Compositions and methods for treating viral infections

Abstract

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

Description

Background Technology

[0001] 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.

[0002] 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.

[0003] 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 ).

[0004] 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

[0005] This invention relates to conjugates, compositions, and methods for inhibiting viral growth, and methods for treating viral infections. Specifically, the conjugates contain a monomer or dimer of a portion of influenza virus neuraminidase (e.g., zanamivir, peramivir, or analogues thereof), conjugated to an Fc monomer, an Fc domain, an Fc-binding peptide, albumin, or an albumin-binding peptide. The neuraminidase inhibitor in the conjugate (e.g., zanamivir, peramivir, or analogues thereof) targets the neuraminidase on the surface of viral particles. The Fc monomer or Fc domain in the conjugate binds to FcγRs (e.g., FcRn, FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and FcγRIIIb) on immune cells (e.g., neutrophils) to activate phagocytosis and effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), thereby engulfing and destroying viral particles by immune cells and further enhancing the antiviral activity of the conjugate. The albumin or albumin-binding peptide may prolong the half-life of the conjugate, for example, by conjugating albumin to a recirculating neonatal Fc receptor. The composition is suitable for methods of inhibiting viral growth and for treating viral infections (such as those caused by influenza A, influenza B, and influenza C viruses).

[0006] In one aspect, the present invention provides a conjugate described by formula (1):

[0007]

[0008] Each A1 and each A2 is independently selected from any one of the formulas (AI)-(A-XII):

[0009]

[0010] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0011]

[0012] R6 is selected from

[0013] 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 contains an Fc domain monomer (e.g., having SEQ ID). NO: Fc domain monomer of any of the sequences 1-68; L in each A1-L-A2 is a sulfur atom covalently attached to the hinge cysteine ​​in each E and a connector attached to each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the two wavy lines connected to the two E indicate that each A1-L-A2 is covalently attached (e.g., by means of a covalent bond or connector) to a pair of sulfur atoms of the 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-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0014] In another aspect, the present invention provides a conjugate described by formula (1):

[0015]

[0016] Each A1 and each A2 is independently selected from any one of the formulas (AI)-(AV):

[0017]

[0018] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0019]

[0020] R6 is selected from

[0021] 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 contains an Fc domain monomer (e.g., having SEQ ID). NO: Fc domain monomer of any of the sequences 1-68; L in each A1-L-A2 is a sulfur atom covalently attached to the hinge cysteine ​​in each E and a connector attached to each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the two wavy lines connected to the two E indicate that each A1-L-A2 is covalently attached (e.g., by means of a covalent bond or connector) to a pair of sulfur atoms of the 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-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0022] In another aspect, the present invention provides a conjugate described by formula (1):

[0023]

[0024] Each A1 and each A2 is independently selected from any one of equations (A-VI)-(A-IX):

[0025]

[0026] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0027]

[0028] R6 is selected from

[0029] 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 contains an Fc domain monomer (e.g., having SEQ ID). NO: Fc domain monomer of any of the sequences 1-68; L in each A1-L-A2 is a sulfur atom covalently attached to the hinge cysteine ​​in each E and a connector attached to each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the two wavy lines connected to the two E indicate that each A1-L-A2 is covalently attached (e.g., by means of a covalent bond or connector) to a pair of sulfur atoms of the 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-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0030] In another aspect, the present invention provides a conjugate described by formula (2):

[0031]

[0032] Each A1 is independently selected from any one of the formulas (AI)-(A-XII):

[0033]

[0034] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0035]

[0036] R6 is selected from

[0037] 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 contains an Fc domain monomer (e.g., having SEQ ID). NO: Fc domain monomer of any of the sequences 1-68; L in each L-A1 is a sulfur atom covalently attached to the hinge cysteine ​​in E and a linker 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 connected to the two sulfur atoms indicate that each L-A1 is covalently (e.g., by means of a covalent bond or linker) attached to a pair of sulfur atoms of the 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 can be independently selected from any of the formulas (AI)-(A-XII).

[0038] In another aspect, the present invention provides a conjugate described by formula (2):

[0039]

[0040] Each A1 is independently selected from any one of the formulas (AI)-(AV):

[0041]

[0042] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0043]

[0044] R6 is selected from

[0045] 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 contains an Fc domain monomer (e.g., having SEQ ID). NO: Fc domain monomer of any of the sequences 1-68; L in each L-A1 is a sulfur atom covalently attached to a hinge cysteine ​​in E and a linker 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 connected to the two sulfur atoms indicate that each L-A1 is 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 may be independently selected from any of formulas (AI)-(AV).

[0046] In another aspect, the present invention provides a conjugate described by formula (2):

[0047]

[0048] Each A1 is independently selected from any one of the equations (A-VI)-(A-IX):

[0049]

[0050] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0051]

[0052] R6 is selected from

[0053] 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 contains an Fc domain monomer (e.g., having SEQ ID). NO: Fc domain monomer of any of the sequences 1-68; L in each L-A1 is a sulfur atom covalently attached to the hinge cysteine ​​in E and a linker 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 connected to the two sulfur atoms indicate that each L-A1 is covalently attached (e.g., by means of a covalent bond or linker) to a pair of sulfur atoms of the 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 can be independently selected from any of the formulas (A-VI)-(A-IX).

[0054] In some embodiments of any of the foregoing embodiments, each E includes an Fc domain monomer having a sequence of any of SEQ ID NO:1-68.

[0055] In some implementations, each E contains a sequence.

[0056] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH(SEQ ID NO:10).

[0057] In some implementations, each E contains a sequence.

[0058] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:11).

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

[0060] In some embodiments, when T is 2, the sulfur atom pair is Cys10 and Cys13 in SEQ ID NO:10 or SEQ ID NO:11, or Cys 36 and Cys 38 in SEQ ID NO:10 or SEQ ID NO:11 (e.g., the sulfur atoms corresponding thereto).

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

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

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

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

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

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

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

[0068]

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

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

[0071] In some implementations, each E contains a sequence.

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

[0073] In some implementations, each E contains a sequence.

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

[0075] In some embodiments, at least one of the sulfur atom pairs is a sulfur atom corresponding to the hinge cysteine ​​in SEQ ID NO:4 or SEQ ID NO:33, namely Cys10 and / or Cys13 (e.g., its sulfur atom). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 and Cys13 (e.g., its sulfur atom) in SEQ ID NO:4 or SEQ ID NO:33.

[0076] In some embodiments, the sulfur atom pair comprises a single sulfur atom from each of the E's cysteine ​​residues, i.e., the LA, together with its attached sulfur atom, forms a bridge between two Fc domains (e.g., two Fc domains containing the sequence of SEQ ID NO:4 or SEQ ID NO:33). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from one E's SEQ ID NO:4 or SEQ ID NO:33 and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E's SEQ ID NO:4 or SEQ ID NO:33. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from one E's SEQ ID NO:4 or SEQ ID NO:33 and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from another E's SEQ ID NO:4 or SEQ ID NO:33. In some embodiments, when T is 2, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:4 or SEQ ID NO:33 of one E and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:4 or SEQ ID NO:33 of another E, and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:4 or SEQ ID NO:33 of one E and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:4 or SEQ ID NO:33 of another E.

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

[0078]

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

[0080] In some implementations, each E contains a sequence.

[0081] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH(SEQ ID NO:8).

[0082] In some embodiments, at least one of the sulfur atom pairs is a sulfur atom corresponding to the hinge cysteine ​​in SEQ ID NO:8, namely Cys10 and / or Cys13 (e.g., its sulfur atom). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 and Cys13 (e.g., its sulfur atom) in SEQ ID NO:8.

[0083] In some embodiments, the sulfur atom pair comprises a single sulfur atom from each E's cysteine ​​residue, i.e., LA together with its attached sulfur atom forms a bridge between two Fc domains (e.g., two Fc domains containing the sequence of SEQ ID NO: 8). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from one E's SEQ ID NO: 8 and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E's SEQ ID NO: 8. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from one E's SEQ ID NO: 8 and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from another E's SEQ ID NO: 8. In some embodiments, when T is 2, the sulfur atom pair is the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:8 of one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E, and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:8 of one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from another E.

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

[0085]

[0086] Where a and b are each independently 0 or 1, and when a or b is 0, the two sulfur atoms form a disulfide bond. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0087] In another aspect, the invention also provides a group 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.

[0088] In another aspect, the present invention provides a conjugate described by formula (3):

[0089]

[0090] Each A1 and each A2 is independently selected from any one of equations (AI)-(A-VII):

[0091]

[0092] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0093]

[0094] R6 is selected from

[0095] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: sequence of any one of 1-68); L in each A1-L-A2 is a sulfur atom of a hinge cysteine ​​covalently attached to E and a connector attached to each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the wavy line connected to E indicates a sulfur atom of a hinge cysteine ​​covalently (e.g., by means of a covalent bond or connector) attached to E in each A1-L-A2, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0096] In another aspect, the present invention provides a conjugate described by formula (3):

[0097]

[0098] Each A1 and each A2 is independently selected from any one of the formulas (AI)-(AV):

[0099]

[0100] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0101]

[0102] R6 is selected from

[0103] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: sequence of any one of 1-68); L in each A1-L-A2 is a sulfur atom of a hinge cysteine ​​covalently attached to E and a connector attached to each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the wavy line connected to E indicates that each A1-L-A2 is covalently attached (e.g., by means of a covalent bond or connector) to a sulfur atom of a hinge cysteine ​​in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0104] In another aspect, the present invention provides a conjugate described by formula (3):

[0105]

[0106] Each A1 and each A2 is independently selected from any one of equations (A-VI)-(A-IX):

[0107]

[0108] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0109]

[0110] R6 is selected from

[0111] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: sequence of any one of 1-68); L in each A1-L-A2 is a sulfur atom of a hinge cysteine ​​covalently attached to E and a connector attached to each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the wavy line connected to E indicates that each A1-L-A2 is covalently attached (e.g., by means of a covalent bond or connector) to a sulfur atom of a hinge cysteine ​​in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0112] In some embodiments, each E includes an Fc domain monomer having a sequence of any of SEQ ID NO:1-68.

[0113] In some implementations, each E contains a sequence.

[0114] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH(SEQ ID NO:10).

[0115] In some implementations, each E contains a sequence.

[0116] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:11).

[0117] In some embodiments, at least one of the sulfur atom pairs is a hinge cysteine ​​corresponding to SEQ ID NO:10 or SEQ ID NO:11, i.e., a sulfur atom of Cys10, Cys13, Cys16 or Cys18 (e.g., its sulfur atom) of SEQ ID NO:10 or SEQ ID NO:11. In some embodiments, the sulfur atom pairs are sulfur atoms corresponding to Cys10 and Cys13, Cys10 and Cys16, Cys30 and Cys18, Cys13 and Cys36, Cys13 and Cys38, and / or Cys36 and Cys38 (e.g., their sulfur atoms) in SEQ ID NO:10 or SEQ ID NO:11.

[0118] In some embodiments, when T is 2, the sulfur atom pair is a sulfur atom corresponding to Cys10 and Cys13 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., their sulfur atoms).

[0119] In some embodiments, the sulfur atom pair comprises a single sulfur atom from the cysteine ​​residues of each E, i.e., LA together with its attached sulfur atom forms a bridge between two Fc domains (e.g., two Fc domains containing the sequence of SEQ ID NO: 10 or SEQ ID NO: 11). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from one E and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from one E and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from another E. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of another E. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of another E.

[0120] In some embodiments, when T is 2, the sulfur atom pair is the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of another E, and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of another E. In some embodiments, when T is 2, the sulfur atom pair is the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E, and the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from another E. In some embodiments, when T is 2, the sulfur atom pair is the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E, and the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from another E.

[0121] In some embodiments, when T is 2, the sulfur atom pair is the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of another E, and the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and the sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of another E. In some embodiments, when T is 2, the sulfur atom pair is the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of another E, and the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and the sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of another E.

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

[0123] In some embodiments, when T is 3, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E; a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from another E; and a sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from another E. In some embodiments, when T is 3, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E; a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from another E; and a sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from another E.In some embodiments, when T is 3, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E; a sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from another E; and a sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from another E. In some embodiments, when T is 3, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from another E; a sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys18 (e.g., its sulfur atom) from another E; and a sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from SEQ ID NO:10 or SEQ ID NO:11 of one E and a sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from another E.

[0124] In some embodiments, when T is 3, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from one E and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E; a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from one E and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from another E; a sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from one E and a sulfur atom corresponding to Cys16 (e.g., its sulfur atom) from another E; and a sulfur atom corresponding to SEQ ID NO:10 or SEQ ID NO:11 from one E. The sulfur atom of Cys18 (e.g., its sulfur atom) of NO:11 and the sulfur atom of Cys18 (e.g., its sulfur atom) corresponding to another E from SEQ ID NO:10 or SEQ ID NO:11.

[0125] In some embodiments, the conjugate has the following structure:

[0126]

[0127] Where a, b, c, and d are each independently 0 or 1, and when a, b, c, or d is 0, two sulfur atoms form a disulfide bond.

[0128] 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, 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.

[0129] In some implementations, each E contains a sequence.

[0130] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:4).

[0131] In some implementations, each E contains a sequence.

[0132] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:33).

[0133] In some embodiments, at least one of the sulfur atom pairs is a sulfur atom corresponding to the hinge cysteine ​​in SEQ ID NO:4 or SEQ ID NO:33, namely Cys10 and / or Cys13 (e.g., its sulfur atom). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 and Cys13 (e.g., its sulfur atom) in SEQ ID NO:4 or SEQ ID NO:33.

[0134] In some embodiments, the sulfur atom pair comprises a single sulfur atom from each of the E's cysteine ​​residues, i.e., the LA, together with its attached sulfur atom, forms a bridge between two Fc domains (e.g., two Fc domains containing the sequence of SEQ ID NO:4 or SEQ ID NO:33). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from one E's SEQ ID NO:4 or SEQ ID NO:33 and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E's SEQ ID NO:4 or SEQ ID NO:33. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from one E's SEQ ID NO:4 or SEQ ID NO:33 and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from another E's SEQ ID NO:4 or SEQ ID NO:33. In some embodiments, when T is 2, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:4 or SEQ ID NO:33 of one E and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:4 or SEQ ID NO:33 of another E, and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:4 or SEQ ID NO:33 of one E and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:4 or SEQ ID NO:33 of another E.

[0135] In some embodiments, the conjugate has the following structure:

[0136]

[0137] Where a and b are each independently 0 or 1, and when a or b is 0, the two sulfur atoms form a disulfide bond. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0138] In some implementations, each E contains a sequence.

[0139] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH(SEQ ID NO:8).

[0140] In some embodiments, at least one of the sulfur atom pairs is a sulfur atom corresponding to the hinge cysteine ​​in SEQ ID NO:8, namely Cys10 and / or Cys13 (e.g., its sulfur atom). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 and Cys13 (e.g., its sulfur atom) in SEQ ID NO:8.

[0141] In some embodiments, the sulfur atom pair comprises a single sulfur atom from each E's cysteine ​​residue, i.e., LA together with its attached sulfur atom forms a bridge between two Fc domains (e.g., two Fc domains containing the sequence of SEQ ID NO: 8). In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from one E's SEQ ID NO: 8 and a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E's SEQ ID NO: 8. In some embodiments, the sulfur atom pair is a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from one E's SEQ ID NO: 8 and a sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from another E's SEQ ID NO: 8. In some embodiments, when T is 2, the sulfur atom pair is the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from SEQ ID NO:8 of one E and the sulfur atom corresponding to Cys10 (e.g., its sulfur atom) from another E, and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from SEQ ID NO:8 of one E and the sulfur atom corresponding to Cys13 (e.g., its sulfur atom) from another E.

[0142] In some embodiments, the conjugate has the following structure:

[0143]

[0144] Where a and b are each independently 0 or 1, and when a or b is 0, the two sulfur atoms form a disulfide bond. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a and b are 1.

[0145] In another aspect, the present invention provides a conjugate described by formula (4):

[0146]

[0147] Each A1 is independently selected from any one of the formulas (AI)-(A-XII):

[0148]

[0149] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0150]

[0151] R6 is selected from

[0152] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: any of the sequences 1-68); L in each L-A1 is a sulfur atom of a hinge cysteine ​​covalently attached to E and a linker 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-A1 is covalently attached (e.g., by means of a covalent bond or linker) to a 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 may be independently selected from any of the formulas (AI)-(A-XII).

[0153] In another aspect, the present invention provides a conjugate described by formula (4):

[0154]

[0155] Each A1 is independently selected from any one of the formulas (AI)-(AV):

[0156]

[0157] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0158]

[0159] R6 is selected from

[0160] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: any of the sequences 1-68); L in each L-A1 is a sulfur atom of a hinge cysteine ​​covalently attached to E and a linker 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-A1 is covalently attached (e.g., by means of a covalent bond or linker) to a 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 may be independently selected from any of the formulas (AI)-(AV).

[0161] In another aspect, the present invention provides a conjugate described by formula (4):

[0162]

[0163] Each A1 is independently selected from any one of the equations (A-VI)-(A-IX):

[0164]

[0165] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0166]

[0167] R6 is selected from

[0168] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: any of the sequences 1-68); L in each L-A1 is a sulfur atom of a hinge cysteine ​​covalently attached to E and a linker 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-A1 is covalently attached (e.g., by means of a covalent bond or linker) to a 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 may be independently selected from any of formulas (A-VI)-(A-IX).

[0169] In some embodiments, each E includes an Fc domain monomer having a sequence of any of SEQ ID NO:1-68.

[0170] In some implementations, each E contains a sequence.

[0171] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:4).

[0172] In some implementations, each E contains a sequence.

[0173] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:33).

[0174] In some embodiments, at least one of the sulfur atoms is a sulfur atom corresponding to the hinge cysteine ​​in SEQ ID NO:4 or SEQ ID NO:33, namely Cys10 and / or Cys13 (e.g., its sulfur atom). In some embodiments, the sulfur atom is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) in SEQ ID NO:4 or SEQ ID NO:33. In some embodiments, it is a sulfur atom corresponding to Cys10 (e.g., its sulfur atom) in SEQ ID NO:4 or SEQ ID NO:33.

[0175] In some embodiments, the conjugate has the following structure:

[0176]

[0177] Wherein a and b are each independently 0 or 1, and where 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.

[0178] In another aspect, the present invention provides a group of conjugates 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.

[0179] In another aspect, the present invention provides a conjugate described by formula (3):

[0180]

[0181] Each A1 and each A2 is independently selected from any one of the formulas (AI)-(A-XII):

[0182]

[0183] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0184]

[0185] R6 is selected from

[0186] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: any of the sequences 1-68); L in each A1-L-A2 is a nitrogen atom covalently attached to the surface-exposed lysine in E and to each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the wavy line connected to E indicates that each A1-L-A2 is covalently attached (e.g., by means of a covalent bond or a connector) to the surface-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0187] In another aspect, the present invention provides a conjugate described by formula (3):

[0188]

[0189] Each A1 and each A2 is independently selected from any one of the formulas (AI)-(AV):

[0190]

[0191] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0192]

[0193] R6 is selected from

[0194] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: any of the sequences 1-68); L in each A1-L-A2 is a nitrogen atom covalently attached to the surface-exposed lysine in E and to each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the wavy line connected to E indicates that each A1-L-A2 is covalently attached (e.g., by means of a covalent bond or a connector) to the surface-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0195] In another aspect, the present invention provides a conjugate described by formula (3):

[0196]

[0197] Each A1 and each A2 is independently selected from any one of equations (A-VI)-(A-IX):

[0198]

[0199] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0200]

[0201] R6 is selected from

[0202] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: any of the sequences 1-68); L in each A1-L-A2 is a nitrogen atom covalently attached to the surface-exposed lysine in E and to each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and the wavy line connected to E indicates that each A1-L-A2 is covalently attached (e.g., by means of a covalent bond or a connector) to the surface-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0203] In another aspect, the present invention provides a conjugate described by formula (4):

[0204]

[0205] Each A1 is independently selected from any one of the formulas (AI)-(A-XII):

[0206]

[0207] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0208]

[0209] R6 is selected from

[0210] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: any of the sequences 1-68); L in each L-A1 is 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), and the wavy line connected to E indicates that each L-A1 is 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 A may be independently selected from any of the formulas (AI)-(A-XII).

[0211] In another aspect, the present invention provides a conjugate described by formula (4):

[0212]

[0213] Each A1 is independently selected from any one of the formulas (AI)-(AV):

[0214]

[0215] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0216]

[0217] R6 is selected from

[0218] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: any of the sequences 1-68); L in each L-A1 is a linker covalently attached to a nitrogen atom of a surface-exposed lysine in E and to A1; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each L-A1 is 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 may be independently selected from any of the formulas (AI)-(AV).

[0219] In another aspect, the present invention provides a conjugate described by formula (4):

[0220]

[0221] Each A1 is independently selected from any one of the equations (A-VI)-(A-IX):

[0222]

[0223] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0224]

[0225] R6 is selected from

[0226] 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; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer independently having SEQ ID). NO: any of the sequences 1-68); L in each L-A1 is 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), and the wavy line connected to E indicates that each L-A1 is 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 may be independently selected from any of formulas (A-VI)-(A-IX).

[0227] In another aspect, the present invention provides a conjugate described by formula (5):

[0228]

[0229] Each Int is independently selected from any intermediate in Table 1; E contains an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer having independently the sequence of any of SEQ ID NO: 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), and 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 in E or a sulfur atom of a surface-exposed cysteine, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (for example, 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 intermediate in Table 1.

[0230] The intermediates in Table 1 can be conjugated to an Fc domain or an Fc domain monomer by any suitable method known to those skilled in the art, including any method described or exemplified herein (e.g., by means of a linker). 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 of SEQ ID NO: 1-68). In a preferred embodiment, one or more nitrogen atoms of one or more surface-exposed lysine residues of E or one or more surface-exposed cysteine ​​sulfur atoms of E are covalently conjugated to a linker (e.g., PEG2-PEG). 20 (Connector). The connector conjugated to E may be functionalized such that it can react to form a covalent bond with any Int described herein (e.g., Int of Table 1). In a preferred embodiment, E is conjugated to an azide-functionalized connector and Int (e.g., Int of Table 1) is alkynyl-functionalized. The connector-azido group of E and the connector-alkynyl group of Int (e.g., by click chemistry) form the conjugate of the present invention, such as the conjugate described by formula (5). In other embodiments, E is conjugated to an alkynyl-functionalized connector and Int (e.g., Int of Table 1) is azide-functionalized. The connector-alkynyl group of E and the connector-azido group of Int (e.g., by click chemistry) form the conjugate of the present invention, such as the conjugate described by formula (5).

[0231] Table 1: Intermediates

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251] In some embodiments, each E includes an Fc domain monomer having a sequence of any of SEQ ID NO:1-68.

[0252] In some implementations, E includes a sequence.

[0253] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:4).

[0254] In some implementations, each E includes a sequence.

[0255] MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:33).

[0256] In some implementations, E includes a sequence.

[0257] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH(SEQ ID NO:10)

[0258] In some implementations, each E contains a sequence.

[0259] MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:11).

[0260] In some embodiments of the foregoing three aspects, the nitrogen atom is nitrogen with surface-exposed lysine, such as nitrogen atoms corresponding to Lys35, Lys63, Lys77, Lys79, Lys106, Lys123, Lys129, Lys181, Lys203, Lys228, or Lys236 (e.g., nitrogen atoms thereof) of SEQ ID NO:10 or SEQ ID NO:11. In some embodiments, the nitrogen atom is nitrogen atom corresponding to Lys65, Lys79, Lys108, Lys230, and / or Lys238 (e.g., nitrogen atoms thereof) of SEQ ID NO:10 or SEQ ID NO:11.

[0261] In some embodiments, the conjugate has the following structure:

[0262]

[0263] Wherein a, b, c, d, and e are each independently 0 or 1, and where 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 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.

[0264] In another aspect, the invention provides a group 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.

[0265] In some embodiments of the conjugates described herein, the conjugates form homodimers including Fc domains.

[0266] In some embodiments of the conjugates described herein, E homodimerizes with another E to form an Fc domain.

[0267] In another aspect, the present invention provides a conjugate described by formula (3):

[0268]

[0269] Each A1 and each A2 is independently selected from any one of the formulas (AI)-(A-XII):

[0270]

[0271] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0272]

[0273] R6 is selected from

[0274] 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; E contains albumin (e.g., having SEQ ID NO: ... The sequence of any one of IDNO:69-71 is an albumin, albumin-binding peptide, or Fc-binding peptide; L in each A1-L-A2 is independently covalently attached to a sulfur atom of surface-exposed cysteine ​​or a nitrogen atom of surface-exposed lysine in E and to a connector of each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2 is independently covalently attached (e.g., by means of a bond or connector) to a sulfur atom of solvent-exposed cysteine ​​or a nitrogen atom of solvent-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0275] In another aspect, the present invention provides a conjugate described by formula (3):

[0276]

[0277] Each A1 and each A2 is independently selected from any one of the formulas (AI)-(AV):

[0278]

[0279] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0280]

[0281] R6 is selected from

[0282] 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; E contains albumin (e.g., having SEQ ID NO: ... The sequence of any one of IDNO:69-71 is an albumin, albumin-binding peptide, or Fc-binding peptide; L in each A1-L-A2 is independently covalently attached to a sulfur atom of surface-exposed cysteine ​​or a nitrogen atom of surface-exposed lysine in E and to a connector of each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2 is independently covalently attached (e.g., by means of a bond or connector) to a sulfur atom of solvent-exposed cysteine ​​or a nitrogen atom of solvent-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0283] In another aspect, the present invention provides a conjugate described by formula (3):

[0284]

[0285] Each A1 and each A2 is independently selected from any one of equations (A-VI)-(A-IX):

[0286]

[0287] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0288]

[0289] R6 is selected from

[0290] 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; E contains albumin (e.g., having SEQ ID NO: ... The sequence of any one of IDNO:69-71 is an albumin, albumin-binding peptide, or Fc-binding peptide; L in each A1-L-A2 is independently covalently attached to a sulfur atom of surface-exposed cysteine ​​or a nitrogen atom of surface-exposed lysine in E and to a connector of each of A1 and A2; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the wavy line connected to E indicates that each A1-L-A2 is independently covalently attached (e.g., by means of a bond or connector) to a sulfur atom of solvent-exposed cysteine ​​or a nitrogen atom of solvent-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0291] In another aspect, the present invention provides a conjugate described by formula (4):

[0292]

[0293] Each A1 is independently selected from any one of the formulas (AI)-(A-XII):

[0294]

[0295] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0296]

[0297] R6 is selected from

[0298] 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; E contains albumin (e.g., having SEQ ID NO: ... The sequence of any one of IDNO:69-71 is an albumin, albumin-binding peptide, or Fc-binding peptide; L in each L-A1 is independently covalently attached to a sulfur atom of surface-exposed cysteine ​​or a nitrogen atom of surface-exposed lysine in E and attached 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-A1 is independently covalently attached (e.g., by means of a bond or linker) to a sulfur atom of solvent-exposed cysteine ​​or a nitrogen atom of 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 of the formulas (AI)-(A-XII).

[0299] In another aspect, the present invention provides a conjugate described by formula (4):

[0300]

[0301] Each A1 is independently selected from any one of the formulas (AI)-(AV):

[0302]

[0303] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0304]

[0305] R6 is selected from

[0306] 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; E contains albumin (e.g., having SEQ ID NO: ... The sequence of any one of IDNO:69-71 is an albumin, albumin-binding peptide, or Fc-binding peptide; each L-A1 is independently covalently attached to a sulfur atom of surface-exposed cysteine ​​or a nitrogen atom of surface-exposed lysine in E and attached 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 LA is independently covalently attached (e.g., by means of a bond or linker) to a sulfur atom of solvent-exposed cysteine ​​or a nitrogen atom of solvent-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1 can be independently selected from any of the formulas (AI)-(AV).

[0307] In another aspect, the present invention provides a conjugate described by formula (4):

[0308]

[0309] Each A1 is independently selected from any one of the equations (A-VI)-(A-IX):

[0310]

[0311] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0312]

[0313] R6 is selected from

[0314] 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; E contains albumin (e.g., having SEQ ID NO: ... The sequence of any one of IDNO:69-71 is an albumin, albumin-binding peptide, or Fc-binding peptide; L in each L-A1 is independently covalently attached to a sulfur atom of surface-exposed cysteine ​​or a nitrogen atom of surface-exposed lysine in E and attached 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-A1 is independently covalently attached (e.g., by means of a bond or linker) to a sulfur atom of solvent-exposed cysteine ​​or a nitrogen atom of 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 of the formulas (A-VI)-(A-IX).

[0315] In another aspect, the present invention provides a conjugate described by formula (5):

[0316]

[0317] Each Int is independently selected from any intermediate in Table 1; E comprises albumin (e.g., albumin having the sequence of any of SEQ ID NO: 69-71), albumin-binding peptide, or Fc-binding peptide; L in each L-Int is independently covalently attached to a sulfur atom of surface-exposed cysteine ​​or a nitrogen atom of surface-exposed lysine in E and to a connector 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 solvent-exposed cysteine ​​or a nitrogen atom of solvent-exposed lysine in E, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (for example, 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 intermediate in Table 1.

[0318] The intermediates in Table 1 can be conjugated to albumin, albumin-binding peptides, or Fc-binding peptides (e.g., by means of a linker) by any suitable method known to those skilled in the art, including any method described or exemplified herein. In some embodiments, the conjugate (e.g., the conjugate described by formula (5)) comprises E, wherein E is albumin (e.g., albumin having the sequence of any of SEQ ID NO: 69-71), albumin-binding peptide, or Fc-binding peptide. In a preferred embodiment, one or more nitrogen atoms of lysine residues on the surface of E or one or more sulfur atoms of cysteine ​​residues on the surface of E are covalently conjugated to a linker (e.g., PEG2-PEG). 20 (Connector). The connector conjugated to E may be functionalized such that it can react to form a covalent bond with any Int described herein (e.g., Int of Table 1). In a preferred embodiment, E is conjugated to an azide-functionalized connector and Int (e.g., Int of Table 1) is alkynyl-functionalized. The connector-azido group of E and the connector-alkynyl group of Int (e.g., by click chemistry) form the conjugate of the present invention, such as the conjugate described by formula (5). In other embodiments, E is conjugated to an alkynyl-functionalized connector and Int (e.g., Int of Table 1) is azide-functionalized. The connector-alkynyl group of E and the connector-azido group of Int (e.g., by click chemistry) form the conjugate of the present invention, such as the conjugate described by formula (5).

[0319] In some embodiments, each E includes albumin having the sequence of any of SEQ ID NO:69-71.

[0320] In some implementations, T is 1 and LA is covalently attached to the sulfur atom of Cys34 corresponding to SEQ ID NO:69.

[0321] In another aspect, the invention provides a group 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.

[0322] In another aspect, the present invention provides a conjugate comprising (i) a first portion A1; (ii) a second portion A2; (iii) an Fc domain monomer or an Fc domain; and (iv) a connector 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 formulas (A1)-(A-XII):

[0323]

[0324] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0325]

[0326] R6 is selected from

[0327] 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, or pharmaceutically acceptable salts thereof.

[0328] In another aspect, the present invention provides a conjugate comprising (i) a first portion A1; (ii) a second portion A2; (iii) an Fc domain monomer or an Fc domain; and (iv) a connector 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 formulas (AI)-(AV):

[0329]

[0330] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0331]

[0332] R6 is selected from

[0333] 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, or pharmaceutically acceptable salts thereof.

[0334] In another aspect, the present invention provides a conjugate comprising (i) a first portion A1; (ii) a second portion A2; (iii) an Fc domain monomer or an Fc domain; and (iv) a connector 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 formulas (A-VI)-(A-IX):

[0335]

[0336] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0337]

[0338] R6 is selected from

[0339] 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, or pharmaceutically acceptable salts thereof.

[0340] In another aspect, the present invention provides a conjugate comprising (i) a first portion Int; (ii) an Fc domain monomer or an Fc domain; and (iv) a connector covalently attached to Int and to the Fc domain monomer or the Fc domain; wherein each Int is independently selected from any intermediate in Table 1.

[0341] In another aspect, the present invention provides a conjugate comprising (i) a first portion A1; (ii) a second portion A2; (iii) albumin, an albumin-binding peptide, or an Fc-binding peptide; and (iv) a connector covalently attached to A1 and A2 and to said albumin, said albumin-binding peptide, or said Fc-binding peptide; wherein each A1 and each A2 is independently selected from any one of formulas (A1)-(A-XII):

[0342]

[0343] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0344]

[0345] R6 is selected from

[0346] 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, or pharmaceutically acceptable salts thereof.

[0347] In another aspect, the present invention provides a conjugate comprising (i) a first portion A1; (ii) a second portion A2; (iii) albumin, an albumin-binding peptide, or an Fc-binding peptide; and (iv) a connector covalently attached to A1 and A2 and to the albumin, the albumin-binding peptide, or the Fc-binding peptide; wherein each A1 and each A2 is independently selected from any one of formulas (AI)-(AV):

[0348]

[0349] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0350]

[0351] R6 is selected from

[0352] 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, or pharmaceutically acceptable salts thereof.

[0353] In another aspect, the present invention provides a conjugate comprising (i) a first portion A1; (ii) a second portion A2; (iii) albumin, an albumin-binding peptide, or an Fc-binding peptide; and (iv) a connector covalently attached to A1 and A2 and to said albumin, said albumin-binding peptide, or said Fc-binding peptide; wherein each A1 and each A2 is independently selected from any one of formulas (A-VI)-(A-IX):

[0354]

[0355] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0356]

[0357] R6 is selected from

[0358] 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, or pharmaceutically acceptable salts thereof.

[0359] In another aspect, the present invention provides a conjugate described by formula (DI):

[0360]

[0361] Each A1 and each A2 is independently selected from any one of the formulas (AI)-(A-XII):

[0362]

[0363] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0364]

[0365] R6 is selected from

[0366] 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 (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68), albumin (e.g., albumin having the sequence of any of SEQ ID NO: 69-71), albumin-binding peptide or Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); and L is a linker covalently attached to each of E, A1 and A2, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0367] In another aspect, the present invention provides a conjugate described by formula (DI):

[0368]

[0369] Each A1 and each A2 is independently selected from any one of the formulas (AI)-(AV):

[0370]

[0371] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0372]

[0373] R6 is selected from

[0374] 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 (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68), albumin (e.g., albumin having the sequence of any of SEQ ID NO: 69-71), albumin-binding peptide or Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); and L is a linker covalently attached to each of E, A1 and A2, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0375] In another aspect, the present invention provides a conjugate described by formula (DI):

[0376]

[0377] Each A1 and each A2 is independently selected from any one of equations (A-VI)-(A-IX):

[0378]

[0379] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0380]

[0381] R6 is selected from

[0382] 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 (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68), albumin (e.g., albumin having the sequence of any of SEQ ID NO: 69-71), albumin-binding peptide or Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); and L is a linker covalently attached to each of E, A1 and A2, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein).

[0383] In some embodiments, the conjugate is described by formula (D-II):

[0384]

[0385] Or its pharmaceutically acceptable salt.

[0386] In some embodiments, the conjugate is described by formula (D-II-1):

[0387]

[0388] Or its pharmaceutically acceptable salt.

[0389] In some embodiments, the conjugate is described by formula (D-II-2):

[0390]

[0391] Or its pharmaceutically acceptable salt.

[0392] In some embodiments, the conjugate is described by formula (D-II-3):

[0393]

[0394] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0395] In some embodiments, the conjugate has a structure selected from the following:

[0396]

[0397] In some embodiments, the conjugate is described by formula (D-II-4):

[0398]

[0399] Or its pharmaceutically acceptable salt.

[0400] In some embodiments, the conjugate is described by formula (D-II-5):

[0401]

[0402] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0403] In some embodiments, the conjugate has a structure selected from the following:

[0404]

[0405] Or its pharmaceutically acceptable salt.

[0406] In some embodiments, the conjugate has a structure selected from the following:

[0407]

[0408] Or its pharmaceutically acceptable salt.

[0409] In some embodiments, the conjugate is described by formula (D-II-6):

[0410]

[0411] R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; or pharmaceutically acceptable salts thereof.

[0412] In some embodiments, the conjugate is described by formula (D-II-7):

[0413]

[0414] Or its pharmaceutically acceptable salt.

[0415] In some embodiments, the conjugate is described by formula (D-II-8):

[0416]

[0417] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0418] In some embodiments, the conjugate has a structure

[0419]

[0420] Or its pharmaceutically acceptable salt.

[0421] In some embodiments, the conjugate has a structure

[0422]

[0423] Or its pharmaceutically acceptable salt.

[0424] In some embodiments, the conjugate has a structure

[0425]

[0426] Or its pharmaceutically acceptable salt.

[0427] In some embodiments, the conjugate is described by formula (D-II-9):

[0428]

[0429] Or its pharmaceutically acceptable salt.

[0430] In some embodiments, the conjugate is described by formula (D-II-10):

[0431]

[0432] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0433] In some embodiments, the conjugate has the following structure:

[0434]

[0435] Or its pharmaceutically acceptable salt.

[0436] In some embodiments, the conjugate has the following structure:

[0437]

[0438] Or its pharmaceutically acceptable salt.

[0439] In some embodiments, the conjugate is described by formula (D-III):

[0440]

[0441] Or its pharmaceutically acceptable salt.

[0442] In some embodiments, the conjugate is described by formula (D-III-1):

[0443]

[0444] Or its pharmaceutically acceptable salt.

[0445] In some embodiments, the conjugate is described by formula (D-III-2):

[0446]

[0447] Or its pharmaceutically acceptable salt.

[0448] In some embodiments, the conjugate is described by formula (D-III-3):

[0449]

[0450] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0451] In some embodiments, the conjugate is described by formula (D-III-4):

[0452]

[0453] Or its pharmaceutically acceptable salt.

[0454] In some embodiments, the conjugate is described by formula (D-III-5):

[0455]

[0456] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0457] In some embodiments, the conjugate is described by formula (D-III-6):

[0458]

[0459] Or its pharmaceutically acceptable salt.

[0460] In some embodiments, the conjugate is described by formula (D-III-7):

[0461]

[0462] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0463] In some embodiments, the conjugate is described by formula (D-III-8):

[0464]

[0465] Or its pharmaceutically acceptable salt.

[0466] In some embodiments, the conjugate is described by formula (D-III-9):

[0467]

[0468] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0469] In some embodiments, the conjugate is described by formula (D-IV):

[0470]

[0471] Or its pharmaceutically acceptable salt.

[0472] In some embodiments, the conjugate is described by formula (D-IV-1):

[0473]

[0474] Or its pharmaceutically acceptable salt.

[0475] In some embodiments, the conjugate is described by formula (D-IV-2):

[0476]

[0477] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, the conjugate is described by formula (DV):

[0478]

[0479] Or its pharmaceutically acceptable salt.

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

[0481]

[0482] Or its pharmaceutically acceptable salt.

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

[0484]

[0485] Or its pharmaceutically acceptable salt.

[0486] In some embodiments, the conjugate is described by formula (DV-3):

[0487]

[0488] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0489] In some embodiments, the conjugate is described by formula (DV-4):

[0490]

[0491] Or its pharmaceutically acceptable salt.

[0492] In some embodiments, the conjugate is described by formula (DV-5):

[0493]

[0494] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0495] In some embodiments, the conjugate is described by formula (DV-6):

[0496]

[0497] Or its pharmaceutically acceptable salt.

[0498] In some embodiments, the conjugate is described by formula (DV-7):

[0499]

[0500] Or its pharmaceutically acceptable salt.

[0501] In some embodiments, the conjugate is described by formula (DV-8):

[0502]

[0503] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0504] In some embodiments, the conjugate is described by formula (DV-9):

[0505]

[0506] Or its pharmaceutically acceptable salt.

[0507] In some embodiments, the conjugate is described by formula (DV-10):

[0508]

[0509] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0510] In some embodiments, the conjugate is described by formula (D-VI):

[0511]

[0512] Or its pharmaceutically acceptable salt.

[0513] In some embodiments, the conjugate is described by formula (D-VI-1):

[0514]

[0515] Or its pharmaceutically acceptable salt.

[0516] In some embodiments, the conjugate is described by formula (D-VI-2):

[0517]

[0518] Or its pharmaceutically acceptable salt.

[0519] In some embodiments, the conjugate is described by formula (D-VI-3):

[0520]

[0521] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0522] In some embodiments, the conjugate is described by formula (D-VI-4):

[0523]

[0524] Or its pharmaceutically acceptable salt.

[0525] In some embodiments, the conjugate is described by formula (D-VI-5):

[0526]

[0527] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0528] In some embodiments, the conjugate is described by formula (D-VI-6):

[0529]

[0530] Or its pharmaceutically acceptable salt.

[0531] In some embodiments, the conjugate is described by formula (D-VI-7):

[0532]

[0533] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0534] In some embodiments, the conjugate is described by formula (D-VI-8):

[0535]

[0536] Or its pharmaceutically acceptable salt.

[0537] In some embodiments, the conjugate is described by formula (D-VI-9):

[0538]

[0539] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom. In some embodiments, y1 and y2 are each 1, y1 and y2 are each 2, or y1 and y2 are each 3.

[0540] In some embodiments, the conjugate is described by formula (D-VII):

[0541]

[0542] Or its pharmaceutically acceptable salt.

[0543] In some embodiments of any aspect described herein, R1 is OH. In some embodiments of any aspect described herein, R1 is NH2. In some embodiments of any aspect described herein, R1 is -NHC(=NH)NH2.

[0544] In some embodiments, the conjugate is described by formula (D-VIII):

[0545]

[0546] Or its pharmaceutically acceptable salt.

[0547] In some embodiments, the conjugate is described by formula (D-VIII-1):

[0548]

[0549] Or its pharmaceutically acceptable salt.

[0550] In some embodiments, the conjugate is described by formula (D-VIII-2):

[0551]

[0552] Or its pharmaceutically acceptable salt.

[0553] In some embodiments, the conjugate is described by formula (D-VIII-3):

[0554]

[0555] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0556] In some embodiments, the conjugate has a structure selected from the following:

[0557]

[0558] Or its pharmaceutically acceptable salt.

[0559] In some embodiments, the conjugate is described by formula (D-VIII-4):

[0560]

[0561] Or its pharmaceutically acceptable salt.

[0562] In some embodiments, the conjugate is described by formula (D-VIII-5):

[0563]

[0564] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0565] In some embodiments, the conjugate has a structure selected from the following:

[0566]

[0567] Or its pharmaceutically acceptable salt.

[0568] In some embodiments, the conjugate is described by the following structure:

[0569]

[0570] Or its pharmaceutically acceptable salt.

[0571] In some embodiments, the conjugate is described by formula (D-VIII-6):

[0572]

[0573] Or its pharmaceutically acceptable salt.

[0574] In some embodiments, the conjugate is described by formula (D-VIII-7):

[0575]

[0576] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0577] In some embodiments, the conjugate is described by formula (D-VIII-8):

[0578]

[0579] Or its pharmaceutically acceptable salt.

[0580] In some embodiments, the conjugate is described by formula (D-VIII-9):

[0581]

[0582] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0583] In some embodiments, the conjugate is described by formula (D-VIII-10):

[0584]

[0585] Or its pharmaceutically acceptable salt.

[0586] In some embodiments, the conjugate is described by formula (D-VIII-11):

[0587]

[0588] Where L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (e.g., y1 and y2 are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0589] In some embodiments, the conjugate is described by formula (D-IX):

[0590]

[0591] Or its pharmaceutically acceptable salt.

[0592] In some embodiments, the conjugate is described by formula (D-IX-1):

[0593]

[0594] Or its pharmaceutically acceptable salt.

[0595] In some embodiments, the conjugate is described by formula (D-IX-2):

[0596]

[0597] Or its pharmaceutically acceptable salt.

[0598] In some embodiments, the conjugate is described by formula (D-IX-3):

[0599]

[0600] Or its pharmaceutically acceptable salt.

[0601] In some embodiments, the conjugate is described by formula (D-IX-4):

[0602]

[0603] Or its pharmaceutically acceptable salt.

[0604] In some embodiments, the conjugate is described by formula (D-IX-5):

[0605]

[0606] Or its pharmaceutically acceptable salt.

[0607] In some embodiments, the conjugate is described by formula (D-IX-6):

[0608]

[0609] Or its pharmaceutically acceptable salt.

[0610] In some embodiments, the conjugate is described by formula (DX):

[0611]

[0612] Or its pharmaceutically acceptable salt.

[0613] In some embodiments, the conjugate is described by formula (DX-1):

[0614]

[0615] Or its pharmaceutically acceptable salt.

[0616] In some embodiments, the conjugate is described by formula (DX-2):

[0617]

[0618] Or its pharmaceutically acceptable salt.

[0619] In some embodiments, the conjugate is described by formula (DX-3):

[0620]

[0621] Or its pharmaceutically acceptable salt.

[0622] In some embodiments of any aspect 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 heteroalkylene, optionally substituted C2-C20 alkyne, 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, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate ester, phosphoryl or imino, wherein 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 ynyl, optionally substituted C2-C20 heteroyneyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkenyl, optionally substituted C8-C20 heterocycloalkenyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0623] In some embodiments of any aspect described herein, the skeleton of L or L' is composed of one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkylene, optionally substituted C2-C20 alkyne, 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, optionally substituted C2-C15 heteroarylene, O, S, NR. i Composed of P, carbonyl, thiocarbonyl, sulfonyl, phosphate ester, phosphoryl, or imino groups, wherein 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 ynyl, optionally substituted C2-C20 heteroyneyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkenyl, optionally substituted C8-C20 heterocycloalkenyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0624] In some embodiments of any aspect described herein, L or L' is oxidized. In some embodiments, the skeleton of L or L' comprises no more than 250 atoms. In some embodiments, L or L' is capable of forming amide, urethane, sulfonyl, or urea linkages. In some embodiments, L or L' is a bond. In some embodiments, L or L' is an atom.

[0625] In some implementations of any aspect described herein, each L is described by formula (DLI):

[0626]

[0627] Where L A From formula G A1 -(Z A1 ) g1 -(Y A1 ) h1 -(Z A2 ) i1 -(Y A2 ) j1 -(Z A3 ) k1 -(Y A3 ) l1 -(Z A4 ) m1 -(Y A4 ) n1 -(Z A5 )o1-G A2 Description; L B From formula G B1 -(Z B1 ) g2 -(Y B1 ) h2 -(Z B2 ) i2 -(Y B2 ) j2 -(Z B3 ) k2 -(Y B3 )l2 -(Z B4 ) m2 -(Y B4 ) n2 -(Z B5 )o2-G B2 Description; L C From formula G C1 -(Z C1 ) g3 -(Y C1 ) h3 -(Z C2 ) i3 -(Y C2 ) j3 -(Z C3 ) k3 -(Y C3 ) l3 -(Z C4 ) m3 -(Y C4 ) n3 -(Z C5 )o3-G C2 Description; G A1 It is the key attached to Q; G A2 It is the key attached to A1; G B1 It is the key attached to Q; G B2 It is the key attached to A2; G C1 It is the key attached to Q; G C2 It is a bond attached to E or a functional group capable of reacting with a functional group conjugated to E (e.g., maleimide and cysteine, amine and activated carboxylic acid, thiol and maleimide, activated sulfonic acid and amine, isocyanate and amine, azide and alkyne, and 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 ynynylene, 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 B3 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 ynyl, optionally substituted C2-C20 heteroyneyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkenyl, optionally substituted C8-C20 heterocycloalkenyl, optionally substituted C5-C15 aryl or optionally substituted C2-C15 heteroaryl; g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g 3, h3, i3, j3, k3, l3, m3, n3, and o3 are each independently 0 or 1; Q is a nitrogen atom, an optionally substituted C1-C20 alkylene group, an optionally substituted C1-C20 heteroalkylene group, an optionally substituted C2-C20 alkenylene group, an optionally substituted C2-C20 alkenylene group, an optionally substituted C2-C20 alkenylene group, an optionally substituted C2-C20 alkenylene group, an optionally substituted C3-C20 cycloalkylene group, an optionally substituted C3-C20 heteroalkylene group, an optionally substituted C4-C20 cycloalkenylene group, an optionally substituted C4-C20 cycloalkenylene group, an optionally substituted C8-C20 cycloalkenylene group, an optionally substituted C8-C20 cycloalkenylene group, an optionally substituted C5-C15 arylene group, or an optionally substituted C2-C15 heteroarylene group.

[0628] In some implementations, L C It may have two sites that attach to an Fc domain, an Fc-binding peptide, albumin, or an albumin-binding peptide (e.g., two G sites). C2 ).

[0629] In some embodiments of any aspect described herein, L includes a polyethylene glycol (PEG) connector. The PEG connector comprises a repeating unit structure (-CH2CH2O-). n The polyethylene glycol (PEG) connector can covalently bind a neuraminidase inhibitor and E (e.g., in a conjugate of any of formulas (MI)-(MX)). The PEG connector can covalently bind a first neuraminidase inhibitor and a second neuraminidase inhibitor (e.g., in a conjugate of any of formulas (DI)-(DX)). The PEG connector can covalently bind a neuraminidase inhibitor dimer and E (e.g., in a conjugate of any of formulas (DI)-(DX)). The PEG connector can be selected from PEG2 to PEG3. 100 Any of these (e.g., PEG2, PEG3, PEG4, PEG5, PEG5-PEG) 10 PEG10 -PEG 20 PEG 20 -PEG 30 PEG 30 -PEG 40 PEG 50 -PEG 60 PEG 60 -PEG 70 PEG 70 -PEG 80 PEG 80 -PEG 90 PEG 90 -PEG 100 In some implementations, L c Includes PEG connectors, where L C It is covalently attached to each of Q and E.

[0630] In some implementations, L is

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641] Where z1 and z2 are each an integer from 1 to 20; and R9 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl.

[0642] In some implementations, L is

[0643]

[0644]

[0645]

[0646]

[0647]

[0648] Wherein R* is a bond or includes optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkylene, optionally substituted C2-C20 alkyne, 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, optionally substituted C2-C15 heteroarylene, O, S, NR i One or more of the following groups: P, carbonyl, thiocarbonyl, sulfonyl, phosphate ester, and imino, wherein 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 ynyl, optionally substituted C2-C20 heteroyneyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkenyl, optionally substituted C8-C20 heterocycloalkenyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0649] In some implementation schemes, Y is: (-NH(C=O)O-) and L is:

[0650] In some implementation schemes, Y is: (-NH(C=O)O-) and L is:

[0651] In some implementation schemes, Y is: (-NH(C=O)O-) and L is:

[0652] In some implementation schemes, Y is: (-O-) and L is:

[0653] In another aspect, the present invention provides a conjugate described by formula (MI):

[0654]

[0655] Each A1 is independently selected from any one of the formulas (AI)-(A-XII):

[0656]

[0657] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0658]

[0659] R6 is selected from

[0660] 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 (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68), albumin (e.g., albumin having the sequence of any of SEQ ID NO: 69-71), albumin-binding peptide or Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); and L is a linker covalently attached to each of E and A1, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1 can be independently selected from any of the formulas (AI)-(A-XII).

[0661] In another aspect, the present invention provides a conjugate described by formula (MI):

[0662]

[0663] Each A1 is independently selected from any one of the formulas (AI)-(AV):

[0664]

[0665] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0666]

[0667] R6 is selected from

[0668] 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 (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68), albumin (e.g., albumin having the sequence of any of SEQ ID NO: 69-71), albumin-binding peptide or Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); and L is a linker covalently attached to each of E and A1, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1 can be independently selected from any of the formulas (AI)-(AV).

[0669] In another aspect, the present invention provides a conjugate described by formula (MI):

[0670]

[0671] Each A1 is independently selected from any one of the equations (A-VI)-(A-IX):

[0672]

[0673] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0674]

[0675] R6 is selected from

[0676] 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 (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68), albumin (e.g., albumin having the sequence of any of SEQ ID NO: 69-71), albumin-binding peptide or Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); and L is a linker covalently attached to each of E and A1, or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1 can be independently selected from any of the formulas (A-VI)-(A-IX).

[0677] In some embodiments, the conjugate is described by formula (M-II):

[0678]

[0679] Or its pharmaceutically acceptable salt.

[0680] In some embodiments, the conjugate is described by formula (M-II-1):

[0681]

[0682] Or its pharmaceutically acceptable salt.

[0683] In some embodiments, the conjugate is described by formula (M-II-2):

[0684]

[0685] Or its pharmaceutically acceptable salt.

[0686] In some embodiments, the conjugate is described by formula (M-II-3):

[0687]

[0688] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0689] In some embodiments, the conjugate is described by formula (M-II-4):

[0690]

[0691] Or its pharmaceutically acceptable salt.

[0692] In some embodiments, the conjugate is described by formula (M-II-5):

[0693]

[0694] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0695] In some embodiments, the conjugate has a structure

[0696]

[0697] Or its pharmaceutically acceptable salt.

[0698] In some embodiments, the conjugate is described by formula (M-II-6):

[0699]

[0700] R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; or pharmaceutically acceptable salts thereof.

[0701] In some embodiments, the conjugate is described by formula (M-II-7):

[0702]

[0703] Or its pharmaceutically acceptable salt.

[0704] In some embodiments, the conjugate is described by formula (M-II-8):

[0705]

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

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

[0708]

[0709] In some embodiments, the conjugate is described by formula (M-II-9):

[0710]

[0711] Or its pharmaceutically acceptable salt.

[0712] In some embodiments, the conjugate is described by formula (M-II-10):

[0713]

[0714] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0715] In some embodiments, the conjugate has a structure

[0716]

[0717] Or its pharmaceutically acceptable salt.

[0718] In some embodiments, the conjugate is described by formula (M-III):

[0719]

[0720] Or its pharmaceutically acceptable salt.

[0721] In some embodiments, the conjugate is described by formula (M-III-1):

[0722]

[0723] Or its pharmaceutically acceptable salt.

[0724] In some embodiments, the conjugate is described by formula (M-III-2):

[0725]

[0726] Or its pharmaceutically acceptable salt.

[0727] In some embodiments, the conjugate is described by formula (M-III-3):

[0728]

[0729] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0730] In some embodiments, the conjugate is described by formula (M-III-4):

[0731]

[0732] Or its pharmaceutically acceptable salt.

[0733] In some embodiments, the conjugate is described by formula (M-III-5):

[0734]

[0735] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0736] In some embodiments, the conjugate is described by formula (M-III-6):

[0737]

[0738] Or its pharmaceutically acceptable salt.

[0739] In some embodiments, the conjugate is described by formula (M-III-7):

[0740]

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

[0742] In some embodiments, the conjugate is described by formula (M-III-8):

[0743]

[0744] Or its pharmaceutically acceptable salt.

[0745] In some embodiments, the conjugate is described by formula (M-III-9):

[0746]

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

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

[0749]

[0750] Or its pharmaceutically acceptable salt.

[0751] In some embodiments, the conjugate is described by formula (M-IV-1):

[0752]

[0753] Or its pharmaceutically acceptable salt.

[0754] In some embodiments, the conjugate is described by formula (M-IV-2):

[0755]

[0756] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0757] In some embodiments, the conjugate is described by formula (MV):

[0758]

[0759] Or its pharmaceutically acceptable salt.

[0760] In some embodiments, the conjugate is described by formula (MV-1):

[0761]

[0762] Or its pharmaceutically acceptable salt.

[0763] In some embodiments, the conjugate is described by formula (MV-2):

[0764]

[0765] Or its pharmaceutically acceptable salt.

[0766] In some embodiments, the conjugate is described by formula (MV-3):

[0767]

[0768] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0769] In some embodiments, the conjugate is described by formula (MV-4):

[0770]

[0771] Or its pharmaceutically acceptable salt.

[0772] In some embodiments, the conjugate is described by formula (MV-5):

[0773]

[0774] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0775] In some embodiments, the conjugate is described by formula (MV-6):

[0776]

[0777] Or its pharmaceutically acceptable salt.

[0778] In some embodiments, the conjugate is described by formula (MV-7):

[0779]

[0780] Or its pharmaceutically acceptable salt.

[0781] In some embodiments, the conjugate is described by formula (MV-8):

[0782]

[0783] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0784] In some embodiments, the conjugate is described by formula (MV-9):

[0785]

[0786] Or its pharmaceutically acceptable salt.

[0787] In some embodiments, the conjugate is described by formula (MV-10):

[0788]

[0789] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0790] In some embodiments, the conjugate is described by formula (M-VI):

[0791]

[0792] Or its pharmaceutically acceptable salt.

[0793] In some embodiments, the conjugate is described by formula (M-VI-1):

[0794]

[0795] Or its pharmaceutically acceptable salt.

[0796] In some embodiments, the conjugate is described by formula (M-VI-2):

[0797]

[0798] Or its pharmaceutically acceptable salt.

[0799] In some embodiments, the conjugate is described by formula (M-VI-3):

[0800]

[0801] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0802] In some embodiments, the conjugate is described by formula (M-VI-4):

[0803]

[0804] Or its pharmaceutically acceptable salt.

[0805] In some embodiments, the conjugate is described by formula (M-VI-5):

[0806]

[0807] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0808] In some embodiments, the conjugate is described by formula (M-VI-6):

[0809]

[0810] Or its pharmaceutically acceptable salt.

[0811] In some embodiments, the conjugate is described by formula (M-VI-7):

[0812]

[0813] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0814] In some embodiments, the conjugate is described by formula (M-VI-8):

[0815]

[0816] Or its pharmaceutically acceptable salt.

[0817] In some embodiments, the conjugate is described by formula (M-VI-9):

[0818]

[0819] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0820] In some embodiments, the conjugate is described by formula (M-VII):

[0821]

[0822] Or its pharmaceutically acceptable salt.

[0823] In some embodiments of any aspect described herein, R1 is OH. In some embodiments of any aspect described herein, R1 is NH2. In some embodiments of any aspect described herein, R1 is -NHC(=NH)NH2.

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

[0825]

[0826] Or its pharmaceutically acceptable salt.

[0827] In some embodiments, the conjugate is described by formula (M-VIII-1):

[0828]

[0829] Or its pharmaceutically acceptable salt.

[0830] In some embodiments, the conjugate is described by formula (M-VIII-2):

[0831]

[0832] Or its pharmaceutically acceptable salt.

[0833] In some embodiments, the conjugate is described by formula (M-VIII-3):

[0834]

[0835] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0836] In some embodiments, the conjugate is described by formula (M-VIII-4):

[0837]

[0838] Or its pharmaceutically acceptable salt.

[0839] In some embodiments, the conjugate is described by formula (M-VIII-5):

[0840]

[0841] Where L' is the remainder of L, and y1 is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

[0842] In some embodiments, the conjugate has a structure

[0843]

[0844] Or its pharmaceutically acceptable salt.

[0845] In some embodiments, the conjugate is described by formula (M-VIII-6):

[0846]

[0847] Or its pharmaceutically acceptable salt.

[0848] In some embodiments, the conjugate is described by formula (M-VIII-7):

[0849]

[0850] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0851] In some embodiments, the conjugate is described by formula (M-VIII-8):

[0852]

[0853] Or its pharmaceutically acceptable salt.

[0854] In some embodiments, the conjugate is described by formula (M-VIII-9):

[0855]

[0856] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0857] In some embodiments, the conjugate is described by formula (M-VIII-10):

[0858]

[0859] Or its pharmaceutically acceptable salt.

[0860] In some embodiments, the conjugate is described by formula (M-VIII-11):

[0861]

[0862] Where L' is the remainder of L, and y1 is an integer from 1 to 20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), or a pharmaceutically acceptable salt thereof.

[0863] In some embodiments, the conjugate is described by formula (M-IX):

[0864]

[0865] Or its pharmaceutically acceptable salt.

[0866] In some embodiments, the conjugate is described by formula (M-IX-1):

[0867]

[0868] Or its pharmaceutically acceptable salt.

[0869] In some embodiments, the conjugate is described by formula (M-IX-2):

[0870]

[0871] Or its pharmaceutically acceptable salt.

[0872] In some embodiments, the conjugate is described by formula (M-IX-3):

[0873]

[0874] Or its pharmaceutically acceptable salt.

[0875] In some embodiments, the conjugate is described by formula (M-IX-4):

[0876]

[0877] Or its pharmaceutically acceptable salt.

[0878] In some embodiments, the conjugate is described by formula (M-IX-5):

[0879]

[0880] Or its pharmaceutically acceptable salt.

[0881] In some embodiments, the conjugate is described by formula (M-IX-6):

[0882]

[0883] Or its pharmaceutically acceptable salt.

[0884] In some embodiments, the conjugate is described by formula (MX):

[0885]

[0886] Or its pharmaceutically acceptable salt.

[0887] In some embodiments, the conjugate is described by formula (MX-1):

[0888]

[0889] Or its pharmaceutically acceptable salt.

[0890] In some embodiments, the conjugate is described by formula (MX-2):

[0891]

[0892] Or its pharmaceutically acceptable salt.

[0893] In some embodiments, the conjugate is described by formula (MX-3):

[0894]

[0895] Or its pharmaceutically acceptable salt.

[0896] In some embodiments 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 heteroalkylene, optionally substituted C2-C20 alkyne, 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, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate ester, phosphoryl or imino, wherein 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 ynyl, optionally substituted C2-C20 heteroyneyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkenyl, optionally substituted C8-C20 heterocycloalkenyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0897] In some embodiments of any aspect described herein, the skeleton of L or L' is composed of one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkylene, optionally substituted C2-C20 alkyne, 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, optionally substituted C2-C15 heteroarylene, O, S, NR. i Composed of P, carbonyl, thiocarbonyl, sulfonyl, phosphate ester, phosphoryl, or imino groups, wherein 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 ynyl, optionally substituted C2-C20 heteroyneyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkenyl, optionally substituted C8-C20 heterocycloalkenyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0898] In some embodiments of any aspect described herein, L or L' is oxidically substituted. In some embodiments, the skeleton of L or L' comprises no more than 250 atoms. In some embodiments, L or L' is capable of forming amide, urethane, sulfonyl, or urea linkages. 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.

[0899] In some implementations, each L is described by equation (ML-1):

[0900] 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

[0901] Among them: J 1 It is the key attached to A1; J 2 It is a bond attached to E or a functional group capable of reacting with a functional group conjugated to E (e.g., maleimide and cysteine, amine and activated carboxylic acid, thiol and maleimide, activated sulfonic acid and amine, isocyanate and amine, azide and alkyne, and olefin and tetrazine); Q 1 Q 2 Q 3 Q 4 and Q 5Each 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; T 1 T 2 T 3 T 4 Each of them is independently O, S, NR i P, carbonyl, thiocarbonyl, sulfonyl, phosphate ester, phosphoryl, or imino; 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 ynyl, optionally substituted C2-C20 heteroyneyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloyneyl, optionally substituted C8-C20 heterocycloyneyl, optionally substituted C5-C15 aryl or optionally substituted C2-C15 heteroaryl; and g, h, i, j, k, l, m, n and o are each independently 0 or 1; or a pharmaceutically acceptable salt thereof.

[0902] In some implementation schemes, J 2 It may have two sites that attach to an Fc domain, an Fc-binding peptide, albumin, or an albumin-binding peptide (e.g., two J sites). 2 ).

[0903] In some implementations, L is

[0904]

[0905] Where d is an integer from 1 to 20 (for example, d is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).

[0906] In some implementations, L is

[0907]

[0908] Where d and e are each an integer from 1 to 26; or a pharmaceutically acceptable salt thereof.

[0909] In some embodiments of any aspect described herein, L includes a polyethylene glycol (PEG) connector. The PEG connector comprises a repeating unit structure (-CH2CH2O-). n The polyethylene glycol (PEG) connector can covalently bind a neuraminidase inhibitor and E (e.g., in a conjugate of any of formulas (MI)-(MX)). The PEG connector can covalently bind a first neuraminidase inhibitor and a second neuraminidase inhibitor (e.g., in a conjugate of any of formulas (DI)-(DX)). The PEG connector can covalently bind a neuraminidase inhibitor dimer and E (e.g., in a conjugate of any of formulas (DI)-(DX)). The PEG connector can be selected from PEG2 to PEG3. 100 Any of these (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 implementations, L c Includes PEG connectors, where L C It is covalently attached to each of Q and E.

[0910] In some embodiments of any aspect described herein, R1 is -NHC(=NH)NH2. In some embodiments of any aspect described herein, R2 is -F. In some embodiments of any aspect described herein, R3 is -F. In some embodiments of any aspect described herein, R4 is -CO2H. In some embodiments of any aspect described herein, R5 is -COCH3.

[0911] In some embodiments of any aspect described herein, L is covalently attached to the surface of E exposing the nitrogen atom of lysine or L is covalently attached to the surface of E exposing the sulfur atom of cysteine.

[0912] In some embodiments of any aspect described herein, E is an Fc domain monomer. In some embodiments, n is 2 and each E dimers to form an Fc domain.

[0913] In some implementations, n is 2, each E is an Fc domain monomer, each E dimers to form an Fc domain, and the conjugate is described by formula (DI-1):

[0914]

[0915] 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.

[0916] In some implementations, n is 2, each E is an Fc domain monomer, each E dimers to form an Fc domain, and the conjugate is described by formula (MI-1):

[0917]

[0918] 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.

[0919] In some embodiments of any aspect described herein, E has a sequence of any of SEQ ID NO:1-68.

[0920] In some embodiments of any aspect described herein, E is albumin, an albumin-binding peptide, or an Fc-binding peptide. In some embodiments in which E is albumin, an albumin-binding peptide, or an Fc-binding peptide, n is 1.

[0921] In some embodiments, n is 1, E is albumin, albumin-binding peptide, or Fc-binding peptide, and the conjugate is described by formula (DI-2):

[0922]

[0923] Where E is albumin, albumin-binding peptide, or Fc-binding peptide; and T is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

[0924] In some embodiments, n is 1, E is albumin, albumin-binding peptide, or Fc-binding peptide, and the conjugate is described by formula (MI-2):

[0925]

[0926] Where E is albumin, albumin-binding peptide, or Fc-binding peptide; and T is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.

[0927] In some embodiments of any aspect described herein, E is albumin having a sequence of any of SEQ ID NO:69-71.

[0928] In some implementations of any aspect described herein, T is 1, 2, 3, 4, or 5.

[0929] In another aspect, the present invention provides a group of conjugates having the structure of any of the conjugates described herein (e.g., a group of conjugates having any of the formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I),) 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.

[0930] In some embodiments of any aspect described herein, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2 may be independently selected (e.g., independently selected from any of the A1-L-A2 structures described herein). In some embodiments, E may be attached to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different A1-L-A2 portions. In some embodiments, E is attached to a first A1-L-A2 portion and a second A1-L-A2 portion. In some embodiments, A1 and A2 of the first A1-L-A2 portion are independently selected from any of formulas (A-III)-(AV):

[0931]

[0932] Furthermore, A1 and A2 in the second A1-L-A2 part are independently selected from any one of formulas (AI), (A-II), (A-VI), (A-VII), (A-VIII), and (A-IX):

[0933]

[0934] In some embodiments, each of the first A1-L-A2 portions is specifically conjugated to a lysine residue of E (e.g., the surface of E exposes a nitrogen atom of the lysine residue), and each of the second A1-L-A2 portions is specifically conjugated to a cysteine ​​residue of E (e.g., the surface of E exposes a sulfur atom of the cysteine ​​residue). In some embodiments, each of the first A1-L-A2 portions is specifically conjugated to a cysteine ​​residue of E (e.g., the surface of E exposes a sulfur atom of the cysteine ​​residue), and each of the second A1-L-A2 portions is specifically conjugated to a lysine residue of E (e.g., the surface of E exposes a nitrogen atom of the lysine residue).

[0935] In some embodiments, the number of first A1-L-A2 portions adjoining 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 portions adjoining E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0936] In some embodiments of any aspect described herein, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L may be independently selected (e.g., independently selected from any of the A1-L structures described herein). In some embodiments, E may be attached to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different A1-L portions. In some embodiments, E is attached to a first A1-L portion and a second A1-L portion. In some embodiments, the A1 of the first A1-L portion is selected from any of formulas (A-III)-(AV):

[0937]

[0938] Furthermore, A1 in the second A1-L part is selected from any one of formulas (AI), (A-II), (A-VI), (A-VII), (A-VIII), or (A-IX):

[0939]

[0940] In some embodiments, each of the first A1-L portions is specifically conjugated to a lysine residue of E (e.g., the surface of E exposes a nitrogen atom of a lysine residue), and each of the second A1-L portions is specifically conjugated to a cysteine ​​residue of E (e.g., the surface of E exposes a sulfur atom of a cysteine ​​residue). In some embodiments, each of the first A1-L portions is specifically conjugated to a cysteine ​​residue of E (e.g., the surface of E exposes a sulfur atom of a cysteine ​​residue), and each of the second A1-L portions is specifically conjugated to a lysine residue of E (e.g., the surface of E exposes a nitrogen atom of a lysine residue).

[0941] In some embodiments, the number of first A1-L portions affixed 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 portions affixed to E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0942] In another aspect, the present invention provides a conjugate described by formula (D'-I):

[0943]

[0944] Each A1 is independently selected from any one of the formulas (A-III)-(AV):

[0945]

[0946] Each A2 is independently selected from any one of equations (AI), (A-II), (A-VI), (A-VII), (A-VIII), and (A-IX):

[0947]

[0948] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0949]

[0950] R6 is selected from

[0951] 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 contains an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NO:1-68), albumin (e.g., having SEQ ID NO:1-68), and albumin (e.g., having the sequence of any one of SEQ ID NO:1-68). The sequence of any one of NO:69-71 is an albumin, albumin-binding peptide, or Fc-binding peptide; n is 1 or 2; T1 is an integer from 1 to 10 (e.g., T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L1 is a linker covalently conjugated to E and each A1; T1 is an integer from 1 to 10 (e.g., T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L2 is a linker covalently conjugated to E and each A2; T2 is an integer from 1 to 10 (e.g., T2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), or a pharmaceutically acceptable salt thereof.

[0952] In some embodiments, each A1-L-A1 is specifically conjugated to a lysine residue of E (e.g., the surface of E exposes a nitrogen atom of the lysine residue), and each A2-L-A2 is specifically conjugated to a cysteine ​​residue of E (e.g., the surface of E exposes a sulfur atom of the cysteine ​​residue). In some embodiments, each A1-L-A1 portion is specifically conjugated to a cysteine ​​residue of E (e.g., the surface of E exposes a sulfur atom of the cysteine ​​residue), and each A2-L-A2 portion is specifically conjugated to a lysine residue of E (e.g., the surface of E exposes a nitrogen atom of the lysine residue).

[0953] In another aspect, the present invention provides a conjugate described by formula (M'-I):

[0954]

[0955] Each A1 is independently selected from any (M-IX) in equations (A-III)-(AV):

[0956]

[0957] Each A2 is independently selected from any one of equations (AI), (A-II), (A-VI), (A-VII), (A-VIII), and (A-IX):

[0958]

[0959] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[0960]

[0961] R6 is selected from

[0962] 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 contains an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NO:1-68), albumin (e.g., having SEQ ID NO:1-68), and albumin (e.g., having the sequence of any one of SEQ ID NO:1-68). The sequence of any one of NO:69-71 is an albumin, albumin-binding peptide, or Fc-binding peptide; n is 1 or 2; T1 is an integer from 1 to 10 (e.g., T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L1 is a linker covalently conjugated to E and A1; T1 is an integer from 1 to 10 (e.g., T1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L2 is a linker covalently conjugated to E and A2; T2 is an integer from 1 to 10 (e.g., T2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), or a pharmaceutically acceptable salt thereof.

[0963] In some embodiments, each A1-L is specifically conjugated to a lysine residue of E (e.g., the surface of E exposes a nitrogen atom of the lysine residue), and each A2-L is specifically conjugated to a cysteine ​​residue of E (e.g., the surface of E exposes a sulfur atom of the cysteine ​​residue). In some embodiments, each A1-L portion is specifically conjugated to a cysteine ​​residue of E (e.g., the surface of E exposes a sulfur atom of the cysteine ​​residue), and each A2-L portion is specifically conjugated to a lysine residue of E (e.g., the surface of E exposes a nitrogen atom of the lysine residue).

[0964] In another aspect, the present invention provides a pharmaceutical composition comprising any conjugate described herein (e.g., a conjugate of any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX) or (M'-I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0965] In another aspect, the present invention provides a method for treating a subject who has or is presumed to have a viral infection, the method comprising administering to the subject an effective amount of any of the conjugates or compositions described herein (e.g., conjugates of any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I).

[0966] In another aspect, the present invention provides a method for the preventive treatment of viral infection in a subject in need, the method comprising administering to the subject an effective amount of any of the conjugates or compositions described herein (e.g., conjugates of any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I).

[0967] 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.

[0968] In some implementations, the subject is immune-impaired.

[0969] In some implementations, the subject has been diagnosed with humoral immune deficiency, T-cell deficiency, neutropenia, asplenia, or complement deficiency.

[0970] In some implementations, the subject is receiving or is about to receive immunosuppressive therapy.

[0971] In some embodiments, the subject has been diagnosed with a disease that causes immunosuppression. In some embodiments, the disease is cancer or acquired immunodeficiency syndrome. In some embodiments, the cancer is leukemia, lymphoma, or multiple myeloma.

[0972] In some implementations, the subject has already received or is about to receive a hematopoietic stem cell transplant.

[0973] In some implementations, the subject has received or is about to receive an organ transplant.

[0974] In some embodiments, the conjugate or composition is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intra-articularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, via the surface, intratumorally, via the peritoneum, subcutaneously, subconjunctivally, intracysticly, via the mucosa, intraperitoneally, intraumbilically, intraocularly, via the mouth, via local, by inhalation, by injection, or by infusion.

[0975] 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 induces an immune response in the subject against influenza A, B, or C virus or parainfluenza virus.

[0976] In some embodiments, 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),(MV-6), (MV-7), (MV-8), (MV-9), (MV-10), (M-VI), (M-VI-1), (M-VI-2), (M-VI-3), (M-VI-4), (M-VI-5), (M-VI-6), (M-V I-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-VII In any of the formulas (I-6), (M-VIII-7), (M-VIII-8), (M-VIII-9), (M-VIII-10), (M-VIII-11), (M-IX), (M-IX-1), (M-IX-2), (M-IX-3), (M-IX-4), (M-IX-5), (M-IX-6), (MX), (MX-1), (MX-2), (MX-3), or (M'-I), the Fc domain-containing composition may replace the Fc domain, and the Fc domain-containing monomer composition may replace the Fc domain monomer. In any of the formulas described herein (e.g., any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I), when n is 1, E is the Fc domain-containing monomer composition. In any of the formulas described herein (e.g., any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I), when n is 2, E is a composition containing an Fc domain.

[0977] In some embodiments, the Fc domain-containing composition is an antibody or an antibody fragment. Antibodies may include any form of immunoglobulin, heavy chain antibodies, light chain antibodies, LRR-based antibodies, or other protein backbones with antibody-like properties, and any other immune-binding motif 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 may include binding portions comprising portions derived from or significantly homologous to the antibody, such as the antigenic determinant region of the antibody. Exemplary antibody fragments include Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, scFv, and SMIP.

[0978] In certain embodiments, the antibody or antibody fragment is a human, mouse, camelid (e.g., llama, alpaca, or camel), goat, sheep, rabbit, chicken, guinea pig, hamster, horse, or rat antibody or antibody fragment. In certain embodiments, the antibody is IgG, IgA, IgD, IgE, IgM, or an endosome. In some embodiments, the antibody fragment includes scFv, sdAb, dAb, Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, or SMIP.

[0979] In some embodiments, the Fc domain-containing composition (e.g., an antibody or antibody fragment) imparts binding specificity to one or more targets (e.g., an antigen).

[0980] In some embodiments, the one or more targets (e.g., antigens) bound by the Fc domain-containing composition (e.g., antibody or antibody fragment) are viral (e.g., influenza) proteins, such as neuraminidase or hemagglutinin. In some embodiments, the antibody or antibody fragment recognizes 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., the antibody or antibody fragment described in Wu et al., J. Mol. Biol. 429:2694-2709 (2017)). In some embodiments, the antibody or antibody fragment targets a viral matrix protein (e.g., matrix 2 protein). TCN032 is a matrix 2 protein-targeting monoclonal antibody.

[0981] In some embodiments, the Fc domain-containing composition (e.g., an antibody or antibody fragment) comprises one or more single-domain antibodies (sdAbs). In some embodiments, the Fc domain-containing composition is an antibody or antibody fragment that includes an sdAb reactivity with influenza A, such as an sdAb conjugated to an influenza A hemagglutinin (e.g., SD36 or SD38, described in Laursen et al., Science. 362:598-602 (2018)). In some embodiments, the Fc domain-containing composition is an antibody or antibody fragment that includes an sdAb reactivity with influenza B, such as an sdAb conjugated to an influenza B hemagglutinin (e.g., SD83 or SD84, described in Laursen et al., Science. 362:598-602 (2018)).

[0982] 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.

[0983] In another aspect, the present invention includes any one of formulas (1)-(5), (D-I)-(D-X), (D'-I), (M-I)-(M-X) or (M'-I) (for example, 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),(MV-6), (MV-7), (MV-8), (MV-9), (MV-10), (M-VI), (M-VI-1), (M-VI-2), (M-VI-3), (M-VI-4), (M-VI-5), (M-VI-6 ), (M-VI-7), (M-VI-8), (M-VI-9), (M-VII), (M-VIII), (M-VIII-1), (M-VIII-2), (M-VIII-3), (M-VIII-4), (M-VI The conjugates described in (M-VIII-5), (M-VIII-6), (M-VIII-7), (M-VIII-8), (M-VIII-9), (M-VIII-10), (M-VIII-11), (M-IX), (M-IX-1), (M-IX-2), (M-IX-3), (M-IX-4), (M-IX-5), (M-IX-6), (MX), (MX-1), (MX-2), (MX-3), or (M'-I) are provided, wherein E is an antibody or antibody fragment. In a preferred embodiment where E is an antibody or antibody fragment, n is 1. In some embodiments, the antibody or antibody fragment includes any antibody or antibody fragment described herein, such as monoclonal antibodies conjugated to viral hemagglutinins (e.g., CR6261, CR8020, MEDI8852, MHAA4549A, or VIS410); broadly neutralizing antibodies or antibody fragments targeting viral hemagglutinins (e.g., antibodies or antibody fragments described in Wu et al., J. Mol. Biol. 429:2694-2709 (2017)); sdAbs targeting viral hemagglutinins (e.g., SD36, SD38, SD83, or SD84); or MDAbs or fragments thereof targeting viral hemagglutinins (e.g., JNJ-7445).

[0984] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:1. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:1.

[0985] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:2. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:2.

[0986] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:3. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:3.

[0987] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:4. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:4.

[0988] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:5. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:5.

[0989] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:6. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:6.

[0990] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:7. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:7.

[0991] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:8. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:8.

[0992] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:9. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:9.

[0993] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:10. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:10.

[0994] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:11. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:11.

[0995] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:12. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:12.

[0996] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:13. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:13.

[0997] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:14. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:14.

[0998] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:15. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:15.

[0999] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:16. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:16.

[1000] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:17. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:17.

[1001] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:18. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:18.

[1002] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:19. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:19.

[1003] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:20. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:20.

[1004] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:21. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:21.

[1005] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:22. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:22.

[1006] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:23. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:23.

[1007] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:24. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:24.

[1008] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:25. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:25.

[1009] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:26. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:26.

[1010] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:27. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:27.

[1011] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:28. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:28.

[1012] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:29. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:29.

[1013] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:30. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:30.

[1014] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:31. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:31.

[1015] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:32. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:32.

[1016] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:33. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:33.

[1017] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:34. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:34.

[1018] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:35. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:35.

[1019] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:36. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:36.

[1020] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:37. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:37.

[1021] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:38. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:38.

[1022] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:39. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:39.

[1023] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:40. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:40.

[1024] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:41. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:41.

[1025] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:42. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:42.

[1026] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:43. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:43.

[1027] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:44. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:45.

[1028] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:46. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:46.

[1029] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:47. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:47.

[1030] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:48. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:48.

[1031] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:49. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:49.

[1032] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:50. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:50.

[1033] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:51. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:51.

[1034] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:52. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:52.

[1035] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:53. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:53.

[1036] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:54. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:54.

[1037] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:55. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:55.

[1038] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:56. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:56.

[1039] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:57. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:57.

[1040] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:58. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:58.

[1041] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:59. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:59.

[1042] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:60. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:60.

[1043] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:61. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:61.

[1044] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:62. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:62.

[1045] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:63. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:63.

[1046] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:64. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:64.

[1047] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:65. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:65.

[1048] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:66. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:66.

[1049] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:67. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:67.

[1050] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:68. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:68.

[1051] In some embodiments of any aspect described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO:69. In some embodiments, E comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:69.

[1052] 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 having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:70.

[1053] 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 having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:71.

[1054] In some embodiments where E includes an Fc domain monomer of any aspect described herein, the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68) includes a triple mutation corresponding to M252Y / S254T / T256E (YTE). As used herein, it should be understood that the amino acid “corresponding to” (e.g., a specific SEQ ID NO.) a specific amino acid residue includes any amino acid residue that a person skilled in the art would understand to be compared with (e.g., the specific residue of the specific sequence). For example, any of SEQ ID NO: 1-68 may be mutated to include a YTE mutation.

[1055] In some embodiments where E includes an Fc domain monomer in any of the aspects described herein, the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68) includes a double mutant corresponding to M428L / N434S(LS). As used herein, it should be understood that the amino acid “corresponding to” (e.g., a specific SEQ ID NO.) a specific amino acid residue includes any amino acid residue that a person skilled in the art would understand to be compared with (e.g., the specific residue of the specific sequence). For example, any of SEQ ID NO: 1-68 may be mutated to include an LS mutation.

[1056] In some embodiments where E includes an Fc domain monomer of any aspect described herein, the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68) includes a mutant corresponding to N434H. As used herein, it should be understood that "corresponding to" (e.g., a specific SEQ ID NO.) a specific amino acid residue includes any amino acid residue that a person skilled in the art would understand to be compared to (e.g., the specific residue of the specific sequence). For example, any of SEQ ID NO: 1-68 may be mutated to include the N434H mutation.

[1057] In some embodiments where E includes an Fc domain monomer of any aspect described herein, the Fc domain monomer (e.g., an Fc domain monomer having the sequence of any of SEQ ID NO: 1-68) includes a mutant corresponding to C220S. As used herein, it should be understood that "corresponding to" (e.g., a specific SEQ ID NO.) a specific amino acid residue includes any amino acid residue that a person skilled in the art would understand to be compared to (e.g., the specific residue of the specific sequence). For example, any of SEQ ID NO: 1-68 may be mutated to include a C220S mutation.

[1058] In some embodiments where E includes an Fc domain monomer in any aspect described herein, the Fc domain monomer (e.g., an Fc domain monomer having a sequence of any of SEQ ID NO: 1-68) is a fragment of the Fc domain monomer (e.g., at least 25 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more) or at least 50 (e.g., 51, 52, 53, 54, 55, 56, 57, 58, 59, 60) from SEQ ID NO: 1-68. Fragments of 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) consecutive amino acid lengths.

[1059] In some embodiments of any aspect described herein (e.g., conjugates of any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I), one or more nitrogen atoms of lysine residues exposed on one or more surfaces of E, or one or more sulfur atoms of cysteine ​​exposed on one or more surfaces of E, are covalently conjugated to a linker (e.g., PEG2-PEG). 20 (Connector). The connector conjugated to E may be functionalized such that it can react to form a covalent bond with the L of any A1-L or any A2-L-A1 described herein. In a preferred embodiment, E is conjugated to an azide-functionalized connector and the L of A1-L or any A2-L-A1 is alkynyl-functionalized. The connector-azido group of E and the connector-alkynyl group of A1-L or A2-L-A1 (e.g., by click chemistry) form the conjugates of the present invention, such as those described by any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I). In other embodiments, E is conjugated to an alkynyl-functionalized connector and the L of any A1-L or any A2-L-A1 is azido-functionalized. The conjugates of the present invention are formed by linker-alkyne of E and linker-azido group of A1-L or A2-L-A1 (e.g., by click chemistry), such as the conjugates described by formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX) or (M'-I).

[1060] In some embodiments of any aspect described herein, the wavy line of any of equations (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX) or (M'-I) may represent a covalent bond between E and L in A1-L or A2-L-A1.

[1061] In some embodiments of any aspect described herein, the wavy line of any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I) may indicate that one or more amino acid side chains of E (e.g., one or more nitrogen atoms of one or more surface-exposed lysine residues of E or one or more surface-exposed sulfur atoms of cysteine ​​in E) have been concatenated to a linker (e.g., PEG2-PEG). 20 A linker), wherein the reactive portion is functionalized such that the reactive portion forms a covalent bond with the L of any A1-L or any A2-L-A1 described herein (e.g., via click chemistry between an azide-functionalized linker and an alkyne-functionalized linker, as described above). In some embodiments of any aspect described herein, A1 and / or A2 have the structure described by (AI):

[1062]

[1063] In a preferred embodiment, A1 and / or A2 have the structure described by (AI): R1 is -NHC(=NH)NH2, R4 is -CO2H, R5 is -COCH3, and / or X is -O-. In a preferred embodiment, A1 and / or A2 have the zanamivir structure described by the following formula:

[1064]

[1065] In some embodiments of any aspect described herein, A1 and / or A2 have the structure described by (A-II):

[1066]

[1067] In a preferred embodiment, A1 and / or A2 have the structure described by (A-II): R1 is -NHC(=NH)NH2, R2 is H or F, R3 is H or F, R4 is -CO2H, R5 is -COCH3, and / or X is -O-. In a preferred embodiment, A1 and / or A2 have the structure described by the following formula:

[1068]

[1069] In some embodiments of any aspect described herein, A1 and / or A2 have the structure described by (A-III):

[1070]

[1071] In a preferred embodiment, A1 and / or A2 have the structure described by (A-III): R1 is -NHC(=NH)NH2, R4 is -CO2H, and / or R5 is -COCH3. In a preferred embodiment, A1 and / or A2 have the peramivir structure described by the following formula:

[1072]

[1073] In some embodiments of any aspect described herein, A1 and / or A2 have the structure described by (A-IV):

[1074]

[1075] In a preferred embodiment, A1 and / or A2 have the structure described by (A-IV): R1 is -NHC(=NH)NH2, R4 is -CO2H, and / or R5 is -COCH3. In a preferred embodiment, A1 and / or A2 have the structure described by the following formula:

[1076]

[1077] In some embodiments of any aspect described herein, A1 and / or A2 have the structure described by (AV):

[1078]

[1079] In a preferred embodiment, A1 and / or A2 have the structure described by (AV): R1 is -NHC(=NH)NH2, R4 is -CO2H, and / or R5 is -COCH3. In a preferred embodiment, A1 and / or A2 have the structure described by the following formula:

[1080]

[1081] In some embodiments of any aspect described herein, A1 and / or A2 have the structure described by (A-VI):

[1082]

[1083] In a preferred embodiment, A1 and / or A2 have the structure described by (A-VI): R1 is -NHC(=NH)NH2, R4 is -CO2H, R5 is -COCH3, and / or X is -O-. In a preferred embodiment, A1 and / or A2 have the zanamivir structure described by the following formula:

[1084]

[1085] In some embodiments of any aspect described herein, A1 and / or A2 have the structures described by (A-VII):

[1086]

[1087] In a preferred embodiment, A1 and / or A2 have the structure described by (A-VII): R1 is -NHC(=NH)NH2, R2 is H or F, R3 is H or F, R4 is -CO2H, R5 is -COCH3, and / or X is -O-. In a preferred embodiment, A1 and / or A2 have the structure described by the following formula:

[1088]

[1089] In some embodiments of any aspect described herein, A1 and / or A2 have the structure described by (A-VIII):

[1090]

[1091] In a preferred embodiment, A1 and / or A2 have the structure described by (A-VIII): R1 is -NHC(=NH)NH2, R5 is -COCH3, and / or X is -O-. In a preferred embodiment, A1 and / or A2 have the structure described by the following formula:

[1092]

[1093] In some embodiments of any aspect described herein, A1 and / or A2 have the structure described by (A-IX):

[1094]

[1095] In a preferred embodiment, A1 and / or A2 have the structure described by (A-IX): R1 is -NHC(=NH)NH2, R2 is H or F, R3 is H or F, R5 is -COCH3, and / or X is -O-. In a preferred embodiment, A1 and / or A2 have the structure described by the following formula:

[1096]

[1097] In some embodiments of any aspect described herein, A1 and / or A2 have the structure described by (AX):

[1098]

[1099] In a preferred embodiment, A1 and / or A2 have the structure described by (AX): R1 is -NHC(=NH)NH2, R3 is H, R5 is -COCH3, and / or X is -O-. In a preferred embodiment, A1 and / or A2 have the sulfozanamivir structure described by the following formula:

[1100]

[1101] In some embodiments of any aspect described herein, A1 and / or A2 have the structure described by (A-XI):

[1102]

[1103] In a preferred embodiment, A1 and / or A2 have the structure described by (A-XI): R4 is -CO2H, and / or R5 is -COCH3. In a preferred embodiment, the olefin is a racemic mixture of (E), (Z), or (E) / (Z). In a preferred embodiment, A1 and / or A2 have the A-315675 (Abbott) structure described by the following formula:

[1104]

[1105] In some embodiments of any aspect described herein, A1 and / or A2 have the structure described by (A-XII):

[1106]

[1107] In a preferred embodiment, A1 and / or A2 have the structure described by (A-XII): R4 is -CO2H. In a preferred embodiment, A1 and / or A2 have the A-315675 (Abbott) structure described by the following formula:

[1108]

[1109] In some embodiments, the conjugate is conjugate 1 or any of its regioisomers, and the drug:antibody ratio (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 implementations, 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.

[1110] In some embodiments, the conjugate is conjugate 2 or any of its regioisomers, 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 implementations, 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.

[1111] In some embodiments, the conjugate is conjugate 3 or any of its regioisomers, 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 implementations, 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.

[1112] In some embodiments, the conjugate is conjugate 4 or any of its regioisomers, 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 implementations, 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.

[1113] 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, 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 implementations, 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.

[1114] In some embodiments, the conjugate is conjugate 6 or any of its regioisomers, 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 implementations, 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.

[1115] In some embodiments, the conjugate is conjugate 7 or any of its regioisomers, 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 implementations, 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.

[1116] In some embodiments, the conjugate is conjugate 8 or any of its regioisomers, 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 implementations, 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.

[1117] 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, 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 implementations, 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.

[1118] In some embodiments, the conjugate is conjugate 10 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, 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 implementations, 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.

[1119] In some embodiments, the conjugate is conjugate 11 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, 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 implementations, 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.

[1120] In some embodiments, the conjugate is conjugate 12 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, 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 implementations, 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.

[1121] In some embodiments, the conjugate is conjugate 13 or any of its regioisomers, 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 implementations, 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.

[1122] In some embodiments, the conjugate is conjugate 14 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, 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 implementations, 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.

[1123] In some embodiments, the conjugate is conjugate 15 or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, for example, 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 implementations, 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.

[1124] In some embodiments, the conjugate is conjugate 16 or any regiomeric isomer 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 implementations, 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 17 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 implementations, 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 18 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 implementations, 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 19 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 implementations, 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 20 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 implementations, 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 21 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 implementations, 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 22 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 implementations, 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 23 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 implementations, 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 24 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 implementations, 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 25 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 implementations, 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 26 or any regiomeric isomer 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 implementations, 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 27 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 implementations, 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 28 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 implementations, 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 29 or any regiomeric isomer 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 implementations, 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 30 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 implementations, 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 31 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 implementations, 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 32 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 implementations, 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 33 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 implementations, 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 34 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 implementations, 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 35 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 implementations, 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 36 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 implementations, 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 37 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 implementations, 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 38 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 implementations, 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 39 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 implementations, 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 40 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 implementations, 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 41 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 implementations, 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 42 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 implementations, 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 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 implementations, 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] definition

[1153] To facilitate understanding of the invention, several terms are defined below. The terms defined herein have meanings as commonly understood by those skilled in the art related to this invention. Terms such as “a,” “an,” and “the” are not intended to refer to a single entity, but rather to encompass the general category to which a particular instance may be described. These terms are used herein to describe specific embodiments of the invention, but their use does not limit the invention except as set forth in the claims.

[1154] As used herein, the term "neuraminidase inhibitor" or "viral neuraminidase inhibitor" refers to a compound that reduces the activity of the enzyme influenza virus neuraminidase (e.g., from influenza A, B, or C viruses). Neuraminidase inhibitors can be identified by methods known to those skilled in the art, such as by a reduction in viral replication in an influenza virus plaque reduction assay, for example, at concentrations below 20 μM (e.g., below 10 μM, 5 μM, 2 μM, 1 μM, 500 nM, or 100 nM). Viral neuraminidase inhibitors known to those skilled in the art include zanamivir, sulfozanamivir, peramivir, and A-315675 (Abbott) (see, for example, Hadházi et al., A sulfozanamivir analogue has potent anti-influenza virus activity. ChemMedChem Comm. 13:785-789 (2018) and In vitro characterization of A-315675, a highly potent inhibitor of A and B strains of influenza virus neuraminidases and influenza virus replication. AntimicrobialAgents and Chemotherapy 46(4):1014-1021 (2002)). The viral neuraminidase inhibitors of the present invention include zanamivir, sulfozanamivir, peramivir, A-315675, and analogues thereof, such as viral neuraminidase inhibitors of formula (AI)-(A-XII):

[1155]

[1156] R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, and -SO3H; R5 is selected from -COCH3, -COCF3, and -SO2CH3; X is selected from -O- and -S-; Y is selected from...

[1157]

[1158] R6 is selected from

[1159] R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl and C2-C15 heteroaryl; and R8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl and C2-C15 heteroaryl.

[1160] As used herein, the term "inhibition of neuraminidase activity" refers to an IC50 concentration of less than or equal to 1,000 nM. 50 For example, as measured by the neuraminidase inhibition analysis according to Example 2 of this document. Specifically, IC 50 This indicates the concentration of influenza virus neuraminidase inhibitor required for 50% inhibition in vitro. In some aspects, this is determined by the IC50 concentration of 100 nM or less, or 10 nM or less, based on neuraminidase inhibition analysis. 50 Indicates compounds that inhibit neuraminidase activity.

[1161] "Viral infection" refers to the pathogenic growth of a virus (e.g., influenza virus) in a host organism (e.g., a human subject). A viral infection can be any situation in which the presence of a viral population is harming the host's body. Therefore, a subject is "experiencing" a viral infection when an excessive viral population is present in or on the subject's body, or when the presence of a viral population is harming the subject's cells or other tissues.

[1162] As used herein, the term "Fc domain monomer" refers to a polypeptide chain comprising at least one hinge domain and second and third antibody constant domains (C). H 2 and C H3) or a functional fragment thereof (e.g., a fragment capable of (i) dimerizing with another Fc domain monomer to form an Fc domain, and (ii) binding to an Fc receptor). The Fc domain monomer may be any immunoglobulin antibody isotype, including IgG, IgE, IgM, IgA, or IgD (e.g., IgG). Additionally, the Fc domain monomer may be an IgG subtype (e.g., IgG1, IgG2a, IgG2b, IgG3, or IgG4) (e.g., IgG1). The Fc domain monomer does not include any portion of the immunoglobulin capable of functioning as an antigen-recognition region, such as a variable domain or complementarity-determining region (CDR). The Fc domain monomer in the conjugates described herein may contain one or more alterations to the sequence of the wild-type Fc domain monomer. (For example, substitutions, additions, or deletions of 1-10, 1-8, 1-6, or 1-4 amino acids) that alter the interaction between the Fc domain and the Fc receptor. Examples of suitable alterations are known in the art. In some embodiments, the human Fc domain monomer (e.g., the IgG heavy chain, such as IgG1) comprises a region extending from any of Asn208, Glu216, Asp221, Lys222, or Cys226 to the C-terminus of the heavy chain at Lys447. The C-terminal Lys447 of the Fc region may or may not be present, without affecting the structure or stability of the Fc region. Unless otherwise specified herein, the amino acid residues in the IgG or Fc domain monomer are numbered according to the EU numbering system for antibodies, also known as the Kabat EU index, as described, for example, in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[1163] As used herein, the term "Fc domain" refers to a dimer of two Fc domain monomers capable of binding to an Fc receptor. In the wild-type Fc domain, the two Fc domain monomers bind to each other via two C-terminals. H 3. Interactions between constant antibody domains dimerize, and in some embodiments, one or more disulfide bonds are formed between the hinge domains of the two dimerized Fc domain monomers.

[1164] The term "covalent attachment" refers to two parts of a conjugate that are connected to each other by a covalent bond, which is formed between two atoms in the two parts of the conjugate.

[1165] 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, having an affinity for and function in binding to an Fc domain (such as any Fc domain described herein). Fc-binding peptides can have different origins, such as synthetic, human, mouse, or rat. The Fc-binding peptides of the present invention comprise Fc-binding peptides engineered to include one or more (e.g., two, three, four, or five) solvent-exposed cysteine ​​or lysine residues, which provide sites for conjugation to compounds of the present invention (e.g., conjugation to neuraminidase inhibitor monomers or dimers, including by means of a linker). Most preferably, the Fc-binding peptide will contain a single solvent-exposed cysteine ​​or lysine, thus enabling site-specific conjugation of compounds of the present invention. Fc-binding peptides may comprise only naturally occurring amino acid residues, or may include one or more non-naturally occurring amino acid residues. When included, non-naturally occurring amino acid residues (e.g., side chains of non-naturally occurring amino acid residues) may serve as attachment sites for compounds of the present invention (e.g., neuraminidase inhibitor monomers or dimers, including those via linkers). The Fc-binding peptides of the present invention may be linear or cyclic. The Fc-binding peptides of the present invention include any Fc-binding peptide known to those skilled in the art.

[1166] As used herein, the term "albumin" refers to a polypeptide containing amino acids corresponding to naturally occurring albumin (e.g., human serum albumin) or variants thereof (such as engineered variants of naturally occurring albumin). Variants of albumin include polymorphisms, fragments such as domains and subdomains, and fusion proteins (e.g., albumin having C-terminal or N-terminal fusions such as polypeptide linkers). Preferably, the albumin has the amino acid sequence of human serum albumin (HSA) or variants or fragments thereof, and most preferably has the amino acid sequence of its functional variants or fragments. The albumin of the present invention comprises a protein having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with any of SEQ ID NO: 69-71. The albumin of the present invention comprises an albumin 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 compounds of the present invention (e.g., conjugation to neuraminidase inhibitor monomers or dimers, including by means of a linker). Most preferably, the albumin will contain a single solvent-exposed cysteine ​​or lysine, thus enabling site-specific conjugation of the compounds of the present invention. The albumin may comprise only naturally occurring amino acid residues, or may include one or more non-naturally occurring amino acid residues. When included, non-naturally occurring amino acid residues (e.g., side chains of non-naturally occurring amino acid residues) can serve as attachment sites for compounds of the present invention (e.g., neuraminidase inhibitor monomers or dimers, including by means of a linker).

[1167] 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, having an affinity for albumin (such as any albumin described herein) and having the function of binding said albumin. Preferably, the albumin-binding peptide is conjugated to naturally occurring serum albumin, most preferably human serum albumin. Albumin-binding peptides can have different origins, such as synthetic, human, mouse, or rat. The albumin-binding peptides of the present invention include albumin-binding peptides engineered to include one or more (e.g., two, three, four, or five) solvent-exposed cysteine ​​or lysine residues, which provide sites for conjugation to compounds of the present invention (e.g., conjugation to neuraminidase inhibitor monomers or dimers, including by means of a linker). Most preferably, the albumin-binding peptide will contain a single solvent-exposed cysteine ​​or lysine, thus enabling site-specific conjugation of the compounds of the present invention. The albumin-binding peptide may comprise only naturally occurring amino acid residues, or may include one or more non-naturally occurring amino acid residues. When included, non-naturally occurring amino acid residues (e.g., side chains of non-naturally occurring amino acid residues) may serve as attachment sites for compounds of the present invention (e.g., neuraminidase inhibitor monomers or dimers, including those by means of linkers). The albumin-binding peptide of the present invention may be linear or cyclic. The albumin-binding peptide of the present invention includes any albumin-binding peptide known to those skilled in the art, examples of which are provided herein. Further illustrative albumin-binding peptides are provided in U.S. Patent Application No. 2005 / 0287153, which is incorporated herein by reference in its entirety.

[1168] As used herein, "surface-exposed amino acid," such as surface-exposed cysteine ​​or surface-exposed lysine, or "solvent-exposed amino acid," refers to an amino acid that is readily accessible to the solvent surrounding the protein. Surface-exposed amino acids may be naturally occurring or engineered variants of the protein (e.g., substituted or inserted). In some embodiments, surface-exposed amino acids are those whose substitution does not substantially alter the three-dimensional structure of the protein.

[1169] As used herein, the terms “connector,” “L,” and “L’” refer to a covalent link between two or more components in a conjugate (e.g., between two neuraminidase inhibitors in the conjugate described herein, between a neuraminidase inhibitor and an Fc domain or albumin in the conjugate described herein, and between a dimer of two neuraminidase inhibitors and an Fc domain or albumin in the conjugate described herein). In some embodiments, the conjugate described herein may contain a connector having a trivalent structure (e.g., a trivalent connector). The trivalent connector has three arms, each of which 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).

[1170] Molecules that can be used as connectors include at least two functional groups, which may 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 alkynyl 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 alkynyl group, or an amino group and a sulfonic acid group. A first functional group may be covalently linked to a first component of the conjugate, and a second functional group may be covalently linked to a second component of the conjugate. In some embodiments of a trivalent connector, the two arms of the connector may contain two dicarboxylic acids, wherein the first carboxylic acid may be covalently linked to a first neuraminidase inhibitor in the conjugate, and the second carboxylic acid may be covalently linked to a second neuraminidase inhibitor in the conjugate, and the third arm of the connector may be covalently linked to an Fc domain or albumin in the conjugate. Examples of dicarboxylic acids are further described herein. In some embodiments, a molecule containing one or more maleimide groups may be used as a linker, wherein the maleimide group may form a carbon-sulfur link with a cysteine ​​residue of a component in the conjugate (e.g., an Fc domain or albumin). In some embodiments, a molecule containing one or more alkynyl groups may be used as a linker, wherein the alkynyl group may form a 1,2,3-triazole link with an azide of a component in the conjugate (e.g., an Fc domain or albumin). In some embodiments, a molecule containing one or more azido groups may be used as a linker, wherein the azido group may form a 1,2,3-triazole link with an alkynyl group of a component in the conjugate (e.g., an Fc domain or albumin). In some embodiments, a molecule containing one or more disulfone groups may be used as a linker, wherein the disulfone group may form a link with an amino group of a component in the conjugate (e.g., an Fc domain or albumin). In some embodiments, a molecule containing one or more sulfonic acid groups may be used as a linker, wherein the sulfonic acid group may form a sulfonamide link with a component in the conjugate. In some embodiments, a molecule containing one or more isocyanate groups may be used as a connector, wherein the isocyanate groups may form a urea link with a component in the conjugate. In some embodiments, a molecule containing one or more haloalkyl groups may be used as a connector, wherein the haloalkyl groups may form a covalent link with a component in the conjugate, such as a CN and CO link.

[1171] In some embodiments, the connector provides space, rigidity, and / or flexibility between two or more components. In some embodiments, the connector may be a bond, such as a covalent bond. The term "bond" refers to a chemical bond, such as an amide bond, disulfide bond, CO bond, CN bond, NN bond, CS bond, or any kind of bond generated by a chemical reaction (e.g., chemical conjugation). In some embodiments, the connector comprises no more than 250 atoms. In some embodiments, the connector comprises no more than 250 non-hydrogen atoms. In some embodiments, the framework of the connector comprises no more than 250 atoms. The "framework" of the connector refers to the atoms in the connector that, together, form the shortest path from one part of the 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 framework of the connector directly participate in connecting one part of the conjugate to another part of the conjugate (e.g., connecting a first neuraminidase inhibitor and a second neuraminidase inhibitor). For example, hydrogen atoms of carbon attached to the framework of the connector are not considered to directly participate in connecting one part of the conjugate to another part of the conjugate.

[1172] In some embodiments, the linker may comprise a synthetic group derived from, for example, a synthetic polymer (e.g., polyethylene glycol (PEG) polymer). In some embodiments, the linker may comprise one or more amino acid residues, such as D- or L-amino acid residues. In some embodiments, the linker may be residues 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, the connector may comprise one or more (e.g., 1-100, 1-50, 1-25, 1-10, 1-5, or 1-3) optionally substituted alkylene groups, optionally substituted heteroalkylene groups (e.g., PEG units), optionally substituted alkenyl groups, optionally substituted heteroalkenyl groups, optionally substituted ynylene groups, optionally substituted heteroalkenyl groups, optionally substituted cycloalkylene groups, optionally substituted heteroalkylene groups, optionally substituted heteroalkenyl groups, optionally substituted cycloalkenyl groups, optionally substituted heteroalkenyl groups, optionally substituted aryl groups, optionally substituted heteroaryl groups (e.g., pyridine), O, S, NR i (R i(H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkenyl, optionally substituted cycloalkynyl, optionally substituted heterocycloalkynyl, optionally substituted aryl or optionally substituted heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate ester, phosphoryl, or imino. For example, the connector may comprise one or more optionally substituted C1-C20 alkylene groups, optionally substituted C1-C20 heteroalkylene groups (e.g., PEG units), optionally substituted C2-C20 alkenylene groups (e.g., C2 alkenylene groups), optionally substituted C2-C20 heteroalkylene groups, optionally substituted C2-C20 alkyneylene groups, optionally substituted C2-C20 heteroalkylene groups, optionally substituted C3-C20 cycloalkylene groups (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20 heteroalkylene groups, optionally substituted C4-C20 cycloalkenylene groups, optionally substituted C4-C20 cycloalkenylene groups, optionally substituted C8-C20 cycloalkynylene groups, optionally substituted C8-C20 cycloalkynylene groups, optionally substituted C5-C15 arylene groups (e.g., C6 arylene groups), optionally substituted C2-C15 heteroarylene groups (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 ynyl, optionally substituted C2-C20 heteroyneyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkenyl, optionally substituted C8-C20 heterocycloalkenyl, optionally substituted C5-C15 aryl or optionally substituted C2-C15 heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate ester, phosphoryl, or imino.

[1173] As used herein, the terms “alkyl,” “alkenyl,” and “alkynyl” include straight-chain and branched monovalent substituents, and combinations thereof, which, when unsubstituted, contain only C and H. When an alkyl group comprises at least one carbon-carbon double or triple bond, the alkyl group may be referred to as “alkenyl” or “alkynyl,” respectively. The monovalent of an alkyl, alkenyl, or alkynyl group does not include any substituents optionally present on the alkyl, alkenyl, or alkynyl group. For example, if an alkyl, alkenyl, or alkynyl group is attached to a compound, the monovalent of the alkyl, alkenyl, or alkynyl group refers to its attachment to the compound without including any additional substituents that may be present on the alkyl, alkenyl, or alkynyl group. In some embodiments, the alkyl or heteroalkyl group may contain, for example, 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4 or 1-2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4 or C1-C2). In some embodiments, the alkenyl, heteroalkenyl, ynyl, or heteroynyl group may contain, for example, 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-propenyl, and 3-butynyl.

[1174] As used herein, the term "cycloalkyl" refers to a monovalent saturated or unsaturated non-aromatic cycloalkyl group. A cycloalkyl group may have, for example, three to twenty carbons (e.g., C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl). Examples of cycloalkyl 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, it may be referred to as a "cycloalkenyl". A cycloalkenyl 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 cycloalkenyl). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. When a cycloalkyl group comprises at least one carbon-carbon triple bond, the cycloalkyl group may be referred to as a "cycloalkynyl group." A cycloalkynyl group may have, for example, eight to twenty carbons (e.g., C8-C9, C8-C10, C8-C11, C8-C12, C8-C14, C8-C16, C8-C18, or C8-C20 cycloalkynyl groups). The term "cycloalkyl" also includes cyclic compounds having a bridging polycyclic structure, wherein one or more carbons bridge two non-adjacent members of a monocyclic ring, such as bicyclic [2.2.1.]heptyl and adamantane. The term "cycloalkyl" also includes bicyclic, tricyclic, and tetracyclic fused-ring structures, such as decahydronaphthalene and spirocyclic compounds. As used herein, the term "aryl" refers to any monocyclic or fused-ring bicyclic or tricyclic system that is aromatic in terms of electron distribution within the ring system, such as phenyl, naphthyl, or phenanthrene. In some embodiments, the ring system contains 5-15 ring member atoms or 5-10 ring member atoms. The aryl group 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 aryl groups). The term "heteroaryl" also refers to the monocyclic or fused bicyclic system containing one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms selected from O, S, and N. Heteroaryl groups can have, for example, two to fifteen carbons (e.g., C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C2-C11, C2-C12, C2-C13, C2-C14, or C2-C15 heteroaryl groups). The inclusion of heteroatoms allows for the inclusion of 5-membered and 6-membered rings that will be considered aromatic. Therefore, typical heteroaryl systems include, for example, pyridinyl, pyrimidinyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolinyl, quinolinyl, benzothiazolyl, benzofuranyl, thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, and imidazolyl.Because tautomerism is possible, groups such as phthalimide are also considered heteroaryl groups. In some embodiments, the aryl or heteroaryl group is optionally a 5- or 6-membered aromatic ring system containing 1-2 nitrogen atoms. In some embodiments, the aryl or heteroaryl group is optionally substituted with phenyl, pyridyl, indolyl, pyrimidinyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, or imidazopyridyl. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group may optionally be substituted with a substituent such as an aryl substituent (e.g., biphenyl).

[1175] The term "alkylaryl" refers to an aryl group attached to an alkylene, alkenyl, or ynylene group. Generally, if a compound is attached to an alkylaryl group, the alkylene, alkenyl, or ynylene portion of the alkylaryl group is attached to the compound. In some embodiments, the alkylaryl group is a C6-C35 alkylaryl group (e.g., C6-C16, C6-C14, C6-C12, C6-C10, C6-C9, C6-C8, C7, or C6 alkylaryl group), wherein the number of carbons indicates the total number of carbons in the aryl and alkylene, alkenyl, or ynylene portions of the alkylaryl group. Examples of alkylaryl groups include, but are not limited to, (C1-C8)alkylene (C6-C12)aryl, (C2-C8)alkenyl (C6-C12)aryl, or (C2-C8)ynyl (C6-C12)aryl. In some embodiments, the alkylaryl group is benzyl or phenethyl. In a heteroaryl alkyl group, one or more heteroatoms selected from N, O, and S may be present in the alkylene, alkenyl, or alkyneyl group and / or in the aryl group. In an optionally substituted alkylaryl alkyl group, substituents may be present on the alkylene, alkenyl, or alkyneyl group and / or on the aryl group.

[1176] As used herein, the term "amino" represents -N(R) x )2 or -N + (R x )3, where R x Each can be independently H, alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, or two R groups. x They combine to form heterocyclic alkyl groups. In some embodiments, the amino group is -NH2.

[1177] As used herein, the term "alkylamino" refers to an amino group attached to an alkylene group (e.g., C1-C5 alkylene), an alkenyl group (e.g., C2-C5 alkenyl), or an alkyne group (e.g., C2-C5 alkenyl). Generally, if a compound is attached to an alkylamino group, the alkylene, alkenyl, or alkyne portion of the alkylamino group is attached to the compound. The amino group of an alkylamino group refers to -N(R) x )2 or -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.

[1178] 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.

[1179] As used herein, the terms "alkylene", "alkenylene", and "alkynylene" refer to a divalent group having a specified size. In some embodiments, the alkylene may contain, for example, 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, the alkenyl or ynyl group may contain, for example, 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). The alkylene, alkenyl, and / or ynyl group includes straight-chain and branched-chain forms, as well as combinations thereof. The divalent nature of the alkylene, alkenyl, or ynyl group does not include any substituents optionally present on the alkylene, alkenyl, or ynyl group. For example, two neuraminidase inhibitors may be attached to each other by means of a linker comprising an alkylene, alkenyl, and / or ynyl group or a combination thereof. Each of the alkylene, alkenyl, and / or yntylide groups in the connector is considered divalent if its two attachments to either end of the alkylene, alkenyl, and / or yntylide group are divalent. For example, if the connector comprises -(optionally substituted alkylene)-(optionally substituted alkenyl)-(optionally substituted alkylene)-, then the alkenyl group is considered divalent if its attachments to the two alkylene groups at the end of the connector are divalent. Optional substituents on the alkenyl group are not included in the divalent nature of the alkenyl group. The divalent nature of the alkylene, alkenyl, or yntylide group (e.g., the alkylene, alkenyl, or yntylide group in the connector) means that the two ends of the group do not include optional substituents that may be present in the alkylene, alkenyl, or yntylide group. Because it is divalent, it can link multiple (e.g., two) parts of the conjugate (e.g., a first neuraminidase inhibitor and a second neuraminidase inhibitor) together. Alkylene, alkenylene, and / or yntylide groups may be substituted by groups typically suitable as substituents for alkyl, alkenyl, and yntylide groups as described herein. For example, C=O is a C1 alkylene group substituted with oxo (=O). For example, -HCR-C≡C- can be considered an optionally substituted yntylide group and is considered a divalent group, even if it has an optionally present substituent R. Heteroalkylene, alkenylene, and / or yntylide groups refer to alkylene, alkenylene, and / or yntylide groups comprising one or more (e.g., 1-4, 1-3, 1, 2, 3, or 4) heteroatoms (e.g., N, O, and S). For example, the PEG unit -(CH2)2-O- in a polyethylene glycol (PEG) polymer or a PEG polymer is considered a heteroalkylene group containing one or more oxygen atoms.

[1180] 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.

[1181] 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).

[1182] As used herein, the term "optional substitution" refers to having 0, 1, or more substituents, such as 0-25, 0-20, 0-10, or 0-5 substituents. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkylaryl, acyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, halogen, oxo, cyano, nitro, amino, alkylamino, hydroxyl, alkoxy, alkylacyl, carbonyl, carbamoyl, guanidinyl, ureyl, amidinyl, any of the above groups or portions, and heteroforms of any of the above groups or portions. 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 optional substituents on the same or adjacent atoms may join to form a fused, optionally substituted aromatic or non-aromatic, saturated or unsaturated ring containing 3-8 members, or two optional substituents on the same atom may join to form an optionally substituted aromatic or non-aromatic, saturated or unsaturated ring containing 3-8 members. An optionally substituted group or portion refers to a group or portion (e.g., any of the above groups or portions) in which one atom (e.g., a hydrogen atom) is optionally replaced by another substituent. For example, the optionally substituted alkyl group may be an optionally substituted methyl group, wherein the hydrogen atom of the methyl group is replaced by, for example, OH. As another example, the substituent on the heteroalkyl group or its divalent paired heteroalkyl group may replace the hydrogen atom on the carbon or the hydrogen atom on a heteroatom such as N. For example, the hydrogen atom in the group -R-NH-R- may be replaced by an alkamide substituent, such as -RN[(CH2C(O)N(CH3)2]-R.

[1183] Generally, any substituents present are optional non-interfering substituents. A “non-interfering substituent” is a substituent that retains the ability of the conjugates described herein (e.g., conjugates of any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I)) to bind to viral neuraminidase or inhibit the proliferation of influenza virus. Therefore, in some embodiments, the substituent may alter the degree of activity. However, as long as the conjugate retains the ability to bind to viral neuraminidase or inhibit viral proliferation, the substituent will be classified as “non-interfering.” For example, a non-interfering substituent will retain the ability of the compound to provide antiviral efficacy based on an IC50 value of 10 μM or lower in a viral plaque reduction assay (such as an IC50 value against influenza virus neuraminidase based on less than 500 nM in Example 2). Therefore, the substituent may alter the degree of inhibition based on plaque reduction or influenza virus neuraminidase inhibition. However, as long as the compounds described herein (such as compounds of formulas (AI), (A-II), (A-III), (A-IV), (AV), (A-VI), (A-VII), (A-VIII), (A-IX), (AX), (A-XI), and (A-XII)) retain the ability to inhibit influenza virus neuraminidase activity, the substituents will be classified as "non-interfering". Various analyses for determining viral plaque reduction or the ability of any compound to inhibit influenza virus neuraminidase are available in the art, and some are illustrated in the examples below.

[1184] The term "hetero" when used to describe a chemical group or portion refers to a heteroatom having at least one non-carbon or non-hydrogen atom, such as N, O, and S. If any of the aforementioned groups or portions contains at least one heteroatom, it may be called hetero. For example, heterocyclic alkyl, heterocyclic alkenyl, or heterocyclic alkynyl refers to a cycloalkyl, cycloalkenyl, or cycloalkynyl group having one or more heteroatoms independently selected from, for example, N, O, and S. An example of a heterocyclic alkenyl group is a maleimide group. For example, a heteroaryl refers to an aromatic group having one or more heteroatoms independently selected from, for example, N, O, and S. One or more heteroatoms may also be included in substituents that replace hydrogen atoms in groups or portions as described herein. For example, in an optionally substituted heteroaryl, if one hydrogen atom of the heteroaryl is replaced by a substituent (e.g., methyl), the substituent may also contain one or more heteroatoms (e.g., methanol).

[1185] As used herein, the term "acyl" refers to a group having the following structure: Where R z The substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkylaryl, alkylamino, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaryl, heteroalkylaryl, or heteroalkylamino are optional.

[1186] As used herein, the terms “halogen” or “halogen” refer to any halogen atom, such as F, Cl, Br, or I. If any of the groups or portions described herein contain at least one halogen atom, it may be referred to as a “halogen moiety,” such as a haloalkyl group.

[1187] As used in this article, the term "hydroxyl group" refers to the -OH group.

[1188] As used in this article, the term "oxo" refers to a substituent with the structure =O, in which a double bond exists between the atom and the oxygen atom.

[1189] As used herein, the term "carbonyl" refers to a group having the following structure:

[1190] As used herein, the term "thiocarbonyl" refers to a group having the following structure:

[1191] As used herein, the term "phosphate ester group" refers to a group having the following structure:

[1192] As used herein, the term "phosphoryl" refers to a group having the following structure:

[1193] As used herein, the term "sulfonyl" refers to a group having the following structure:

[1194] As used herein, the term "imino" refers to a group having the following structure: Where R is an optional substituent.

[1195] As used herein, the term “N-protecting group” refers to those groups intended to protect amino groups from unwanted reactions during the synthetic process. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 5th edition (John Wiley & Sons, New York, 2014), which is incorporated herein by reference. N-protecting groups include, for example, acyl, aromatic, and carbamoyl groups, such as formyl, acetyl, propionyl, tert-pentanoyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl chloride, α-chlorobutyryl, benzoyl, carboxybenzyl (CBz), 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and antagonistic auxiliaries, such as... Protected or unprotected D,L or D,L-amino acid residues, such as alanine, leucine, phenylalanine; sulfonyl groups, such as benzenesulfonyl and p-toluenesulfonyl; carbamate forming groups, such as benzeneoxycarbonyl, p-chlorobenzeneoxycarbonyl, p-methoxybenzeneoxycarbonyl, p-nitrobenzeneoxycarbonyl, 2-nitrobenzeneoxycarbonyl, p-bromobenzeneoxycarbonyl, 3,4-dimethoxybenzeneoxycarbonyl, 3 5-Dimethoxybenzoxycarbonyl, 2,4-Dimethoxybenzoxycarbonyl, 4-Methoxybenzoxycarbonyl, 2-Nitro-4,5-Dimethoxybenzoxycarbonyl, 3,4,5-Trimethoxybenzoxycarbonyl, 1-(p-Biphenyl)-1-Methylethoxycarbonyl, α,α-Dimethyl-3,5-Dimethoxybenzoxycarbonyl, Diphenylmethyloxycarbonyl, Tert-Butyloxycarbonyl (BOC), Diisopropyl Methoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl and phenylthiocarbonyl; alkylaryl, such as benzyl, triphenylmethyl and benzyloxymethyl; and silyl, such as trimethylsilyl.

[1196] As used in this article, the term "amino acid" refers to both naturally occurring and non-naturally occurring amino acids.

[1197] As used herein, the term “naturally occurring amino acids” means amino acids including Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val.

[1198] As used herein, the term "non-naturally occurring amino acid" refers to an α-amino acid that is not naturally occurring or discovered in mammals. Examples of non-naturally occurring amino acids include D-amino acids; amino acids having an acetylaminomethyl group attached to a sulfur atom of cysteine; polyethylene glycol-modified amino acids; and 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 (o-aminobenzoyl), D-cyclohexylalanine, 4-phenyl-phenylalanine, L-citrulline, α-cyclohexylglycine, L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolyl-4-carboxylic acid, L-homotyrosine, L-2-furanylalanine, L-histidine (3-methyl), N-(3-guanidinopropyl)glycine, O-methyl-L-tyrosine, O-glycan-serine, m-tyrosine, n-tyrosine, LN,N′,N″-trimethyllysine, homolysine, n-lysine, N-glycan asparagine, 7-hydroxy-1,2,3,4- Tetrahydro-4-fluorophenylalanine, 4-methylphenylalanine, bis-(2-pyridinemethyl)amine, pentafluorophenylalanine, indoline-2-carboxylic acid, 2-aminobenzoic acid, 3-amino-2-naphthoic acid, asymmetric dimethylarginine, L-tetrahydroisoquinoline-1-carboxylic acid, D-tetrahydroisoquinoline-1-carboxylic acid, 1-amino-cyclohexaneacetic acid, D / L-allylglycine, 4-aminobenzoic acid, 1-amino-cyclobutanecarboxylic acid, 2, 3, or 4-aminocyclohexanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic acid, 1-aminoindan-1-carboxylic acid, 4-aminopyrrolidine-2-carboxylic acid, 2-aminonaphtholine-2-carboxylic acid, azacyclobutane-3-carboxylic acid, 4-benzylmethylpyrrolidine-2-carboxylic acid, tert-... Butylated glycine, β-(benzothiazolyl-2-yl)-alanine, β-cyclopropylalanine, 5,5-dimethyl-1,3-thiazolidin-4-carboxylic acid, (2R,4S)4-hydroxypiperidine-2-carboxylic acid, (2S,4S) and (2S,4R)-4-(2-naphthylmethoxy)-pyrrolidine-2-carboxylic acid, (2S,4S) and (2S,4R)4-phenoxy-pyrrolidine-2-carboxylic acid, (2R,5S) and (2S,5R)-5-phenyl-pyrrolidine-2-carboxylic acid, (2S,4S)-4-amino-1-benzoyl-pyrrolidine-2-carboxylic acid, tert-butylalanine, (2S,5R)-5-phenyl-pyrrolidine-2-carboxylic acid, 1-aminomethyl-cyclopropylalanine Hexane-acetic acid, 3,5-bis-(2-amino)ethoxybenzoic acid, 3,5-diaminobenzoic acid, 2-methylaminobenzoic acid, N-methyl-o-aminobenzoic acid, LN-methylalanine, LN-methylarginine, LN-methylasparagine, LN-methylaspartic acid, LN-methylcysteine, LN-methylglutamine, LN-methylglutamic acid, LN-methylhistidine, LN-methylisoleucine, LN-methyllysine, LN-methylnorleucine, LN-methylornithine, LN-methylthreonine, LN-methyltyrosine, LN-methylvaline, LN-methyl-tert-butylglycine, L-norvaline, α-methyl-γ-aminobutyrate, 4,4′-Diphenylalanine, α-Methylcyclopentylalanine, α-Methyl-α-naphthylalanine, α-Methylpenicillamine, N-(4-aminobutyl)glycine, N-(2-aminoethyl)glycine, N-(3-aminopropyl)glycine, N-amino-α-methylbutyrate, α-naphthylalanine, N-phenylmethylglycine, N-(2-carbamoylethyl)glycine, N-(carbamoylmethyl)glycine, N-(2-carboxyethyl)glycine, N-(carboxymethyl)glycine, N-cyclobutylglycine, N-cyclodecylglycine, N-cycloheptylglycine, N-cyclohexylglycine, N-cyclodecylglycine, N-cyclododecylglycine, N-cyclooctylglycine, N-cyclopropylglycine, N-cyclodecylglycine Alkylglycine, N-(2,2-diphenylethyl)glycine, N-(3,3-diphenylpropyl)glycine, N-(3-guanidinopropyl)glycine, N-(1-hydroxyethyl)glycine, N-(hydroxyethyl))glycine, N-(imidazolylethyl))glycine, N-(3-indolylethyl)glycine, N-methyl-γ-aminobutyrate, DN-methylmethionine, N-methylcyclopentylalanine, DN-methylphenylalanine, DN-methylproline, DN-methylthreonine, N-(1-methylethyl)glycine, N-methyl-naphthylalanine, N-methylpenicillamine, N-(p-hydroxyphenyl)glycine, N-(thiomethyl)glycine, penicillamine, L-α-methylalanine, L-α-methyl... L-Asparagine, L-α-methyl-tert-butylglycine, L-methylethylglycine, L-α-methylglutamate, L-α-methylhomophenylalanine, N-(2-methylthioethyl)glycine, L-α-methyllysine, L-α-methylnorleucine, L-α-methylornithine, L-α-methylproline, L-α-methylthreonine, L-α-methyltyrosine, LN-methyl-homophenylalanine, N-(N-(3,3-diphenylpropyl)carbamoylmethylglycine, L-pyroglutamic acid, D-pyroglutamic acid, O-methyl-L-serine, O-methyl-L-homoserine, 5-hydroxylysine, α-carboxyglutamate, phenylglycine, L-piperacic acid (homoproline), L-homoleucine, L-lysine Amino acid (dimethyl), L-2-naphthylalanine, L-dimethyldopa or L-dimethoxy-phenylalanine, L-3-pyridylalanine, L-histidine (benzoyloxymethyl), N-cycloheptylglycine, L-diphenylalanine, O-methyl-L-homotyrosine, L-β-homolysine, O-glycan-threonine, o-tyrosine, LN,N′-dimethyllysine, L-homoarginine, neotryptophan, 3-benzothiophene alanine, isoquinoline-3-carboxylic acid, diaminopropionic acid, homocysteine, 3,4-dimethoxyphenylalanine, 4-chlorophenylalanine, L-1,2,3,4-tetrahydronorhalman-3-carboxylic acid, adamantylalanine, symmetrical dimethylarginine, 3-carboxythiomorpholine, D-1,2,3,4-Tetrahydronorhalman-3-carboxylic acid, 3-aminobenzoic acid, 3-amino-1-carboxymethyl-pyridin-2-one, 1-amino-1-cyclohexanecarboxylic acid, 2-aminocyclopentanecarboxylic acid, 1-amino-1-cyclopropanecarboxylic acid, 2-aminoindan-2-carboxylic acid, 4-amino-tetrahydrothiaran-4-carboxylic acid, azacyclobutane-2-carboxylic acid, β-(benzothiazol-2-yl)-alanine, neopentylglycine, 2-carboxymethylpiperidine, β-cyclobutylalanine, allylglycine, diaminopropionic acid, homo-cyclohexylalanine, (2S,4R)-4-hydroxypiperidine-2- Formic acid, octahydroindole-2-carboxylic acid, (2S,4R) and (2S,4R)-4-(2-naphthyl), pyrrolidine-2-carboxylic acid, piperidinecarboxylic acid, (2S,4R) and (2S,4S)-4-(4-phenylbenzyl)pyrrolidine-2-carboxylic acid, (3S)-1-pyrrolidine-3-carboxylic acid, (2S,4S)-4-triphenylmethylmercapto-pyrrolidine-2-carboxylic acid, (2S,4S)-4-mercaptoproline, tert-butylglycine, N,N-bis(3-aminopropyl)glycine, 1-amino-cyclohexane-1-carboxylic acid, N-mercaptoethylglycine, and selenocysteine. In some embodiments, the amino acid residues may be charged or polar. Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid, or their non-natural analogues. Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan, or their non-natural analogues. Specifically, in some embodiments, it is anticipated that the terminal amino group of the amino acid may be an amide group or a carbamate group.

[1199] As used herein, the term "percentage (%) identity" refers to the percentage of amino acid residues in a candidate sequence (e.g., Fc-IgG or a fragment thereof) that are identical to amino acid residues in a reference sequence after alignment of the sequence, with gaps introduced if necessary to achieve maximum percentage identity (i.e., gaps may be introduced in one or both of the candidate and reference sequences for optimal alignment and non-homologous sequences may be ignored for comparison purposes). Alignment for determining percentage identity can be performed in various ways within the skill of the art, such as using publicly available computer software, such as BLAST, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithm required to achieve maximum alignment across the full length of the sequences being compared. In some embodiments, the percentage amino acid sequence identity of a given candidate sequence relative to, and or against, a given reference sequence (which may be expressed as a given candidate sequence having or including a certain percentage amino acid sequence identity relative to, and or against, a given reference sequence) is calculated as follows:

[1200] 100 × (fraction of A / B)

[1201] Where A is the number of amino acid residues that are identified as identical in the alignment of the candidate sequence and the reference sequence, and B is the total number of amino acid residues in the reference sequence. In some embodiments where the length of the candidate sequence is not equal to the length of the reference sequence, the percentage amino acid sequence identity between the candidate sequence and the reference sequence will not be equal to the percentage amino acid sequence identity between the reference sequence and the candidate sequence.

[1202] When performing a maximum correspondence alignment as described above, two polynucleotide or polypeptide sequences are said to be "identical" if the nucleotide or amino acid sequences are identical. Comparisons between two sequences are typically performed by comparing the sequences within a comparison window to identify and compare local regions with sequence similarity. As used herein, a "comparison window" refers to a segment of at least about 15, about 20, about 25, or more (e.g., about 30 to about 75, or about 40 to about 50) adjacent positions, wherein the two sequences can be compared after optimal alignment of the sequence and a reference sequence at the same number of adjacent positions.

[1203] As used herein, the term "treating" or "to treat" refers to therapeutic treatment of a subject's viral infection (e.g., a viral infection such as influenza). In some embodiments, therapeutic treatment may slow the progression of the viral infection, improve the subject's outcome, and / or eliminate the infection. In some embodiments, therapeutic treatment of a subject's viral infection may alleviate or improve one or more symptoms or signs associated with the viral infection, reduce the severity of 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 symptoms of the viral infection without the presence of said therapeutic treatment.

[1204] As used herein, the term "average of T" refers to the average number of neuraminidase inhibitor monomers or neuraminidase inhibitor dimers conjugated to the Fc domain or albumin within a conjugate population. In some embodiments, the average number of neuraminidase inhibitor monomers or neuraminidase inhibitor dimers conjugated to the Fc domain within the conjugate population may be 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 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.

[1205] As used herein, the term “subject” can refer to a human, a non-human primate or other mammal, such as, but not limited to, dogs, cats, horses, cattle, pigs, turkeys, goats, fish, monkeys, chickens, rats, mice and sheep.

[1206] As used herein, the term “therapeutic effective amount” means the amount that effectively induces the desired effect in a subject or treats a subject having the symptoms or condition described herein (e.g., a viral infection, such as influenza infection), for example, a drug dose. It should also be understood herein that “therapeutic effective amount” can be interpreted as the amount that gives the desired therapeutic and / or preventive effect, administered at one or more doses or in any dose or route, and / or alone or in combination with other therapeutic agents (e.g., antiviral agents of prime numbers as described herein). For example, in the case of administration of a conjugate described herein for the treatment of a viral infection (e.g., a conjugate of any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I), the therapeutic effective amount of the conjugate is, for example, an amount sufficient to prevent, slow, or reverse the progression of the viral infection compared to a response obtained without administration of the conjugate.

[1207] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical or pharmaceutical formulation containing at least one active ingredient (e.g., a conjugate of any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I)) and one or more excipients and diluents to make said active ingredient suitable for a method of administration. The pharmaceutical compositions of the present invention comprise pharmaceutically acceptable components compatible with the conjugates described herein (e.g., conjugates of any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I)).

[1208] As used herein, the term "pharmaceuticalally acceptable carrier" refers to an excipient or diluent in a pharmaceutical composition. For example, a pharmaceutically acceptable carrier may be a medium capable of suspending or dissolving an active conjugate (e.g., a conjugate of any of formulas (1)-(5), (DI)-(DX), or (MI)-(M-VI)). A pharmaceutically acceptable carrier must be compatible with the other components of the formulation and be harmless to the recipient. In this invention, a pharmaceutically acceptable carrier must provide appropriate pharmaceutical stability to the conjugates described herein. The properties of the carrier vary depending on the method of administration. For example, solid carriers are preferred for oral administration; aqueous carriers (e.g., WFI and / or buffer solutions) are generally used for intravenous administration.

[1209] As used herein, the term "pharmaceuticalally acceptable salt" means a salt of the conjugates described herein (e.g., conjugates of any of formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I)) that is suitable for use in the methods described herein without undue toxicity, irritation, and / or anaphylactic reactions to the extent of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Pharmaceutical Salts: Properties, Selection, and Use (edited by P.H. Stahl and C.W. Germuth), Wiley-VCH, 2008. The salt may be prepared on-site during the final separation and purification of the conjugates described herein, or may be prepared separately by reacting the free base with a suitable organic acid.

[1210] The term “drug:antibody ratio” or “DAR” refers to the average number (e.g., the average number of small molecule drug portions conjugated to the antibody, Fc domain, or albumin described herein). In some embodiments described herein, DAR is represented by “T” (e.g., in formulas (1)-(5), (DI)-(DX), (D'-I), (MI)-(MX), or (M'-I). As used herein, each monomeric portion (e.g., each zanamivir or peramivir monomer) or each dimer portion (e.g., each zanamivir or peramivir dimer) conjugated to the 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 four zanamivir monomers would have a DAR of 4.0 (e.g., a “T” value of 4.0). The Fc domain conjugated to four zanamivir dimers (e.g., a total of eight zanamivir molecules) will also have a DAR of 4.0 (e.g., "T" is 4.0). DAR can also be calculated as the average DAR of a population of molecules (such as a population of Fc domains, antibodies, or albumins). DAR values ​​can affect a drug's efficacy, potency, pharmacokinetics, or toxicity.

[1211] As used herein, the term “about” indicates a deby way of 5%. For example, about 10% means 9.5% to 10.5%.

[1212] Any value provided as a range includes the upper and lower limits, and any value contained within the upper and lower limits.

[1213] As used herein, the term “(1)-(5), (D-I)-(D-X), (D’-I), (M-I)-(M-X) or (M’-I)” refers to 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),(MV-7), (MV-8), (MV-9), (MV-10), (M-VI), (M-VI-1), (M-VI-2), (M-VI-3), (M-VI-4), (M-VI-5), (M-VI-6) , (M-VI-7), (M-VI-8), (M-VI-9), (M-VII), (M-VIII), (M-VIII-1), (M-VIII-2), (M-VIII-3), (M-VIII-4), (M-VIII-5), (M-VIII-6), (M-VIII-7), (M-VIII-8), (M-VIII-9), (M-VIII-10), (M-VIII-11), (M-IX), (M- Any of IX-1), (M-IX-2), (M-IX-3), (M-IX-4), (M-IX-5), (M-IX-6), (MX), (MX-1), (MX-2), (MX-3) or (M'-I)). ,

[1214] Other features and advantages of the conjugates described herein will become apparent from the detailed embodiments and claims. Attached Figure Description

[1215] Figure 1 These are images depicting exemplary methods, for example, by means of a connector, to conjugate a neuraminidase inhibitor monomer or dimer to an Fc domain monomer, an Fc domain, an Fc-binding peptide, albumin, or an albumin-binding peptide.

[1216] Figure 2 The diagram shows non-reduced and reduced SDS-PAGEs of the Fc domain formed by Fc domain monomers having the sequence SEQ ID NO:1.

[1217] Figure 3 The diagram shows the non-reduced and reduced SDS-PAGE of the Fc domain formed by Fc domain monomers having the sequence SEQ ID NO:3.

[1218] Figure 4 The diagram shows the non-reduced and reduced SDS-PAGE of the Fc domain formed by Fc domain monomers having the sequence SEQ ID NO:5.

[1219] Figure 5 The diagram shows the non-reduced and reduced SDS-PAGE of the Fc domain formed by Fc domain monomers having the sequence SEQ ID NO:7.

[1220] Figure 6The diagram shows the non-reduced and reduced SDS-PAGE of the Fc domain formed by Fc domain monomers having the sequence SEQ ID NO:9.

[1221] Figure 7 The diagram shows the non-reduced and reduced SDS-PAGE of the Fc domain formed by Fc domain monomers with the sequence SEQ ID NO:12.

[1222] Figure 8 The diagram shows non-reduced and reduced SDS-PAGE images and schematic diagrams of Fc domains formed by Fc domain monomers having the sequence SEQ ID NO:14.

[1223] Figure 9 The non-reduced SDS-PAGE of conjugate 1 is shown.

[1224] Figure 10 The non-reduced SDS-PAGE of conjugate 2 is shown.

[1225] Figure 11 The non-reduced SDS-PAGE of conjugate 3 is displayed.

[1226] Figure 12 The non-reduced SDS-PAGE of conjugate 4 is displayed.

[1227] Figure 13 The non-reduced SDS-PAGE of conjugate 5 is shown.

[1228] Figure 14 The non-reduced SDS-PAGE of conjugate 6 is displayed.

[1229] Figure 15 This is a graph showing the IC50 values ​​for Int-2 and conjugate 1 in the H1N1 neuraminidase inhibition analysis.

[1230] Figure 16 This is a graph showing the IC50 values ​​for conjugates 1-6 in the H1N1 neuraminidase inhibition assay.

[1231] Figure 17 This is a graph showing the IC50 values ​​for conjugates 1-6 in the H3N2 neuraminidase inhibition analysis.

[1232] Figures 18A-18C It is a series of figures that show the conjugate 3 ( Figure 18A ), conjugate 4 ( Figure 18B ) or conjugate 6 ( Figure 18C Cellular performance of A549 cells treated with the drug.

[1233] Figures 19A-19EThis ...

Claims

1. A compound having the following structure:

Images