060] 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.

[1061] 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.

[1062] 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.

[1063] 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.

[1064] 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.

[1065] 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.

[1066] 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.

[1067] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 70. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 70.

[1068] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 71. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71.

[1069] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 71. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71.

[1070] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 71. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71.

[1071] In some embodiments of any of the aspects described herein in which E comprises an Fc domain monomer, the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68) comprises a mutation corresponding to N434H. As used herein, it is understood that an amino acid “corresponding to” (e.g., of a particular SEQ ID NO.) a particular amino acid residue includes any amino acid residue that one of skill in the art would understand to align with the particular residue (e.g., of the particular sequence). For example, any of SEQ ID NO: 1-68 can be mutated to include an N434H mutation.

[1072] In some embodiments of any of the aspects described herein in which E comprises an Fc domain monomer, the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68) comprises a mutation corresponding to C220S. As used herein, it is understood that an amino acid “corresponding to” (e.g., of a particular SEQ ID NO.) a particular amino acid residue includes any amino acid residue that one of skill in the art would understand to align with the particular residue (e.g., of the particular sequence). For example, any of SEQ ID NO: 1-68 can be mutated to include a C220S mutation.

[1073] In some embodiments of any of the aspects described herein in which E comprises an Fc domain monomer, the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68) is a fragment of the Fc domain monomer (e.g., a fragment of at least 25 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more), at least 50 (e.g., 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 or more), at least 75 (e.g., 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more) contiguous amino acids long of any of SEQ ID NO: 1-68.

[1074] In some embodiments of any of the aspects described herein (e.g., the conjugate of any of Formulas (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), 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 conjugated to a linker (e.g., PEG2-PEG 20 The linker conjugated to E can be functionalized such that it can react to form a covalent bond with any A1-L or L of any A2-L-A1 described herein. In preferred embodiments, E is conjugated to a linker functionalized with an azide group and A1-L or L of any A2-L-A1 is functionalized with an alkyne group. The linker-azide of E and the linker-alkyne of A1-L or A2-L-A1 conjugate (e.g., by click chemistry) to form a conjugate of the application, such as described by any of Formulas (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I). In other embodiments, E is conjugated to a linker functionalized with an alkyne group and any A1-L or L of any A2-L-A1 is functionalized with an azide group. The linker-alkyne of E and the linker-azide of A1-L or A2-L-A1 conjugate (e.g., by click chemistry) to form a conjugate of the application, such as described by any of Formulas (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I).

[1075] In some embodiments of any of the aspects described herein, the wavy line of any of Formulas (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I) can represent a covalent bond between E and L of A1-L or A2-L-A1.

[1076] In some embodiments of any of the aspects described herein, the wavy line of any of Formulas (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I) can represent one or more amino acid side chains of E (e.g., one or more nitrogen atoms of one or more surface-exposed lysine residues of E or one or more sulfur atoms of one or more surface-exposed cysteines in E) have been conjugated to a linker (e.g., PEG2-PEG 20 In some embodiments of any of the aspects described herein, A1 and / or A2 has the structure described by (A-I):

[1077]

[1078] In preferred embodiments, wherein A1and / or A2has a structure described by (A-I): R1is -NHC(=NH)NH2, R4is -CO2H, R5is -COCH3, and / or X is -O-. In preferred embodiments, A1and / or A2has a structure described by the following formula for Zanamivir:

[1079]

[1080] In some embodiments of any of the aspects described herein, A1and / or A2has a structure described by (A-II):

[1081]

[1082] In preferred embodiments, wherein A1and / or A2has a structure described by (A-II): R1is -NHC(=NH)NH2, R2is H or F, R3is H or F, R4is -CO2H, R5is -COCH3, and / or X is -O-. In preferred embodiments, A1and / or A2has a structure described by the following formula:

[1083]

[1084] In some embodiments of any of the aspects described herein, A1and / or A2has a structure described by (A-III):

[1085]

[1086] In preferred embodiments, wherein A1and / or A2has a structure described by (A-III): R1is -NHC(=NH)NH2, R4is -CO2H, and / or R5is -COCH3. In preferred embodiments, A1and / or A2has a structure described by the following formula for Peramivir:

[1087]

[1088] In some embodiments of any of the aspects described herein, A1and / or A2has a structure described by (A-IV):

[1089]

[1090] In preferred embodiments, wherein A1and / or A2has a structure described by (A-IV): R1is -NHC(=NH)NH2, R4is -CO2H, and / or R5is -COCH3. In preferred embodiments, A1and / or A2has a structure described by the following formula:

[1091]

[1092] In some embodiments of any of the aspects described herein, A1and / or A2has a structure described by (A-V):

[1093]

[1094] In preferred embodiments, wherein A1and / or A2has a structure described by (A-V): R1is -NHC(=NH)NH2, R4is -CO2H, and / or R5is -COCH3. In preferred embodiments, A1and / or A2has a structure described by the formula:

[1095]

[1096] In some embodiments of any of the aspects described herein, A1and / or A2has a structure described by (A-VI):

[1097]

[1098] In preferred embodiments, wherein A1and / or A2has a structure described by (A-VI): R1is -NHC(=NH)NH2, R4is -CO2H, R5is -COCH3, and / or X is -O-. In preferred embodiments, A1and / or A2has a structure described by the formula for zanamivir:

[1099]

[1100] In some embodiments of any of the aspects described herein, A1and / or A2has a structure described by (A-VII):

[1101]

[1102] In preferred embodiments, wherein A1and / or A2has a structure described by (A-VII): R1is -NHC(=NH)NH2, R2is H or F, R3is H or F, R4is -CO2H, R5is -COCH3, and / or X is -O-. In preferred embodiments, A1and / or A2has a structure described by the formula:

[1103]

[1104] In some embodiments of any of the aspects described herein, A1and / or A2has a structure described by (A-VIII):

[1105]

[1106] In preferred embodiments, wherein A1and / or A2has a structure described by (A-VIII): R1is -NHC(=NH)NH2, R5is -COCH3, and / or X is -O-. In preferred embodiments, A1and / or A2has a structure described by the formula:

[1107]

[1108] In some embodiments of any of the aspects described herein, A1and / or A2has a structure described by (A-IX):

[1109]

[1110] In preferred embodiments, wherein A1and / or A2has a structure described by (A-IX): R1is -NHC(=NH)NH2, R2is H or F, R3is H or F, R5is -COCH3, and / or X is -O-. In preferred embodiments, A1and / or A2has a structure described by the formula:

[1111]

[1112] In some embodiments of any of the aspects described herein, A1and / or A2has a structure described by (A-X):

[1113]

[1114] In preferred embodiments, wherein A1and / or A2has a structure described by (A-X): R1is -NHC(=NH)NH2, R3is H, R5is -COCH3, and / or X is -O-. In preferred embodiments, A1and / or A2has a structure described by the formula:

[1115]

[1116] In some embodiments of any of the aspects described herein, A1and / or A2has a structure described by (A-XI):

[1117]

[1118] In preferred embodiments, wherein A1and / or A2has a structure described by (A-XI): R4is -CO2H, and / or R5is -COCH3. In preferred embodiments, the olefin is (E), (Z), or a racemic mixture of (E) / (Z). In preferred embodiments, A1and / or A2has a structure described by the formula:

[1119]

[1120] In some embodiments of any of the aspects described herein, A1and / or A2has a structure described by (A-XII):

[1121]

[1122] In preferred embodiments, wherein A1and / or A2has a structure described by (A-XII): R4is -CO2H. In preferred embodiments, A1and / or A2has an A-315675 (Abbott) structure described by the following formula:

[1123]

[1124] In some embodiments, the conjugate is Conjugate 1 or any regioisomer thereof, and the drug-to-antibody ratio (DAR) (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1125] In some embodiments, the conjugate is Conjugate 2 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1126] In some embodiments, the conjugate is Conjugate 3 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1127] In some embodiments, the conjugate is Conjugate 4 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1128] In some embodiments, the conjugate is Conjugate 5 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1129] In some embodiments, the conjugate is Conjugate 6 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1130] In some embodiments, the conjugate is Conjugate 7 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1131] In some embodiments, the conjugate is Conjugate 8 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1132] In some embodiments, the conjugate is Conjugate 9 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1133] In some embodiments, the conjugate is Conjugate 10 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1134] In some embodiments, the conjugate is Conjugate 11 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1135] In some embodiments, the conjugate is Conjugate 12 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1136] In some embodiments, the conjugate is Conjugate 13 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1137] In some embodiments, the conjugate is Conjugate 14 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1138] In some embodiments, the conjugate is Conjugate 15 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1139] In some embodiments, the conjugate is Conjugate 16 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1140] In some embodiments, the conjugate is Conjugate 17 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1141] In some embodiments, the conjugate is Conjugate 18 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1142] In some embodiments, the conjugate is Conjugate 19 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1143] In some embodiments, the conjugate is Conjugate 20 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1144] In some embodiments, the conjugate is Conjugate 21 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1145] In some embodiments, the conjugate is Conjugate 22 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1146] In some embodiments, the conjugate is Conjugate 23 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1147] In some embodiments, the conjugate is Conjugate 24 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1148] In some embodiments, the conjugate is Conjugate 25 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1149] In some embodiments, the conjugate is Conjugate 26 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1150] In some embodiments, the conjugate is Conjugate 27 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1151] In some embodiments, the conjugate is Conjugate 28 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1152] In some embodiments, the conjugate is Conjugate 29 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1153] In some embodiments, the conjugate is Conjugate 30 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1154] In some embodiments, the conjugate is Conjugate 31 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1155] In some embodiments, the conjugate is Conjugate 32 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1156] In some embodiments, the conjugate is Conjugate 33 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1157] In some embodiments, the conjugate is Conjugate 34 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1158] In some embodiments, the conjugate is Conjugate 35 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1159] In some embodiments, the conjugate is Conjugate 36 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1160] In some embodiments, the conjugate is Conjugate 37 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1161] In some embodiments, the conjugate is Conjugate 38 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1162] In some embodiments, the conjugate is Conjugate 39 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1163] In some embodiments, the conjugate is Conjugate 40 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1164] In some embodiments, the conjugate is Conjugate 41 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1165] In some embodiments, the conjugate is Conjugate 42 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1166] In some embodiments, the conjugate is Conjugate 43 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In some embodiments, the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.

[1167] Definitions

[1168] To facilitate the understanding of this application, a number of terms are defined below. The terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present application. Terms such as "a", "an" and "the" are not intended to refer to only a singular entity, but include the general class of which a specific example can be used for illustration. The terminology herein, "one example", "an example" or "one embodiment" means that a particular feature, structure, or characteristic described in connection with the example is included in at least one embodiment of the application. The appearances of the phrase "in one example" in various places in the specification are not necessarily all referring to the same example, nor are they necessarily referring to one example.

[1169] As used herein, the term “neuraminidase inhibitor” or “viral neuraminidase inhibitor” refers to a compound that reduces the activity of the enzyme influenza virus neuraminidase (e.g., from an influenza virus of type A, type B, or type C). A neuraminidase inhibitor can be identified by methods known to one of skill in the art, for example, by a reduction in viral replication in an influenza virus plaque reduction assay, for example, at a concentration of less than 20 µM (e.g., less than 10 µM, 5 µM, 2 µM, 1 µM, 500 nM, or 100 nM). Viral neuraminidase inhibitors known to one of skill in the art include zanamivir, sulfo-zanamivir, peramivir, and A-315675 (Abbott) (see, e.g., Hadházi 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 strain of influenza virus neuraminidases and influenza virus replication. Antimicrobial Agents and Chemotherapy 46(4):1014-1021 (2002)). Viral neuraminidase inhibitors of the present invention include zanamivir, sulfo-zanamivir, peramivir, A-315675, and analogs thereof, such as the viral neuraminidase inhibitors of formula (A-I) - (A-XII):

[1170]

[1171] wherein R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5 is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from

[1172]

[1173] R6 is selected from

[1174] R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl and C2-C15heteroaryl; and R8is selected from C3-C20heterocycloalkyl, C5-C15aryl and C2-C15heteroaryl.

[1175] As used herein, the term "inhibits neuraminidase activity" means an IC 50 , for example, as measured according to the neuraminidase inhibition assay in Example 2 herein. In particular, IC 50 denotes the concentration of an influenza virus neuraminidase inhibitor required for 50% inhibition in vitro. In some aspects, an IC 50 indicates a compound that inhibits neuraminidase activity.

[1176] "Viral infection" means the pathogenic growth of a virus (e.g., an influenza virus) in a host organism (e.g., a human subject). A viral infection can be any situation in which the presence of a viral population is impairing the host body. Thus, a subject is "suffering from" a viral infection when there is an excess viral population in or on the subject's body, or when the presence of the viral population is impairing the subject's cells or other tissues.

[1177] As used herein, the term "Fc domain monomer" refers to a polypeptide chain comprising at least one hinge domain and a second and third antibody constant domains (C H 2 and C H3) or a functional fragment thereof (e.g., a fragment capable of (i) dimerizing with another Fc domain monomer to form an Fc domain, and (ii) binding to an Fc receptor. The Fc domain monomer can be any immunoglobulin antibody isotype, including IgG, IgE, IgM, IgA, or IgD (e.g., IgG). Additionally, the Fc domain monomer can be an IgG subtype (e.g., IgGl, IgG2a, IgG2b, IgG3, or IgG4) (e.g., IgGl). An Fc domain monomer does not include any portion of an immunoglobulin that is capable of acting as an antigen-recognition region, such as a variable domain or a complementarity determining region (CDR). An Fc domain monomer in a conjugate as described herein can contain one or more alterations (e.g., 1-10, 1-8, 1-6, 1-4 amino acid substitutions, additions, or deletions) relative to a wild-type Fc domain monomer sequence that alter the interaction between the Fc domain and an Fc receptor. Examples of suitable alterations are known in the art. In certain embodiments, a human Fc domain monomer (e.g., an IgG heavy chain, such as IgGl) comprises a region extending from any of Asn208, Glu216, Asp221, Lys222, or Cys226 to the heavy chain carboxyl terminus at Lys447. The C-terminal Lys447 of the Fc region can or can not be present without affecting the structure or stability of the Fc region. Unless otherwise specified herein, the numbering of amino acid residues in the IgG or Fc domain monomer is in accordance with the EU numbering system for antibodies, also referred to as the Kabat EU index, as described in, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[1178] As used herein, the term "Fc domain" refers to a dimer of two Fc domain monomers that is capable of binding to an Fc receptor. In a wild-type Fc domain, the two Fc domain monomers are linked by two C H 3The two Fc domain monomers are dimerized by interactions between antibody constant domains, and in some embodiments, one or more disulfide bonds are formed between the hinge domains of the two dimerized Fc domain monomers.

[1179] The term "covalently attached" refers to two moieties in a conjugate that are connected to each other by a covalent bond formed between two atoms in the two moieties of the conjugate.

[1180] As used herein, the term "Fc binding peptide" refers to a polypeptide having an amino acid sequence of 5 to 50 (e.g., 5 to 40, 5 to 30, 5 to 20, 5 to 15, 5 to 10, 10 to 50, 10 to 30, or 10 to 20) amino acid residues that has affinity for and functionality of binding to an Fc domain (such as any Fc domain described herein). An Fc binding peptide peptide can be of different origin, e.g., synthetic, human, mouse, or rat. Fc binding peptides of the present invention include Fc binding peptides that have been engineered to include one or more (e.g., two, three, four, or five) solvent-exposed cysteine or lysine residues, which can provide a site for conjugation to a compound of the present invention (e.g., to a neuraminidase inhibitor monomer or dimer, including by way of a linker). Most preferably, the Fc binding peptide will contain a single solvent-exposed cysteine or lysine, thus enabling site-specific conjugation of a compound of the present invention. An Fc binding peptide can include only naturally occurring amino acid residues, or can include one or more non-naturally occurring amino acid residues. Where included, a non-naturally occurring amino acid residue (e.g., the side chain of a non-naturally occurring amino acid residue) can serve as an attachment point for a compound of the present invention (e.g., a neuraminidase inhibitor monomer or dimer, including by way of a linker). Fc binding peptides of the present invention can be linear or cyclic. Fc binding peptides of the present invention include any Fc binding peptide known to one of skill in the art.

[1181] As used herein, the term "albumin" refers to a polypeptide comprising amino acids corresponding to a naturally occurring albumin (e.g., human serum albumin) or a variant thereof, such as an engineered variant of a naturally occurring albumin. Variants of albumin include polymorphisms, fragments such as domains and subdomains, and fusion proteins (e.g., albumin with a C-terminal or N-terminal fusion such as a polypeptide linker). Preferably, the albumin has the amino acid sequence of human serum albumin (HSA) or a variant or fragment thereof, most preferably the amino acid sequence of a functional variant or fragment thereof. Albumins of the application 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: 69-71. Albumins of the application include albumins that have been engineered to include one or more (e.g., two, three, four, or five) solvent-exposed cysteine or lysine residues, which can provide sites for conjugation to a compound of the application (e.g., to a neuraminidase inhibitor monomer or dimer, including by way of a linker). Most preferably, the albumin will contain a single solvent-exposed cysteine or lysine, thus enabling site-specific conjugation of a compound of the application. The albumin can include only naturally occurring amino acid residues, or can include one or more non-naturally occurring amino acid residues. Where included, the non-naturally occurring amino acid residues (e.g., the side chains of non-naturally occurring amino acid residues) can serve as attachment points for a compound of the application (e.g., a neuraminidase inhibitor monomer or dimer, including by way of a linker).

[1182] As used herein, the term "albumin binding peptide" refers to a polypeptide having an amino acid sequence of 5 to 50 (e.g., 5 to 40, 5 to 30, 5 to 20, 5 to 15, 5 to 10, 10 to 50, 10 to 30, or 10 to 20) amino acid residues that has affinity for albumin (such as any albumin described herein) and has the function of binding said albumin. Preferably, the albumin binding peptide is conjugated to a naturally occurring serum albumin, most preferably human serum albumin. The albumin binding peptide can be of different origin, e.g., synthetic, human, mouse, or rat. Albumin binding peptides of the present invention include albumin binding peptides that have been engineered to include one or more (e.g., two, three, four, or five) solvent-exposed cysteine or lysine residues, which can provide a site for conjugation to a compound of the present invention (e.g., to a neuraminidase inhibitor monomer or dimer, including by way of a linker). Most preferably, the albumin binding peptide will contain a single solvent-exposed cysteine or lysine, thus enabling site-specific conjugation of a compound of the present invention. The albumin binding peptide can include only naturally occurring amino acid residues, or can include one or more non-naturally occurring amino acid residues. Where included, the non-naturally occurring amino acid residues (e.g., the side chains of non-naturally occurring amino acid residues) can serve as attachment points for a compound of the present invention (e.g., a neuraminidase inhibitor monomer or dimer, including by way of a linker). Albumin binding peptides of the present invention can be linear or cyclic. Albumin binding peptides of the present invention include any albumin binding peptide known to one of skill in the art, examples of which are provided herein. Further exemplary albumin binding peptides are provided in U.S. Patent Application No. 2005 / 0287153, which is incorporated herein by reference in its entirety.

[1183] As used herein, a "surface-exposed amino acid" or "solvent-exposed amino acid," such as a surface-exposed cysteine or surface-exposed lysine, refers to an amino acid that is accessible to the solvent surrounding the protein. The surface-exposed amino acid can be naturally occurring, or an engineered variant (e.g., substitution or insertion) of the protein. In some embodiments, the surface-exposed amino acid is one that, when substituted, does not substantially alter the three-dimensional structure of the protein.

[1184] As used herein, the terms "linker," "L," and "L'" refer to a covalent linkage between two or more components in a conjugate (e.g., between two neuraminidase inhibitors in a conjugate described herein, between a neuraminidase inhibitor and an Fc domain or albumin in a conjugate described herein, and between a dimer of two neuraminidase inhibitors and an Fc domain or albumin in a conjugate described herein). In some embodiments, a conjugate described herein can contain a linker having a trivalent structure (e.g., a trivalent linker). A trivalent linker has three arms, wherein each arm is covalently linked to a component of the conjugate (e.g., a first arm conjugated to a first neuraminidase inhibitor, a second arm conjugated to a second neuraminidase inhibitor, and a third arm conjugated to an Fc domain or albumin).

[1185] Molecules useful as linkers include at least two functional groups, which can be the same or different, such as two carboxylic acid groups, two amino 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 amino group, a carboxylic acid group and a sulfonic acid group, an amino group and a maleimide group, an amino group and an alkyne group, or an amino group and a sulfonic acid group. A first functional group can form a covalent linkage to a first component in the conjugate and a second functional group can form a covalent linkage to a second component in the conjugate. In some embodiments of a trivalent linker, two arms of the linker can contain two dicarboxylic acids, where a first carboxylic acid can form a covalent linkage to a first neuraminidase inhibitor in the conjugate and a second carboxylic acid can form a covalent linkage to a second neuraminidase inhibitor in the conjugate and a third arm of the linker can form a covalent linkage to an Fc domain or albumin in the conjugate. Examples of dicarboxylic acids are further described herein. In some embodiments, molecules containing one or more maleimide groups can be used as linkers, where the maleimide group can form a carbon-sulfur linkage to a cysteine of a component (e.g., an Fc domain or albumin) in the conjugate. In some embodiments, molecules containing one or more alkyne groups can be used as linkers, where the alkyne group can form a 1,2,3-triazole linkage to an azide of a component (e.g., an Fc domain or albumin) in the conjugate. In some embodiments, molecules containing one or more azido groups can be used as linkers, where the azido group can form a 1,2,3-triazole linkage to an alkyne of a component (e.g., an Fc domain or albumin) in the conjugate. In some embodiments, molecules containing one or more disulfide groups can be used as linkers, where the disulfide group can form a linkage to an amino group of a component (e.g., an Fc domain or albumin) in the conjugate. In some embodiments, molecules containing one or more sulfonic acid groups can be used as linkers, where the sulfonic acid group can form a sulfonamide linkage to a component in the conjugate. In some embodiments, molecules containing one or more isocyanate groups can be used as linkers, where the isocyanate group can form a urea linkage to a component in the conjugate. In some embodiments, molecules containing one or more haloalkyl groups can be used as linkers, where the haloalkyl group can form a covalent linkage, such as a C-N and C-O linkage, to a component in the conjugate.

[1186] 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, a N-N bond, a C-S bond, or any kind of bond resulting from a chemical reaction, e.g., chemical conjugation. In some embodiments, a linker comprises no more than 250 atoms. In some embodiments, a linker comprises no more than 250 non-hydrogen atoms. In some embodiments, a backbone of a linker comprises no more than 250 atoms. A “backbone” of a linker refers to atoms in a linker that, taken together, form the shortest path from one part of a conjugate to another part of the conjugate (e.g., the shortest path connecting a first neuraminidase inhibitor and a second neuraminidase inhibitor). Atoms in the backbone of a linker directly participate in connecting one part of a conjugate to another part of the conjugate (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 directly participate in connecting one part of a conjugate to another part of the conjugate.

[1187] In some embodiments, a linker can comprise a synthetic group derived from, e.g., a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer). In some embodiments, a linker can comprise one or more amino acid residues, such as D- or L-amino acid residues. In some embodiments, a linker can be a residue of an amino acid sequence (e.g., a sequence of 1-25 amino acids, 1-10 amino acids, 1-9 amino acids, 1-8 amino acids, 1-7 amino acids, 1-6 amino acids, 1-5 amino acids, 1-4 amino acids, 1-3 amino acids, 1-2 amino acids, or 1 amino acid). In some embodiments, a linker can comprise one or more (e.g., 1-100, 1-50, 1-25, 1-10, 1-5, or 1-3) optionally substituted alkylene, optionally substituted heteroalkylene (e.g., a PEG unit), 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 iH, 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, phosphato, phosphoryl, or imino. For example, the linker can comprise one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene (e.g., PEG units), optionally substituted C2-C20 alkenylene (e.g., C2 alkenylene), optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene (e.g., C6 arylene), optionally substituted C2-C15 heteroarylene (e.g., imidazole, pyridine), O, S, NR i (R i 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, phosphato, phosphoryl, or imino.

[1188] As used herein, the terms "alkyl," "alkenyl," and "alkynyl" include straight-chain and branched-chain monovalent substituents, as well as combinations thereof, containing only C and H when unsubstituted. When an alkyl group includes at least one carbon-carbon double bond or carbon-carbon triple bond, the alkyl group can be referred to as an "alkenyl" or "alkynyl," respectively. The monovalence of an alkyl, alkenyl, or alkynyl group does not include optional substituents present on the alkyl, alkenyl, or alkynyl group. For example, if an alkyl, alkenyl, or alkynyl group is attached to a compound, the monovalence of the alkyl, alkenyl, or alkynyl group refers to its attachment to the compound and does not include any additional substituents that can be present on the alkyl, alkenyl, or alkynyl group. In some embodiments, an alkyl or heteroalkyl group can contain, for example, 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., Ci-C2o, Ci-Cis, Ci-Ci6, Ci-Ci4, Ci-Ci2, Ci-Cio, Ci-C8, Ci-C6, Ci-C4, or Ci-C2). In some embodiments, an alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl group can contain, for example, 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C2o, C2-Cis, C2-Ci6, C2-Ci4, C2-Ci2, C2-Cio, C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, t-butyl, 2-propenyl, and 3-butynyl.

[1189] As used herein, the term "cycloalkyl" denotes a monovalent saturated or unsaturated non-aromatic cycloalkyl group. Cycloalkyl groups can have, for example, three to twenty carbons (e.g., C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. When a cycloalkyl group includes at least one carbon-carbon double bond, the cycloalkyl group can be referred to as a "cycloalkenyl." Cycloalkenyl groups can have, for example, four to twenty carbons (e.g., C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. When a cycloalkyl group includes at least one carbon-carbon triple bond, the cycloalkyl group can be referred to as a "cycloalkynyl." Cycloalkynyl groups can have, for example, eight to twenty carbons (e.g., C8-C9, C8-C10, C8-C11, C8-C12, C8-C14, C8-C16, C8-C18, or C8-C20 cycloalkynyl). The term "cycloalkyl" also includes cyclic compounds having bridged polycyclic ring structures, in which one or more carbon bridges two non-adjacent members of a monocyclic 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. As used herein, the term "aryl" refers to any monocyclic or fused bicyclic or tricyclic ring system having aromatic character in the ring system in terms of electronic distribution, such as phenyl, naphthyl, or phenanthrene. In some embodiments, the ring system contains 5-15 ring member atoms or 5-10 ring member atoms. Aryl groups can have, for example, five to fifteen 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 (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms selected from O, S, and N. Heteroaryl groups can have, for example, two to fifteen carbons (e.g., C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C2-C11, C2-C12, C2-C13, C2-C14, or C2-C15 heteroaryl). The inclusion of heteroatoms allows for the inclusion of 5-membered rings as well as 6-membered rings that would be considered aromatic. Thus, typical heteroaryl systems include, for example, pyridyl, pyrimidinyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolinyl, benzothiazolyl, benzofuranyl, thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzisoxazolyl, and imidazolyl.Because tautomers are possible, groups such as phthalimido are also considered heteroaryl groups. In some embodiments, aryl or heteroaryl is a 5- or 6-membered aromatic ring system optionally containing 1-2 nitrogen atoms. In some embodiments, aryl or heteroaryl is optionally substituted phenyl, pyridyl, indolyl, pyrimidinyl, pyridazinyl, benzothiazolyl, benzoimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, or imidazopyridinyl. In some embodiments, aryl is phenyl. In some embodiments, aryl can be optionally substituted with substituents such as aryl substituents (e.g., biphenyl).

[1190] The term "alkaryl" refers to an aryl group attached to an alkylene, alkenylene, or alkynylene group. In general, if a compound is attached to an alkaryl group, the alkylene, alkenylene, or alkynylene portion of the alkaryl group is attached to the compound. In some embodiments, 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 indicates the total number of carbons in the aryl portion and the alkylene, alkenylene, or alkynylene portion of the alkaryl group. Examples of alkaryl groups include, but are not limited to, (C1-C8)alkylene(C6-C12)aryl, (C2-C8)alkenylene(C6-C12)aryl, or (C2-C8)alkynylene(C6-C12)aryl. In some embodiments, alkaryl is benzyl or phenethyl. In heteroalkaryl groups, one or more heteroatoms selected from N, O, and S can be present in the alkylene, alkenylene, or alkynylene portion of the alkaryl group and / or can be present in the aryl portion of the alkaryl group. In optionally substituted alkaryl groups, substituents can be present on the alkylene, alkenylene, or alkynylene portion of the alkaryl group and / or can be present on the aryl portion of the alkaryl group.

[1191] As used herein, the term "amino" means -N(R x )2or -N + (R x )3, where each R x is independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x groups combine to form a heterocycloalkyl group. In some embodiments, amino is -NH2.

[1192] As used herein, the term "alkylamino" refers to an amino group as described herein attached to an alkylene (e.g., C1-C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene (e.g., C2-C5 alkynylene) group. In general, if a compound is attached to an alkylamino group, the alkylene, alkenylene, or alkynylene portion of the alkylamino group is attached to the compound. The amino portion of an alkylamino group refers to -N(R x )2or -N+ (R x )3, where R x Each can be independently H, alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, or two R groups. x The combination forms a heterocyclic alkyl group. In some embodiments, the amino moiety of the alkylamino group is -NH2. Examples of alkylamino groups are C1-C5 alkylamino groups, such as C2 alkylamino groups (e.g., CH2CH2NH2 or CH2CH2N(CH3)2). In the heteroalkylamino group, one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms selected from N, O, and S may be present in the alkylene, alkenyl, or ynylene moiety of the heteroalkylamino group. In some embodiments, the alkylamino group may optionally be substituted. In substituted alkylamino groups, substituents may be present on the alkylene, alkenyl, or ynylene moiety of the alkylamino group and / or may be present on the amino moiety of the alkylamino group.

[1193] As used herein, the term "alkamide" refers to an amide group attached to an alkylene (e.g., C1-C5 alkylene), an alkenyl (e.g., C2-C5 alkenyl), or an alkyne (e.g., C2-C5 alkenyl). Generally, if a compound is attached to an alkamide group, the alkylene, alkenyl, or alkyne portion of the alkamide is attached to the compound. The amide moiety of an alkamide refers to –C(O)-N(R) x )2, where R x Each can be independently H, alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, or two R groups. x The alkamids combine to form heterocyclic alkyl groups. In some embodiments, the amide moiety of the alkamid is -C(O)NH2. The alkamid group may be -(CH2)2-C(O)NH2 or -CH2-C(O)NH2. In the heteroalkamid group, one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms selected from N, O, and S may be present in the alkylene, alkenyl, or ynylene moiety of the heteroalkamid group. In some embodiments, the alkamid group may optionally be substituted. In substituted alkamid groups, the substituent may be present on the alkylene, alkenyl, or ynylene moiety of the alkamid group and / or may be present on the amide moiety of the alkamid group.

[1194] As used herein, the terms "alkylene," "alkenylene," and "alkynylene" refer to divalent groups of the specified size. In some embodiments, an alkylene can contain, for example, 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., Ci-C2o, Ci-Cis, Ci-Ci6, Ci-Ci4, Ci-Ci2, Ci-Cio, Ci-C8, Ci-C6, Ci-C4, or Ci-C2). In some embodiments, an alkenylene or alkynylene can contain, for example, 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C2o, C2-Cis, C2-Ci6, C2-Ci4, C2-Ci2, C2-Cio, C2-C8, C2-C6, or C2-C4). Alkylene, alkenylene, and / or alkynylene includes straight chain and branched chain versions, as well as combinations thereof. The divalence of an alkylene, alkenylene, or alkynylene does not include substituents optionally present on the alkylene, alkenylene, or alkynylene. For example, two neuraminidase inhibitors can be attached to one another by way of a linker that includes an alkylene, alkenylene, and / or alkynylene, or a combination thereof. Each of the alkylene, alkenylene, and / or alkynylene in the linker is considered divalent with respect to the two attachments on either end of the alkylene, alkenylene, and / or alkynylene. For example, if a linker includes -(optionally substituted alkylene)-(optionally substituted alkenylene)-(optionally substituted alkylene)-, the alkenylene is considered divalent with respect to its attachment to the two alkylene groups at the ends of the linker. The optional substituents on the alkenylene are not included in the divalence of the alkenylene. The divalent nature of an alkylene, alkenylene, or alkynylene (e.g., an alkylene, alkenylene, or alkynylene in a linker) refers to both ends of the group and does not include optional substituents that can be present in the alkylene, alkenylene, or alkynylene. Because it is divalent, it can link multiple (e.g., two) moieties (e.g., a first neuraminidase inhibitor and a second neuraminidase inhibitor) of a conjugate together. An alkylene, alkenylene, and / or alkynylene can be substituted by groups typically applicable as substituents for alkyl, alkenyl, and alkynyl as set forth herein. For example, C=0 is a Ci alkylene substituted by an oxo (=0). For example, -HCR-C≡C- can be considered an optionally substituted alkynylene and is considered a divalent group, even though it has an optional substituent R. Heteroalkylene, heteroalkenylene, and / or heteroalkynylene refers to an alkylene, alkenylene, and / or alkynylene that includes one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms (e.g., N, O, and S). For example, a polyethylene glycol (PEG) polymer or a PEG unit in a PEG polymer -(CH2)2-0- is considered a heteroalkylene containing one or more oxygen atoms.

[1195] As used herein, the term "cycloalkylene" refers to a divalent cyclic group that links two parts of a compound together. For example, one carbon atom in a cycloalkylene group may be attached to one part of the compound, while another carbon atom in the cycloalkylene group may be attached to another part of the compound. Cycloalkylene groups may include saturated or unsaturated non-aromatic cyclic groups. Cycloalkylene groups may have, for example, three to twenty carbons in the cyclic portion of the cycloalkylene group (e.g., C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkylene groups). When a cycloalkylene group includes at least one carbon-carbon double bond, the cycloalkylene group may be referred to as a "cycloalkylene group". The cyclic alkenyl group may have, for example, four to twenty carbons (e.g., C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cyclic alkenyl groups) in the cyclic portion of the cyclic alkenyl group. When the cyclic alkyl group includes at least one carbon-carbon triple bond, the cyclic alkyl group may be referred to as a "cyclic alkyne". The cyclic alkyne group may have, for example, four to twenty carbons (e.g., C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C8-C20 cyclic alkyne groups) in the cyclic portion of the cyclic alkyne group. Cycloalkylene groups may be substituted with groups typically used as substituents of alkyl, alkenyl, and alkynyl groups as described herein. Heteroalkylene groups are those comprising one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms (e.g., N, O, and S). Examples of cycloalkylene groups include, but are not limited to, cyclopropylene and cyclobutylene. Tetrahydrofuran can be considered a heteroalkylene group.

[1196] As used herein, the term "arylene" refers to a polyvalent (e.g., divalent or trivalent) aryl group that links multiple (e.g., two or three) parts of a compound together. For example, one carbon in the arylene may be attached to one part of the compound, while another carbon in the arylene may be attached to another part of the compound. The arylene may have, for example, five to fifteen carbons (e.g., C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C11, C5-C12, C5-C13, C5-C14, or C5-C15 arylene) in the aryl moiety of the arylene. The arylene may be substituted by groups typically used as substituents of alkyl, alkenyl, and alkynyl groups as described herein. A heteroarylene refers to an aromatic group comprising one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms (e.g., N, O, and S). The heteroaryl group may have, for example, two to fifteen carbons (e.g., C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C2-C11, C2-C12, C2-C13, C2-C14 or C2-C15 heteroaryl groups).

[1197] As used herein, the term "optionally substituted" means having 0, 1, or multiple substituents, such as 0-25, 0-20, 0-10, or 0-5 substituents. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, alkylaryl, acyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, halo, oxo, cyano, nitro, amino, alkylamino, hydroxyl, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, urea, amidinyl, any of the aforementioned groups or moieties, and the hetero versions of any of the aforementioned groups or moieties. Substituents include, but are not limited to, F, Cl, methyl, phenyl, benzyl, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, SO3R, CONR2, SO2NR2, NRSO2NR2, CN, CF3, OCF3, SiR3, and NO2, wherein each R is independently H, alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, or heteroaryl, and wherein two optionally present substituents on the same or adjacent atom can be joined to form a fused, optionally substituted aromatic or non-aromatic, saturated or unsaturated ring containing 3-8 members, or two optionally present substituents on the same atom can be joined to form an optionally substituted aromatic or non-aromatic, saturated or unsaturated ring containing 3-8 members. An optionally substituted group or moiety refers to a group or moiety (e.g., any of the aforementioned groups or moieties) in which one atom (e.g., a hydrogen atom) is optionally replaced by another substituent. For example, an optionally substituted alkyl can be an optionally substituted methyl group in which a hydrogen atom of the methyl group is replaced by, for example, OH. As another example, a substituent on a heteroalkyl or its divalent counterpart, a heteroalkylene, can replace a hydrogen on a carbon or a hydrogen on a heteroatom such as N. For example, a hydrogen atom in the group -R-NH-R- can be replaced by an alkanoyl amide substituent, e.g., -R-N[(CH2C(O)N(CH3)2]-R.

[1198] In general, an optional substituent is a non-interfering substituent. A "non-interfering substituent" is one that preserves the ability of the conjugate described herein (e.g., a conjugate of any of formulae (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I)) to bind to viral neuraminidase or inhibit the proliferation of influenza virus. Thus, in some embodiments, the substituent can alter the degree of the activity. However, the substituent will be classified as "non-interfering" as long as the conjugate retains the ability to bind to viral neuraminidase or inhibit viral proliferation. For example, a non-interfering substituent will preserve the ability of the compound to provide antiviral efficacy based on a IC50 value of 10 μΜ or less in a viral plaque reduction assay (such as in Example 2 based on an IC50 value against influenza virus neuraminidase of less than 500 nM). Thus, based on plaque reduction or influenza virus neuraminidase inhibition, the substituent can alter the degree of inhibition. However, the substituent will be classified as "non-interfering" as long as the compound herein (such as a compound of formula (A-I), (A-II), (A-III), (A-IV), (A-V), (A-VI), (A-VII), (A-VIII), (A-IX), (A-X), (A-XI), and (A-XII)) retains the ability to inhibit influenza virus neuraminidase activity. Various assays for determining viral plaque reduction or the ability of any compound to inhibit influenza virus neuraminidase are available in the art and some are exemplified in the Examples below.

[1199] 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, and S. A group or moiety described above can be referred to as hetero if any of them contain at least one heteroatom. For example, a heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl means a cycloalkyl, cycloalkenyl, or cycloalkynyl having one or more heteroatoms independently selected from, for example, N, O, and S. An example of a heterocycloalkenyl is a maleimido group. For example, a heteroaryl means an aromatic group having one or more heteroatoms independently selected from, for example, N, O, and S. One or more heteroatoms can also be included in a substituent that replaces a hydrogen atom in a group or moiety as described herein. For example, in an optionally substituted heteroaryl, if one hydrogen atom in the heteroaryl is replaced by a substituent (e.g., a methyl group), the substituent can also contain one or more heteroatoms (e.g., a methanol group).

[1200] As used herein, the term "acyl" refers to a group having the structure: where R z is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkylaryl, alkylamino, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaryl, heteroalkylaryl, or heteroalkylamino.

[1201] As used herein, the term "halo" or "halogen" refers to any halogen atom, for example F, CI, Br, or I. If any of the groups or moieties described herein contain at least one halogen atom, they can be referred to as "halo moieties", such as haloalkyl.

[1202] As used herein, the term "hydroxyl" denotes an -OH group.

[1203] As used herein, the term "oxo" refers to a substituent with the structure =0, wherein there is a double bond between the atom and the oxygen atom.

[1204] As used herein, the term "carbonyl" refers to a group with the structure:

[1205] As used herein, the term "thiocarbonyl" refers to a group with the structure:

[1206] As used herein, the term "phosphate" denotes a group with the structure:

[1207] As used herein, the term "phosphoryl" denotes a group with the structure:

[1208] As used herein, the term "sulfonyl" denotes a group with the structure:

[1209] As used herein, the term "imino" denotes a group with the structure: wherein R is an optional substituent.

[1210] As used herein, the term "N-protecting group" means those groups intended to protect an amino group from undesired reactions during a synthetic procedure. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 5thedition (John Wiley & Sons, New York, 2014), which is incorporated herein by reference. N-protecting groups include, for example, acyl, aroyl, and carbamoyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, alpha-chlorobutyryl, benzoyl, carboxybenzoyl (CBz), 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acid residues such as alanine, leucine, phenylalanine; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, alpha, alpha-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (BOC), diisopropylmethoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; alkylaryls such as benzyl, triphenylmethyl, and phenyloxymethyl; and silyl groups such as trimethylsilyl.

[1211] As used herein, the term "amino acid" means both naturally occurring amino acids and non-naturally occurring amino acids.

[1212] As used herein, the term "naturally occurring amino acid" means an amino acid including Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val.

[1213] As used herein, the term "non-naturally occurring amino acid" means an alpha amino acid that is not naturally produced or found in mammals. Examples of non-naturally occurring amino acids include D-amino acids; amino acids having an acetylamino methyl attached to the sulfur atom of cysteine; pegylated amino acids; amino acids of the formula NH2(CH2) nω-amino acids of COOH, where n is 2-6, are neutral nonpolar amino acids, such as sarcosine, tert-butylalanine, tert-butylglycine, N-methylisoleucine and ortholeucine; oxymethionine; phenylglycine; citrulline; methionine sulfoxide; sulfoalanine; ornithine; diaminobutyric acid; 3-aminoalanine; 3-hydroxy-D-proline; 2,4-diaminobutyric acid; 2-aminovaleric acid; 2-aminooctanoic acid; 2-carboxypiperazine; piperazine-2-carboxylic acid; 2-amino-4-phenylbutyric acid; 3-(2-naphthyl)alanine; and hydroxyproline. Other amino acids include α-aminobutyric acid, α-amino-α-methylbutyrate, aminocyclopropane-carboxylic acid ester, aminoisobutyric acid, aminonorborneol-carboxylic acid ester, L-cyclohexylalanine, cyclopentylalanine, LN-methylleucine, LN-methylmethionine, LN-methylvaline, LN-methylphenylalanine, LN-methylproline, LN-methylserine, LN-methyltryptophan, D-ornithine, LN-methylethylglycine, L-leucine, α-methyl-aminoisobutyrate, α-methylcyclohexylalanine, D-α-methylalanine, and D-α-methyl... D-arginine, D-α-methylasparagine, D-α-methylaspartic acid, 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, D-α-methylserine, D-α-methylthreonine, D-α-methyltryptophan, D-α-methyltyrosine, D-α-methylvaline, D-methylalanine DN-methylarginine, DN-methylasparagine, DN-methylaspartic acid, DN-methylcysteine, DN-methylglutamine, DN-methylglutamate, DN-methylhistidine, DN-methylisoleucine, DN-methylleucine, DN-methyllysine, N-methylcyclohexylalanine, DN-methylornithine, N-methylglycine, N-methylaminoisobutyrate, N-(1-methylpropyl)glycine, N-(2-methylpropyl)glycine, DN-methyltryptophan, DN-methyltyrosine, DN-methylvaline, γ-aminobutyric acid L-tert-butylglycine, L-ethylglycine, L-homophenylalanine, L-α-methylarginine, L-α-methylaspartic acid, L-α-methylcysteine, L-α-methylglutamine, L-α-methylhistidine, L-α-methylisoleucine, L-α-methylleucine, L-α-methylmethionine, L-α-methylvaline, L-α-methylphenylalanine, L-α-methylserine, L-α-methyltryptophan, L-α-methylvaline, N-(N-(2,2-diphenylethyl)carbamoylmethylglycine, 1-carboxy-1-(2,2-diphenyl-ethylamino)cyclopropane, 4-hydroxyproline, ornithine, 2- aminobenzoyl (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-homo tyrosine, L-2-furylalanine, L-histidine (3-methyl), N-(3-guanidinopropyl)glycine, O-methyl-L-tyrosine, O-glycan-serine, m-tyrosine, n-tyrosine, L-N,N',N"-trimethyllysine, homolysine, n-lysine, N-glycan asparagine, 7-hydroxy-1,2,3,4-tetrahydro-4-fluorophenylalanine, 4-methylphenylalanine, bis-(2-pyridylmethyl)amine, pentafluorophenylalanine, indoline-2-carboxylic acid, 2-aminobenzoic acid, 3-amino-2-naphthoic acid, unsymmetrical dimethylarginine, L-tetrahydroisoquinoline-1-carboxylic acid, D-tetrahydroisoquinoline-1-carboxylic acid, 1-amino-cyclohexaneacetic acid, D / L-allylglycine, 4-aminobenzoic acid, 1-amino-cyclobutane carboxylic acid, 2 or 3 or 4-aminocyclohexane carboxylic acid, 1-amino-1-cyclopentane carboxylic acid, 1-aminoindane-1-carboxylic acid, 4-amino-pyrrolidine-2-carboxylic acid, 2-aminotetraline-2-carboxylic acid, azetidine-3-carboxylic acid, 4-benzyl-pyrrolidine-2-carboxylic acid, t-butylglycine, b-(benzothiazolyl-2-yl)-alanine, b-cyclopropylalanine, 5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid, (2R,4S) 4-hydroxypiperidine-2-carboxylic acid, (2S,4S) and (2S,4R)-4-(2-naphthylmethoxy)-pyrrolidine-2-carboxylic acid, (2S,4S) and (2S,4R) 4-phenoxy-pyrrolidine-2-carboxylic acid, (2R,5S) and (2S,5R)-5-phenyl-pyrrolidine-2-carboxylic acid, (2S,4S)-4-amino-1-benzoyl-pyrrolidine-2-carboxylic acid, 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, L-N-methylalanine, L-N-methylarginine, L-N-methylasparagine, L-N-methylaspartate, L-N-methylcysteine, L-N-methylglutamine, L-N-methylglutamate, L-N-methylhistidine, L-N-methylisoleucine, L-N-methyllysine, L-N-methylnorleucine, L-N-methylornithine, L-N-methylphenylalanine, L-N-methyltyrosine, L-N-methylvaline, L-N-methyl-t-butylglycine, L-norvaline, α-methyl-γ-aminobutyrate, 4,4'-diphenylalanine, α-methylcyclopentylalanine, α-methyl-α-naphthylalanine, α-methyl-penicillamine, N-(4-aminobutyl)glycine, N-(2-aminoethyl)glycine, N-(3-aminopropyl)glycine, N-amino-α-methylbutyric acid, α-naphthylalanine, N-phenylmethylglycine, N-(2-carbamoyl- ethyl)glycine, N-(carbamoylmethyl)glycine, N-(2-carboxyethyl)glycine, N-(carboxymethyl)glycine, N-cyclobutylglycine, N-cyclodecylglycine, N-cycloheptylglycine, N-cyclohexylglycine, N-cyclodecylglycine, N-cyclododecylglycine, N-cyclooctylglycine, N-cyclopropylglycine, N-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-indolyethyl)glycine, N-methyl-γ-aminobutyric acid, D-N-methylmethionine, N-methylcyclopentylalanine, D-N-methylphenylalanine, D-N-methylproline, D-N-methyltryptophane, N-(1-methylethyl)glycine, N-methyl-naphthylalanine, N-methylpenicillamine, N-(p-hydroxyphenyl)glycine, N-(thiomethyl)glycine, penicillamine, L-α-methylalanine, L-α-methyIasparagine, L-α-methyl-tert-butylglycine, L-methylethylglycine, L-α-methylglutamic acid, L-α-methylhomophenylalanine, N-(2-methylthioethyl)glycine, L-α-methyllysine, L-α-methylnorleucine, L-α-methyIonitrogen, L-α-methylproline, L-α-methyltryptophane, L-N-methyl-homophenylalanine, N-(N-(3,3-diphenylpropyl)carbamoylmethyl glycine, L-pyroglutamic acid, D-pyroglutamic acid, O-methyl-L-serine, O-methyl-L-homoserine, 5-hydroxylysine, α-carboxyglutamic acid, phenylglycine, L-pipecolic acid (homoproline), L-homoleucine, L-lysine (dimethyl), L-2-naphthylalanine, L-dimethyl-dopa or L-dimethoxy-phenylalanine, L-3-pyridylalanine, L-histidine (benzyloxymethyl), N-cycloheptylglycine, L-diphenylalanine, O-methyl-L-homotyrosine, L-β-homolysine, O-glycosyl-tryptophane, o-tyrosine, L-N,N'-dimethyllysine, L-homoarginine, neocoloramine, 3-benzothienylalanine, isoquinoline-3-carboxylic acid, diaminopropionic acid, homocysteine, 3,4-dimethoxyphenylalanine, 4-chlorophenylalanine, L-1,2,3,4-tetrahydro- norharman-3-carboxylic acid, adamantylalanine, sym-dimethylarginine, 3-carboxy-thiomorpholine, D-1,2,3,4-tetrahydroharmol-3-carboxylic acid, 3-aminobenzoic acid, 3-amino-l- carboxymethyl-pyridin-2-one, l-amino-l-cyclohexanecarboxylic acid, 2- aminocyclopentanecarboxylic acid, l-amino-l-cyclopropanecarboxylic acid, 2- aminoinandane-2-carboxylic acid, 4-amino-tetrahydrothiopyran-4-carboxylic acid, azetidine-2-carboxylic acid, b-(benzothiazol-2-yl)-alanine, neopentylglycine, 2- carboxymethylpiperidine, b-cyclobutylalanine, allylglycine, diaminopropionic acid, homo-cyclohexylalanine, (2S,4R)-4-hydroxypiperidine-2-carboxylic acid, octahydroindole-2-carboxylic acid, (2S,4R) and (2S,4R)-4-(2-naphthyl), pyrrolidine-2-carboxylic acid, piperidinecarboxylic acid, (2S,4R) and (2S,4S)-4-(4-phenylbenzyl)pyrrolidine-2-carboxylic acid, (3S)-l-pyrrolidine-3-carboxylic acid, (2S,4S)-4-tritylmercapto-pyrrolidine-2-carboxylic acid, (2S,4S)-4-mercapto-proline, t-butylglycine, N,N-bis(3-aminopropyl)glycine, l-amino-cyclohexane-l-carboxylic acid, N-mercaptoethylglycine, and seleno-cysteine. In some embodiments, the amino acid residue can be charged or polar. Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid, or a non-naturally occurring analog thereof. Polar amino acids include glutamine, asparagine, histidine, serine, cysteine, tyrosine, methionine, or tryptophan, or a non-naturally occurring analog thereof. In particular, it is contemplated that in some embodiments, the terminal amino group in the amino acid can be an amide group or a carbamate group.

[1214] As used herein, the term "percent (%) identity" means the percentage of amino acid residues in a candidate sequence (e.g., Fc-IgG or fragment thereof) that are identical with the amino acid residues of a reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity, (i.e., gaps can be introduced in one or both of the sequences being compared to achieve the maximum alignment and non-homologous sequences can be disregarded for comparison purposes). Alignment for purposes of determining percent identity can be achieved in a manner that is within the skill 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 aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. In some embodiments, the percent amino acid sequence identity of a given candidate sequence relative to, with, or against a given reference sequence (which can alternatively be expressed as a given candidate sequence having or comprising a certain percent amino acid sequence identity relative to, with, or against a given reference sequence) is calculated as follows:

[1215] 100 x (fraction of A / B)

[1216] wherein A is the number of amino acid residues scored as identical in the alignment of the candidate sequence to the reference sequence, and wherein B is the total number of amino acid residues in the reference sequence. In some embodiments, wherein the length of the candidate sequence is not equal to the length of the reference sequence, the percent amino acid sequence identity of the candidate sequence to the reference sequence will not equal the percent amino acid sequence identity of the reference sequence to the candidate sequence.

[1217] Two sequences are said to be "identical" if, when aligned for maximum correspondence as described above, the sequences of nucleotides or amino acids in the two polynucleotide or polypeptide sequences are the same. Comparison between two sequences is typically performed by comparing the sequences in a comparison window to identify and compare local regions of sequence similarity. As used herein, a "comparison window" refers to a segment of at least about 15 contiguous positions, about 20 contiguous positions, about 25 contiguous positions, or more (e.g., about 30 to about 75 contiguous positions, or about 40 to about 50 contiguous positions), wherein the two sequences can be compared to identify and compare local regions of sequence similarity.

[1218] As used herein, the term "treating" or "to treat" refers to therapeutic treatment of a viral infection (e.g., a viral infection, such as an influenza infection) in a subject. In some embodiments, the therapeutic treatment can slow progression of the viral infection, improve outcomes for the subject, and / or eliminate the infection. In some embodiments, the therapeutic treatment of a viral infection in a subject can alleviate or ameliorate one or more symptoms or conditions associated with the viral infection, attenuate the virus, stabilize the state of the viral infection, prevent the spread of the viral infection, and / or delay or slow the progression of the viral infection, as compared to the state and / or condition of the viral infection in the absence of the therapeutic treatment.

[1219] As used herein, the term "average value of T" refers to the average number of neuraminidase inhibitor monomers or neuraminidase inhibitor dimers conjugated to the Fc domain or albumin within a population of conjugates. In some embodiments, the average number of neuraminidase inhibitor monomers or neuraminidase inhibitor dimers conjugated to the Fc domain monomers within a population of conjugates can be 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20). In some embodiments, the average value of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[1220] As used herein, the term "subject" can be a human, non-human primate, or other mammal, such as, but not limited to, a dog, cat, horse, cow, pig, turkey, goat, fish, monkey, chicken, rat, mouse, and sheep.

[1221] As used herein, the term "therapeutically effective amount" refers to an amount, e.g., a dose of a drug, effective to induce a desired effect in a subject or to treat a subject having a condition or disorder described herein, e.g., a viral infection, such as an influenza infection. It is also understood herein that a "therapeutically effective amount" can be interpreted as an amount that gives a desired therapeutic and / or prophylactic effect, taken in one or more doses or in any dosage or route, and / or taken alone or in combination with other therapeutic agents, e.g., an antiviral agent described herein. For example, in the case of administration of a conjugate described herein (e.g., a conjugate of any of formulae (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I)) for the treatment of a viral infection, a therapeutically effective amount of the conjugate is, e.g., an amount sufficient to prevent, slow, or reverse the progression of the viral infection, e.g., as compared to the response obtained when the conjugate is not administered.

[1222] As used herein, the term "pharmaceutical composition" refers to a medicinal or pharmaceutical formulation containing at least one active ingredient (e.g., a conjugate of any of formulae (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I)) and one or more excipients and diluents to enable the active ingredient(s) to be adapted for the method of administration. Pharmaceutical compositions of the present application include pharmaceutically acceptable components that are compatible with the conjugates described herein (e.g., a conjugate of any of formulae (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I)).

[1223] As used herein, the term "pharmaceutically acceptable carrier" refers to an excipient or diluent in a pharmaceutical composition. For example, a pharmaceutically acceptable carrier can be a vehicle capable of suspending or dissolving an active conjugate (e.g., a conjugate of any of formulae (1)-(5), (D-I)-(D-X), or (M-I)-(M-VI)). A pharmaceutically acceptable carrier must be compatible for use with other ingredients of the formulation and not deleterious to the recipient thereof. In the present application, a pharmaceutically acceptable carrier must provide proper pharmaceutical stability to the conjugates described herein. The nature of the carrier varies depending on the mode of administration. For example, with respect to oral administration, a solid carrier is preferred; with respect to intravenous administration, an aqueous solution carrier (e.g., WFI and / or a buffered solution) is generally used.

[1224] As used herein, the term “pharmaceutically acceptable salt” means a salt of a conjugate described herein (e.g., a conjugate of any of formulae (1)-(5), (D-I)-(D-X), (D’-I), (M-I)-(M-X), or (M’-I)) that is, within the scope of sound medical judgment, useful for the methods described herein without undue toxicity, irritation, and / or allergic response. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Pharmaceutical Salts: Properties, Selection, and Use (ed. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the conjugates described herein, or separately by reacting the free base with a suitable organic acid.

[1225] The term “drug: antibody ratio” or “DAR” refers to the average number of small molecule drug moieties (e.g., the average number of small molecule drug monomers or dimers) conjugated to an antibody, Fc domain, or albumin described herein. In some embodiments described herein, the DAR is denoted by “T” (e.g., in formulae (1)-(5), (D-I)-(D-X), (D’-I), (M-I)-(M-X), or (M’-I)). As used herein, each monomer moiety (e.g., each zanamivir or peramivir monomer) or each dimer moiety (e.g., each zanamivir or peramivir dimer) conjugated to an Fc domain, antibody, or albumin corresponds to a DAR value of 1.0 (e.g., a “T” value of 1.0). For example, an Fc domain conjugated to 4 zanamivir monomers would have a DAR of 4.0 (e.g., a “T” of 4.0). An Fc domain conjugated to 4 zanamivir dimers (e.g., a total of 8 zanamivir molecules) would also have a DAR of 4.0 (e.g., a “T” of 4.0). The DAR can also be calculated as an average DAR for a population of molecules, such as a population of Fc domains, antibodies, or albumins. The DAR value can affect the efficacy, potency, pharmacokinetics, or toxicity of the drug.

[1226] As used herein, the term “about” indicates a deby way oftion of ±5%. For example, about 10% means 9.5% to 10.5%.

[1227] Any value provided in a range of values includes the upper and lower limits, and any value within the range.

[1228] As used herein, the term "(1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X), or (M'-I)" means Formula (1), (2), (3), (4), (5), (D-I), (D-II), (D-II-1), (D-II-2), (D-II-3), (D-II-4), (D-II-5), (D-II-6), (D-II-7), (D-II-8), (D-II-9), (D-II-10), (D-III), (D-III-1), (D-III-2), (D-III-3), (D-III-4), (D-III-5), (D-III-6), (D-III-7), (D-III-8), (D-III-9), (D-IV), (D-IV-1), (D-IV-2), (D-V), (D-V-1), (D-V-2), (D-V-3), (D-V-4), (D-V-5), (D-V-6), (D-V-7), (D-V-8), (D-V-9), (D-V-10), (D-VI), (D-VI-1), (D-VI-2), (D-VI-3), (D-VI-4), (D-VI-5), (D-VI-6), (D-VI-7), (D-VI-8), (D-VI-9), (D-VII), (D-VIII), (D-VIII-1), (D-VIII-2), (D-VIII-3), (D-VIII-4), (D-VIII-5), (D-VIII-6), (D-VIII-7), (D-VIII-8), (D-VIII-9), (D-VIII-10), (D-VIII-11), (D-IX), (D-IX-1), (D-IX-2), (D-IX-3), (D-IX-4), (D-IX-5), (D-IX-6), (D-X), (D-X-1), (D-X-2), (D-X-3), (D'-I), (M-I), (M-II), (M-II-1), (M-II-2), (M-II-3), (M-II-4), (M-II-5), (M-II-6), (M-II-7), (M-II-8), (M-II-9), (M-II-10), (M-III), (M-III-1), (M-III-2), (M-III-3), (M-III-4), (M-III-5), (M-III-6), (M-III-7), (M-III-8), (M-III-9), (M-IV), (M-IV-1), (M-IV-2), (M-V), (M-V-1), (M-V-2), (M-V-3), (M-V-4), (M-V-5), (M-V-6),(M-V-7), (M-V-8), (M-V-9), (M-V-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-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), (M-X), (M-X-1), (M-X-2), (M-X-3), or (M'-I).

[1229] Other features and advantages of the conjugates described herein will be apparent from the detailed description and from the claims. BRIEF DESCRIPTION OF DRAWINGS

[1230] Figure 1 is an image depicting an exemplary method of conjuga...

Claims

1. A conjugate described by formula (1): wherein each A1and each A2is independently selected from any one of formulae (A-I) - (A-XII): wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=0)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -0- and -S-; Y is selected from -0-, -S-, -NR7-, -0(C=0)NR7-, -0(C=S)NR7-, -0(C=0)0-, -0(C=0)-, -NH(C=0)0-, -NH(C=0)-, -NH(C=NH)-, -NH(C=0)NR7-, -NH(C=NH)NR7-, -NH(C=S)NR7-, -NH(C=S)-, -OCH2(C=0)NR7-, -NH(S02)-, -NH(S02)NR7-, -OR8-, -NHR8-, and -SR8-; R7is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl, and C2-C15 heteroaryl; R8is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; each E comprises a Fc domain monomer; L in each A1-L-A2is a linker covalently attached to the sulfur atom of a hinge cysteine in each E and to each of A1and A2; T is an integer from 1 to 20, and the two wavy lines connected to two E indicate that each A1-L-A2is covalently attached to a pair of sulfur atoms of two hinge cysteines in the two E, or a pharmaceutically acceptable salt thereof.

2. A conjugate described by formula (1): wherein each A1and each A2is independently selected from any one of formulae (A-I) - (A-V): wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=0)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -0- and -S-; Y is selected from -0-, -S-, -NR7-, -0(C=0)NR7-, -0(C=S)NR7-, -0(C=0)0-, -0(C=0)-, -NH(C=0)0-, -NH(C=0)-, -NH(C=NH)-, -NH(C=0)NR7-, -NH(C=NH)NR7-, -NH(C=S)NR7-, -NH(C=S)-, -OCH2(C=0)NR7-, -NH(S02)-, -NH(S02)NR7-, -OR8-, -NHR8-, and -SR8-; R7is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl, and C2-C15 heteroaryl; R8is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; each E comprises a Fc domain monomer; L in each A1-L-A2is a linker covalently attached to the sulfur atom of a hinge cysteine in each E and to each of A1and A2; T is an integer from 1 to 20, and the two wavy lines connected to two E indicate that each A1-L-A2is covalently attached to a pair of sulfur atoms of two hinge cysteines in the two E, or a pharmaceutically acceptable salt thereof. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl and C2-C15heteroaryl; each E comprises an Fc domain monomer; L in each A1-L-A2 is a linker covalently attached to the sulfur atom of the hinge cysteine in each E and to each of A1 and A2; T is an integer from 1 to 20, and the two wavy lines connected to two E indicate that each A1-L-A2 is covalently attached to a pair of sulfur atoms of two hinge cysteines in the two E, or a pharmaceutically acceptable salt thereof.

3. A conjugate described by formula (1): wherein each A1and each A2is independently selected from any one of formulae (A-VI)-(A-IX): wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is selected from -O-, -S-, -NR7-, -O(C=O)NR7-, -O(C=S)NR7-, -O(C=O)O-, -O(C=O)-, -NH(C=O)O-, -NH(C=O)-, -NH(C=NH)-, -NH(C=O)NR7-, -NH(C=NH)NR7-, -NH(C=S)NR7-, -NH(C=S)-, -OCH2(C=O)NR7-, -NH(SO2)-, -NH(SO2)NR7-, -OR8-, -NHR8-, and -SR8-; R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl and C2-C15heteroaryl; each E comprises an Fc domain monomer; L in each A1-L-A2 is a linker covalently attached to the sulfur atom of the hinge cysteine in each E and to each of A1 and A2; T is an integer from 1 to 20, and the two wavy lines connected to two E indicate that each A1-L-A2 is covalently attached to a pair of sulfur atoms of two hinge cysteines in the two E, or a pharmaceutically acceptable salt thereof.

4. A conjugate described by formula (2): wherein each A1is independently selected from any one of formulae (A-I)-(A-XII): wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -0- and -S-; Y is selected from -0-, -S-, -NR7-, -0(C=0)NR7-, -0(C=S)NR7-, -0(C=0)0-, -0(C=0)-, -NH(C=0)0-, -NH(C=0)-, -NH(C=NH)-, -NH(C=0)NR7-, -NH(C=NH)NR7-, -NH(C=S)NR7-, -NH(C=S)-, -OCH2(C=0)NR7-, -NH(S02)-, -NH(S02)NR7-, -OR8-, -NHR8-, and -SR8-; R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer; L in each L-A is a linker covalently attached to a sulfur atom of a hinge cysteine in E and to A; T is an integer from 1 to 20, and the two wavy lines connected to two sulfur atoms indicate that each L-A is covalently attached to a pair of sulfur atoms of two hinge cysteines in the two E, or a pharmaceutically acceptable salt thereof.

5. A conjugate described by formula (2): wherein each A1is independently selected from any one of formulae (A-I) - (A-V): wherein R1is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2and R3are each independently selected from -H, -OH, -F, -Cl, and -Br; R4is selected from -CO2H, -P(=0)(OH)2, -SO3H; R5is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -0- and -S-; Y is selected from -0-, -S-, -NR7-, -0(C=0)NR7-, -0(C=S)NR7-, -0(C=0)0-, -0(C=0)-, -NH(C=0)0-, -NH(C=0)-, -NH(C=NH)-, -NH(C=0)NR7-, -NH(C=NH)NR7-, -NH(C=S)NR7-, -NH(C=S)-, -OCH2(C=0)NR7-, -NH(S02)-, -NH(S02)NR7-, -OR8-, -NHR8-, and -SR8-; R7is selected from H, C1-C20alkyl, C3-C20cycloalkyl, C3-C20heterocycloalkyl; C5-C15aryl, and C2-C15heteroaryl; R8is selected from C3-C20heterocycloalkyl, C5-C15aryl, and C2-C15heteroaryl; each E comprises an Fc domain monomer; L in each L-A is a linker covalently attached to a sulfur atom of a hinge cysteine in E and to A; T is an integer from 1 to 20, and the two wavy lines connected to two sulfur atoms indicate that each L-A is covalently attached to a pair of sulfur atoms of two hinge cysteines in the two E, or a pharmaceutically acceptable salt thereof. two wavy lines connected to two sulfur atoms indicate that each L-A is covalently attached to a pair of sulfur atoms of two hinge cysteines in the two E, or a pharmaceutically acceptable salt thereof.

6. A conjugate described by formula (2): wherein each A1 is independently selected from any one of formulae (A-VI)-(A-IX): 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(=0)(OH)2, -SO3H; R5 is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -0- and -S-; Y is selected from -0-, -S-, -NR7-, -0(C=0)NR7-, -0(C=S)NR7-, -0(C=0)0-, -0(C=0)-, -NH(C=0)0-, -NH(C=0)-, -NH(C=NH)-, -NH(C=0)NR7-, -NH(C=NH)NR7-, -NH(C=S)NR7-, -NH(C=S)-, -OCH2(C=0)NR7-, -NH(S02)-, -NH(S02)NR7-, -OR8-, -NHR8-, and -SR8-; 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; each E comprises an Fc domain monomer; L in each L-A is a linker covalently attached to a sulfur atom of a hinge cysteine in E and to A; T is an integer from 1 to 20, and two wavy lines connected to two sulfur atoms indicate that each L-A is covalently attached to a pair of sulfur atoms of two hinge cysteines in the two E, or a pharmaceutically acceptable salt thereof.

7. The conjugate of any one of claims 1-6, wherein each E comprises an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68.

8. The conjugate of any one of claims 1-7, wherein each Fc domain monomer comprises the sequence of SEQ ID NO: 10 or SEQ ID NO:

11.

9. The conjugate of claim 8, wherein at least one of the pair of sulfur atoms is the sulfur atom of Cys10, Cys13, Cys16, or Cys18 of SEQ ID NO: 10 or SEQ ID NO:

11.

10. The conjugate of claim 8, wherein the pair of sulfur atoms are the sulfur atoms of Cys10 and Cys13, Cys10 and Cys16, Cys 10 and Cys18, Cys13 and Cys 16, Cys13 and Cys 18, or Cys 16 and Cys 18 in the two E.

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