Compositions and methods for treatment of viral infections

Abstract

To provide a new and more effective therapy for treating influenza.SOLUTION: Compositions and methods for the treatment of viral infections include conjugates containing inhibitors of viral neuraminidase (e.g., zanamivir, peramivir, or analogs thereof) linked to an Fc monomer, an Fc domain, and Fc-binding peptide, an albumin protein, or albumin-binding peptide. In particular, conjugates can be used in the treatment of viral infections (e.g., influenza viral infections).SELECTED DRAWING: None

Description

Technical Field

[0001] Background In the medical field, the need for new antiviral treatments against influenza is quite large and extremely urgent. The influenza virus is the causative agent of influenza, i.e., flu, and is responsible for 3 million to 5 million severe cases of illness and approximately 500,000 deaths worldwide every year. Most people recover completely from influenza in about 1 to 2 weeks, but others develop life-threatening complications such as pneumonia. For this reason, influenza can be life-threatening, especially for the young, the elderly, or those with chronic diseases. People with a weak or depressed immune system, such as people with advanced HIV infection, or transplant patients whose immune system is medically suppressed to prevent organ rejection, are at a higher risk of influenza-related complications. Pregnant women and young children are also at high risk of complications.

[0002] The development of antiviral treatments against influenza has continued to be a challenge. Some influenza antiviral agents are approved for use in clinics, and these drugs play an important role in modulating disease severity and putting a stop to global pandemics while the vaccine is being prepared. However, drug-resistant strains have emerged against the most commonly used inhibitors.

[0003] Influenza antiviral agents generally target proteins presented on the surface of influenza virus particles. The envelope of the influenza virus contains hemagglutinin and neuraminidase, two immunodominant glycoproteins that play important roles in virus infection and spread. Hemagglutinin causes the virus to bind to host cells through its interaction with surface sialic acid, thereby initiating entry. Neuraminidase is an exoglycosidase enzyme that cleaves sialic acid (terminal neuraminic acid residues) from the glycan structures on the surface of infected host cells, releasing progeny virus and enabling virus spread from the host cell to surrounding uninfected cells. Therefore, inhibition of neuraminidase serves as a pharmacological target for antiviral drugs. Virus neuraminidase inhibitors used to reduce virus spread have been identified and include oseltamivir (Tamiflu (trademark)), zanamivir (Relenza (trademark)), and peramivir (Rapivab (trademark)).

[0004] However, influenza in transplant recipients still features long-term virus shedding, increasing the likelihood of generating drug-resistant strains. New and more effective therapies for treating influenza are needed. SUMMARY OF THE INVENTION

[0005] The present disclosure relates to conjugates, compositions and methods for inhibiting viral growth and methods for treating viral infections. Specifically, such conjugates contain a monomer or dimer of a moiety that inhibits influenza virus neuraminidase (e.g., zanamivir, peramivir or an analog thereof) conjugated to an Fc monomer, an Fc domain, an Fc binding peptide, an albumin protein or an albumin protein binding peptide. The neuraminidase inhibitor (e.g., zanamivir, peramivir or an analog thereof) in the conjugate is directed to neuraminidase on the surface of the viral particle. The Fc monomer or Fc domain in the complex binds to FcγR (e.g., FcRn, FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa and FcγRIIIb) on immune cells, e.g., neutrophils, activating phagocytosis and effector functions, e.g., antibody-dependent cellular cytotoxicity (ADCC), thus leading to engulfment and destruction of viral particles by immune cells, further enhancing the antiviral activity of the complex. Albumin or albumin-binding peptides may extend the half-life of the complex, e.g., by binding of albumin to the recycling fetal Fc receptor. Such compositions are useful in methods of inhibiting viral growth and in methods of treating viral infections, e.g., those due to influenza A, B and C viruses.

[0006] In a first aspect, the present invention provides a method for producing a composition comprising the steps of: A complex represented by any one of formulas (DI), (MI), (1) or (2): [ka] [In the formula, each A1 and each A2 independently represent a group represented by formula (AI) to (A-XII): [ka] is selected from one of the following: R1 is selected from -OH, -NH2, -NHC(=NH)NH2, and -NHC(=NH)NHR6; R2 and R3 are each independently selected from -H, -OH, -F, -Cl, and -Br; R4 is selected from -CO2H, -P(=O)(OH)2, -SO3H; R5 is selected from -COCH3, -COCF3, -SO2CH3; X is selected from -O- and -S-; Y is

Chemical formula

Chemical formula

[0007] In some embodiments, n is 1, and each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide.

[0008] In some embodiments, n is 2, and each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1-138), and the Fc domain monomers dimerize to form an Fc domain. L is a linker that covalently attaches to each E, as well as to each Y, or each of A1 and / or A2. T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and each wavy line in formula (D-I), (M-I), (1), or (2) represents that L is covalently attached to each E (e.g., by a covalent bond or a linker), or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L or each A1-L-A2 can be independently selected (e.g., independently selected from any of the A1-L or A1-L-A2 structures described herein).

[0009] In a preferred embodiment of any of the aspects described herein, n is 2, and each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1-138). In a complex having two Fc domain monomers (e.g., the complex of formula (1), formula (2), formula (D-I) when n is equal to 2, or formula (M-I) when n is equal to 2), the Fc domain monomers dimerize to form an Fc domain.

[0010] In another aspect, the present invention provides a complex represented by formula (D-I): [Chemical formula] [wherein each E contains an Fc domain monomer (for example, an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138), L in each A1-L-A2 is a linker covalently bonded to the sulfur atom of the hinge cysteine in E and to each of A1 and A2, n is 1 or 2 (for example, when n is 2, two Fc domain monomers dimerize to form an Fc domain), T is an integer from 1 to 20 (for example, 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 linked to E represents that each A1-L-A2 is covalently bonded to the sulfur atom of the hinge cysteine in E (for example, by covalent bonding or through a linker)], or a pharmaceutically acceptable salt thereof. When T is greater than 1 (for example, when 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 (for example, can be independently selected from any of the A1-L-A2 structures described herein).

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

[0012] In another aspect, the present invention provides a complex represented by formula (M-I):

Chemical formula

[0013] In another aspect, the present invention provides a complex represented by formula (M-I):

Chemical formula

[0014] In one aspect, the present disclosure provides a complex represented by formula (1):

Chemical formula

[0015] In another aspect, the present disclosure provides a complex represented by formula (1):

Chemical formula

[0016] In another aspect, the present disclosure relates to a complex represented by formula (1): [Chemical formula] [Wherein each A1 and each A2 are independently selected from any one of formulas (A-VI) to (A-IX), each E contains an Fc domain monomer (for example, an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138), L in each A1-L-A2 is a linker that covalently binds to the sulfur atom of the hinge cysteine in each E and to each of A1 and A2, T is an integer from 1 to 20 (for example, 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 Es represent that each A1-L-A2 covalently binds to a pair of sulfur atoms of the two hinge cysteines in the two Es (for example, by covalent bond or linker).] or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), each A1-L-A2 can be independently selected (e.g., can be independently selected from any of the A1-L-A2 structures described herein).

[0017] In another aspect, the present invention provides a complex represented by formula (2):

Chemical formula

[0018] In another aspect, the present invention provides a complex represented by formula (2):

Chemical formula

[0019] In another aspect, the present invention relates to a complex represented by formula (2):

Chemical formula

[0020] In some embodiments of any of the above embodiments, each E comprises an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138. In some embodiments, at least one of the paired sulfur atoms is the hinge cysteine of SEQ ID NO: 10 or SEQ ID NO: 11, i.e., the sulfur atom corresponding to Cys10, Cys13, Cys16 or Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., its sulfur atom). In some embodiments, the paired sulfur atoms are the sulfur atoms corresponding to Cys10 and Cys13 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys10 and Cys16 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys30 and Cys18 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and Cys36 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and Cys38 in SEQ ID NO: 10 or SEQ ID NO: 11, and / or Cys36 and Cys38 in SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., their sulfur atoms). In some embodiments, when T is 2, the paired sulfur atoms are Cys10 and Cys13 in SEQ ID NO: 10 or SEQ ID NO: 11, or Cys36 and Cys38 in SEQ ID NO: 10 or SEQ ID NO: 11 (e.g., the sulfur atoms corresponding thereto).

[0021] In some embodiments, the pair of sulfur atoms includes one sulfur atom from each E that is the sulfur atom of cysteine, i.e., L-A together with the sulfur atom to which it is attached forms a crosslink between two Fc domains (e.g., two Fc domains comprising the sequence of SEQ ID NO: 10 or SEQ ID NO: 11). In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E (e.g., its sulfur atom) and the sulfur atom corresponding to Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E (e.g., its sulfur atom). In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E (e.g., its sulfur atom) and the sulfur atom corresponding to Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E (e.g., its sulfur atom). In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E (e.g., its sulfur atom) and the sulfur atom corresponding to Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E (e.g., its sulfur atom). In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E (e.g., its sulfur atom) and the sulfur atom corresponding to Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E (e.g., its sulfur atom).

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

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

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

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

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

[0027] In some embodiments, the complex has the structure:

Chemical formula

[0028] In some embodiments, a is 1, and b, c, and d are 0. In some embodiments, a and b are 1, and c and d are 0. In some embodiments, a and c are 1, and b and d are 0. In some embodiments, a and d are 1, and b and c are 0. In some embodiments, a, b, and c are 1, and d is 0. In some embodiments, a, b, and d are 1, and c is 0. In some embodiments, a, c, and d are 1, and b is 0. In some embodiments, b and c are 1, and a and d are 0. In some embodiments, b and d are 1, and a and c are 0. In some embodiments, b, c, and d are 1, and a is 0. In some embodiments, c and d are 1, and a and b are 0. In some embodiments, a, b, c, and d are 1.

[0029] In some embodiments, each E is the sequence MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4) and includes.

[0030] In some embodiments, each E is the sequence It contains MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 33).

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

[0032] In some embodiments, the pair of sulfur atoms includes one cysteine sulfur atom from each E, i.e., L-A together with the sulfur atom to which it is attached forms a crosslink between two Fc domains (e.g., two Fc domains comprising the sequence of SEQ ID NO: 4 or SEQ ID NO: 33). In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 of SEQ ID NO: 4 or SEQ ID NO: 33 from one E (e.g., its sulfur atom) and the sulfur atom corresponding to Cys10 of SEQ ID NO: 4 or SEQ ID NO: 33 from another E (e.g., its sulfur atom). In some embodiments, the pair of sulfur atoms is the sulfur atom corresponding to Cys13 of SEQ ID NO: 4 or SEQ ID NO: 33 from one E (e.g., its sulfur atom) and the sulfur atom corresponding to Cys13 of SEQ ID NO: 4 or SEQ ID NO: 33 from another E (e.g., its sulfur atom). In some embodiments, when T is 2, the pair of sulfur atoms is the sulfur atom corresponding to Cys10 of SEQ ID NO: 4 or SEQ ID NO: 33 from one E (e.g., its sulfur atom) and the sulfur atom corresponding to Cys10 of SEQ ID NO: 4 or SEQ ID NO: 33 from another E (e.g., its sulfur atom), and the sulfur atom corresponding to Cys13 of SEQ ID NO: 4 or SEQ ID NO: 33 from one E (e.g., its sulfur atom) and the sulfur atom corresponding to Cys13 of SEQ ID NO: 4 or SEQ ID NO: 33 from another E (e.g., its sulfur atom).

[0033] In some embodiments, the complex has the structure:

Chemical formula

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

[0035] In some embodiments, the pair of sulfur atoms each include one cysteine sulfur atom from each E, i.e., L-A together with the sulfur atom to which it is attached forms a bridge between two Fc domains (e.g., two Fc domains containing the sequence of SEQ ID NO: 8). In some embodiments, the pair of sulfur atoms are the sulfur atom corresponding to Cys10 of SEQ ID NO: 8 (e.g., its sulfur atom) from one E and the sulfur atom corresponding to Cys10 of SEQ ID NO: 8 (e.g., its sulfur atom) from another E. In some embodiments, the pair of sulfur atoms are the sulfur atom corresponding to Cys13 of SEQ ID NO: 8 (e.g., its sulfur atom) from one E and the sulfur atom corresponding to Cys13 of SEQ ID NO: 8 (e.g., its sulfur atom) from another E. In some embodiments, when T is 2, the pair of sulfur atoms are the sulfur atom corresponding to Cys10 of SEQ ID NO: 8 (e.g., its sulfur atom) from one E and the sulfur atom corresponding to Cys10 of SEQ ID NO: 8 (e.g., its sulfur atom) from another E, and the sulfur atom corresponding to Cys13 of SEQ ID NO: 8 (e.g., its sulfur atom) from one E and the sulfur atom corresponding to Cys13 of SEQ ID NO: 8 (e.g., its sulfur atom) from another E.

[0036] In some embodiments, the complex has the structure:

Chemical formula

[0037] In some embodiments, the complex has the structure:

Chemical formula

[0038] In some embodiments, the complex has the structure:

Chemical formula

[0039] In some embodiments, the complex has the structure:

Chemical formula

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

[0041] In some embodiments, the complex has the structure:

Chemical formula

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

[0043] In another aspect, the present invention provides a complex represented by (D-I):

Chemical formula

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

[0045] In another aspect, the present invention provides a complex represented by formula (M-I):

Chemical formula

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

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

[0048] The intermediate of Table 1a can be conjugated to the Fc domain or Fc domain monomer (e.g., by a linker) by any suitable method known to those skilled in the art, including any of the methods described or exemplified herein. In some embodiments, the conjugate (e.g., a conjugate represented by any one of formulas (1), (2), (D-I)-(D-XI), or (M-I)-(M-XI)) comprises E, where E is an Fc domain monomer or Fc domain (e.g., an Fc domain monomer or Fc domain in which each Fc domain monomer independently has a sequence of any one of SEQ ID NOs: 1-138). In a preferred embodiment, one or more nitrogen atoms of one or more surface-exposed lysine residues of E, or one or more sulfur atoms of one or more surface-exposed cysteines in E, are covalently bonded to a linker (e.g., PEG2-PEG 20 linker). The linker conjugated to E can be functionalized such that it can react to form a covalent bond with any of the Ints described herein (e.g., Int of Table 1a). In a preferred embodiment, E is conjugated to a linker functionalized with an azide group, and Int (e.g., Int of Table 1a) is functionalized with an alkyne group. The conjugation of the linker-azide of E and the linker-alkyne of Int (e.g., by click chemistry) forms the conjugate of the present invention, e.g., a conjugate represented by formula (5). In yet other embodiments, E is conjugated to a linker functionalized with an alkyne group, and Int (e.g., Int of Table 1a) is functionalized with an azide group. The conjugation of the linker-alkyne of E and the linker-azide of Int (e.g., by click chemistry; e.g., see Figure 103) forms the conjugate of the present invention, e.g., a conjugate represented by any one of formulas (1), (2), (D-I)-(D-XI), or (M-I)-(M-XI). [Table 1] TIFF2025108559000025.tif241170TIFF2025108559000026.tif202170TIFF2025108559000027.tif238170TIFF2025108559000028.tif230170TIFF2025108559000029.tif225170TIFF2025108559000030.tif227170TIFF2025108559000031.tif247170TIFF2025108559000032.tif216170TIFF2025108559000033.tif197170TIFF2025108559000034.tif244170TIFF2025108559000035.tif247170TIFF2025108559000036.tif219170TIFF2025108559000037.tif230170TIFF2025108559000038.tif232170TIFF2025108559000039.tif248170TIFF2025108559000040.tif241170TIFF2025108559000041.tif119170

[0049] In another aspect, the present invention features the conjugates of Table 1b. Each conjugate of Table 1b corresponds to a conjugate of either formula (M-I) or formula (D-I) shown. The conjugates of Table 1b include conjugates formed by the covalent reaction of Int of Table 1a with a linker, which in turn complexes with E (e.g., an Fc domain monomer, an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide). In some embodiments, the reactive moiety of Int (e.g., an alkyne or azide group) reacts with the corresponding reactive group (e.g., an alkyne or azide group) of the linker (represented as L’) covalently attached to E so as to covalently bind Int of Table 1a to E. As shown in Table 1b, L’ corresponds to the remainder of L as defined in (M-1) or (D-I) (e.g., L’ is the linker that covalently binds Int and E). For example, L’ can include a triazole (formed by a click chemistry reaction between Int and the linker complexed with E), and a linker (e.g., PEG2 to PEG 20 linker), which in turn complexes with the amino acid side chain of E (see, for example, FIG. 103).

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

[0051] In some embodiments of any of the complexes of Table 1b, T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). The present disclosure further provides any population of the complexes of Table 2, where the average value of T is from 1 to 20 (e.g., the average value of T is from 1 to 2, from 1 to 3, from 1 to 4, from 1 to 5, from 5 to 10, from 10 to 15, from 15 to 20, from 1.5 to 3.5, from 2.5 to 4.5, from 3.5 to 5.5, from 4.5 to 6.5, from 5.5 to 7.5, from 6.5 to 8.5, from 7.5 to 9.5, or from 8.5 to 10.5). In some embodiments, the average value of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In one embodiment, the average T is from 1 to 10 (e.g., 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10). In one embodiment, the average T is from 1 to 5 (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5). In some embodiments, the average T is from 5 to 10 (e.g., 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10).In some embodiments, the average T is from 2.5 to 7.5 (e.g., 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4 or 7.5).

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

[0053] [Table 2] TIFF2025108559000043.tif199170TIFF2025108559000044.tif203170TIFF2025108559000045.tif170170TIFF2025108559000046.tif211170TIFF2025108559000047.tif185170TIFF2025108559000048.tif200170TIFF2025108559000049.tif231170TIFF2025108559000050.tif219170TIFF2025108559000051.tif215170TIFF2025108559000052.tif160170TIFF2025108559000053.tif175170TIFF2025108559000054.tif175170TIFF2025108559000055.tif221170TIFF2025108559000056.tif194170TIFF2025108559000057.tif215170TIFF2025108559000058.tif170170TIFF2025108559000059.tif186170TIFF2025108559000060.tif175170TIFF2025108559000061.tif215170TIFF2025108559000062.tif226170TIFF2025108559000063.tif175170TIFF2025108559000064.tif235170TIFF2025108559000065.tif231170TIFF2025108559000066.tif210170TIFF2025108559000067.tif209170TIFF2025108559000068.tif249170TIFF2025108559000069.tif196170TIFF2025108559000070.tif202170TIFF2025108559000071.tif218170TIFF2025108559000072.tif223170

[0054] In some embodiments, each E comprises an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138. In other embodiments, each E comprises an Fc domain monomer having a sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64. In other embodiments, each E comprises an Fc domain monomer having the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64. In other embodiments, each E comprises an Fc domain monomer having a sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 67 or SEQ ID NO: 68. In other embodiments, each E comprises an Fc domain monomer having the amino acid sequence of SEQ ID NO: 67 or SEQ ID NO: 68. In other embodiments, each E comprises an Fc domain monomer having a sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 72 or SEQ ID NO: 73. In other embodiments, each E comprises an Fc domain monomer having the amino acid sequence of SEQ ID NO: 72 or SEQ ID NO: 73. In other embodiments, each E comprises an Fc domain monomer having a sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 76 or SEQ ID NO: 77. In other embodiments, each E comprises an Fc domain monomer having the amino acid sequence of SEQ ID NO: 76 or SEQ ID NO: 77. In other embodiments, each E comprises an Fc domain monomer having a sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 82. In other embodiments, each E comprises an Fc domain monomer having the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 82. In other embodiments, each E comprises an Fc domain monomer having a sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 85 or SEQ ID NO: 86. In other embodiments, each E comprises an Fc domain monomer having the amino acid sequence of SEQ ID NO: 85 or SEQ ID NO: 86.

[0055] In another aspect, the present invention relates to a complex comprising: (i) a first moiety A1, (ii) a second moiety A2, (iii) an Fc domain monomer or an Fc domain, and (iv) a linker covalently attached to both A1 and A2 and to the Fc domain monomer or the Fc domain; each A1 and each A2 being independently selected from any one of formulas (A-I) to (A-XII). In some embodiments, each of A1 and A2 can be independently selected from any one of formulas (A-I), (A-II), (A-VI) or (A-VII). In other embodiments, each of A1 and A2 can be independently selected from formula (A-I). In the above preferred embodiments, x is 2.

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

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

[0058] In another aspect, the present invention relates to a complex represented by formula (D-I):

Chemical formula

[0059] In another aspect, the present invention provides a complex represented by formula (D-I): [Chemical formula] [In the formula, each A1 and each A2 are independently selected from any one of formulas (A-I) to (A-V), each E includes an Fc domain monomer (for example, an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138), an albumin protein (for example, an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 141), an albumin protein-binding peptide or an Fc-binding peptide, n is 1 or 2, T is an integer from 1 to 20 (for example, 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 bound to each of E, A1 and A2], 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 A1-L-A2 can be independently selected (for example, can be independently selected from any of the A1-L-A2 structures described herein).

[0060] In another aspect, the present invention relates to a complex represented by formula (D-I):

Chemical formula

[0061] In some embodiments, the complex is of formula (D-II):

Chemical formula

[0062] In some embodiments, the complex is of formula (D-II-1):

Chemical formula

[0063] In some embodiments, the complex is of formula (D-II-2):

Chemical formula

[0064] In some embodiments, the complex is of formula (D-II-3):

Chemical formula

[0065] In some embodiments, the complex is [Chemical formula] It has a structure selected from the following.

[0066] In some embodiments, the complex is of formula (D-II-4): [Chemical formula] or a pharmaceutically acceptable salt thereof.

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

[0068] In some embodiments, the complex [Chemical formula] has a structure selected from the following, or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the complex [Chemical formula] has a structure selected from TIFF2025108559000085.tif89170, or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the complex is of formula (D-II-6): [Chemical formula] [wherein, R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl] It is represented by or a pharmaceutically acceptable salt thereof. In some embodiments, R7 is selected from C1-C20 alkyl (for example, methyl, ethyl, propyl or butyl).

[0071] In some embodiments, the complex is of formula (D-II-7): [Chemical formula] It is represented by or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the complex is of formula (D-II-8): [Chemical formula] [wherein, L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (for example, 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)] It is represented by or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

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

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

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

[0076] In some embodiments, the complex has the structure [Chemical formula] TIFF2025108559000093.tif65170 or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the complex is of formula (D-II-9): [Chemical formula] represented thereby, or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the complex is of formula (D-II-10): [Chemical formula] [wherein, L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (for example, 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)] represented thereby, or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

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

[0080] In some embodiments, the complex has

Chemical Formula

[0081] In some embodiments, the complex has the formula (D-III):

Chemical Formula

[0082] In some embodiments, the complex has the formula (D-III-1):

Chemical Formula

[0083] In some embodiments, the complex has the formula (D-III-2):

Chemical Formula

[0084] In some embodiments, the complex has the formula (D-III-3):

Chemical Formula

[0085] In some embodiments, the complex is of formula (D-III-4):

Chemical formula

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

[0087]

Chemical formula

[0088] In some embodiments, the complex is of formula (D-III-6):

Chemical formula

[0089] In some embodiments, the complex is of formula (D-III-7):

Chemical formula

[0090] In some embodiments, the complex is of formula (D-III-8): [Chemical formula] is represented by, or is a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the complex is of formula (D-III-9): [Chemical formula] [wherein, L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (for example, 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)] is represented by, or is a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0092] In some embodiments, the complex is of formula (D-IV): [Chemical formula] is represented by, or is a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the complex is of formula (D-IV-1): [Chemical formula] is represented by, or is a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the complex is of formula (D-IV-2): [Chemical formula] [wherein, L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (for example, 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)] It is represented by , or is a pharmaceutically acceptable salt thereof. In some embodiments, L’ is a nitrogen atom.

[0095] In some embodiments, the complex is of formula (D-V):

Chemical formula

[0096] In some embodiments, the complex is of formula (D-V-1):

Chemical formula

[0097] In some embodiments, the complex is of formula (D-V-2):

Chemical formula

[0098] In some embodiments, the complex is of formula (D-V-3):

Chemical formula

[0099] In some embodiments, the complex is of formula (D-V-4):

Chemical formula

[0100] In some embodiments, the complex is of formula (D-V-5):

Chemical formula

[0101] In some embodiments, the complex is of formula (D-V-6):

Chemical formula

[0102] In some embodiments, the complex is of formula (D-V-7):

Chemical formula

[0103] In some embodiments, the complex is of formula (D-V-8):

Chemical formula

[0104] In some embodiments, the complex is of formula (D-V-9):

Chemical formula

[0105] In some embodiments, the complex is of formula (D-V-10):

Chemical formula

[0106] In some embodiments, the complex is of formula (D-VI):

Chemical formula

[0107] In some embodiments, the complex is of formula (D-VI-1):

Chemical formula

[0108] In some embodiments, the complex is of formula (D-VI-2):

Chemical formula

[0109] In some embodiments, the complex is of formula (D-VI-3):

Chemical formula

[0110] In some embodiments, the complex is of formula (D-VI-4):

Chemical formula

[0111] In some embodiments, the complex is of formula (D-VI-5):

Chemical formula

[0112] In some embodiments, the complex is of formula (D-VI-6):

Chemical formula

[0113] In some embodiments, the complex is of formula (D-VI-7):

Chemical formula

[0114] In some embodiments, the complex is of formula (D-VI-8):

Chemical formula

[0115] In some embodiments, the complex is of formula (D-VI-9):

Chemical formula

[0116] In some embodiments, the complex is of formula (D-VII):

Chemical formula

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

[0118] In some embodiments, the complex is of formula (D-VIII):

Chemical formula

[0119] In some embodiments, the complex is of formula (D-VIII-1):

Chemical formula

[0120] In some embodiments, the complex is of formula (D-VIII-2):

Chemical formula

[0121] In some embodiments, the complex is of formula (D-VIII-3):

Chemical formula

[0122] In some embodiments, the complex is

Chemical formula

[0123] In some embodiments, the complex is of formula (D-VIII-4):

Chemical formula

[0124] In some embodiments, the complex is of formula (D-VIII-5):

Chemical formula

[0125] In some embodiments, the complex has a structure selected from

Chemical formula

[0126] In some embodiments, the complex has the structure

Chemical formula

[0127] In some embodiments, the complex is of formula (D-VIII-6):

Chemical formula

[0128] In some embodiments, the complex is of formula (D-VIII-7):

Chemical formula

[0129] In some embodiments, the complex is of formula (D-VIII-8):

Chemical formula

[0130] In some embodiments, the complex is of formula (D-VIII-9): [Chemical formula] 〔wherein, L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (for example, 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)〕 represented thereby, or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0131] In some embodiments, the complex is of formula (D-VIII-10): [Chemical formula] represented thereby, or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the complex is of formula (D-VIII-11): [Chemical formula] 〔wherein, L' is the remainder of L, and y1 and y2 are each independently an integer from 1 to 20 (for example, 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)〕 represented thereby, or a pharmaceutically acceptable salt thereof. In some embodiments, L' is a nitrogen atom.

[0133] In some embodiments, the complex is of formula (D-IX): [Chemical formula] represented thereby, or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the complex is of formula (D-IX-1): [Chemical formula] is represented by, or is a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the complex is of formula (D-IX-2):

Chemical formula

[0136] In some embodiments, the complex is of formula (D-IX-3):

Chemical formula

[0137] In some embodiments, the complex is of formula (D-IX-4):

Chemical formula

[0138] In some embodiments, the complex is of formula (D-IX-5):

Chemical formula

[0139] In some embodiments, the complex is of formula (D-IX-6):

Chemical formula

[0140] In some embodiments, the complex is of formula (D-X):

Chemical formula

[0141] In some embodiments, the complex is of formula (D-X-1): [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the complex is of formula (D-X-2): [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the complex is of formula (D-X-3): [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments of any of the aspects described herein, L or L' is one or more of optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocyclocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino, where R iis H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0145] In some embodiments of any of the aspects described herein, the backbone of L or L’ consists of one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino, and R iis H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

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

[0147] In some embodiments of any of the aspects described herein, each L is of formula (D-L-I):

Chemical formula

[0148] In some embodiments, L C is two binding points for an Fc domain, an Fc-binding peptide, an albumin protein or an albumin protein-binding peptide (e.g., two GC2 ) may have.

[0149] In some embodiments of any of the aspects described herein, L comprises a polyethylene glycol (PEG) linker. The PEG linker includes a linker having a repeating unit structure (-CH2CH2O-), where n is an integer from 2 to 100. The polyethylene glycol linker can covalently link the neuraminidase inhibitor and E (for example, in any one of the complexes of formulas (M-I) to (M-XI)). The polyethylene glycol linker can covalently link the first neuraminidase inhibitor and the second neuraminidase inhibitor (for example, in any one of the complexes of formulas (D-I) to (D-XI)). The polyethylene glycol linker can covalently link the neuraminidase inhibitor dimer and E (for example, in any one of the complexes of formulas (D-I) to (D-XI)). The polyethylene glycol linker is PEG2 to PEG n (for example, PEG2, PEG3, PEG4, PEG5, PEG5 to PEG 100 (for example, PEG2, PEG3, PEG4, PEG5, PEG5 to PEG 10 , PEG 10 to PEG 20 , PEG 20 to PEG 30 , PEG 30 to PEG 40 , PEG 50 to PEG 60 , PEG 60 to PEG 70 , PEG 70 to PEG 80 , PEG 80 to PEG 90 , PEG 90 to PEG 100 ) and can be selected from any one of them. In some embodiments, L c comprises a PEG linker, and L C is covalently bonded to each of Q and E.

[0150] In some embodiments, L is

Chemical formula

[0151] In some embodiments, L is

Chemical formula

[0152] In some embodiments, Y is

Chemical formula

Chemical formula

[0153] In some embodiments, Y is

Chemical formula

Chemical formula

[0154] In some embodiments, Y is

Chemical formula

Chemical formula

[0155] In some embodiments, Y is

Chemical formula

Chemical formula

[0156] In another aspect, the present invention provides a complex represented by formula (M-I):

Chemical formula

[0157] In another aspect, the present invention provides a complex represented by formula (M-I): [Chemical formula] [Wherein each A1 is independently selected from any one of formulas (A-I) to (A-V), and each E includes an Fc domain monomer (for example, an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138), an albumin protein (for example, an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 141), an albumin protein-binding peptide or an Fc-binding peptide, n is 1 or 2, T is an integer from 1 to 20 (for example, T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and L is a linker covalently bonded to each of E and A1]. or a pharmaceutically acceptable salt thereof. When T is greater than 1 (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 A1 can be independently selected from any one of formulas (A-I) to (A-V).

[0158] In another aspect, the present invention relates to a complex represented by formula (M-I):

Chemical formula

[0159] In some embodiments, the complex is of formula (M-II):

Chemical formula

[0160] In some embodiments, the complex is of formula (M-II-1):

Chemical formula

[0161] In some embodiments, the complex has the formula (M-II-2):

Chemical formula

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

Chemical formula

[0163] In some embodiments, the complex has the formula (M-II-4):

Chemical formula

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

Chemical formula

[0165] In some embodiments, the complex has the structure

Chemical formula

[0166] In some embodiments, the complex is of formula (M-II-6): [Chemical formula] [wherein, R7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl] represented by, or a pharmaceutically acceptable salt thereof. In some embodiments, R7 is selected from C1-C20 alkyl (for example, methyl, ethyl, propyl or butyl).

[0167] In some embodiments, the complex is of formula (M-II-7): [Chemical formula] represented by, or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the complex is of formula (M-II-8): [Chemical formula] [wherein, L’ is the remainder of L, and y1 is an integer from 1 to 20 (for example, y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20)] represented by, or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the complex has the structure [Chemical formula] having.

[0170] In some embodiments, the complex is of formula (M-II-9): [Chemical formula] represented by or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the complex is of formula (M-II-10): [Chemical formula] wherein L’ is the remainder of L and y1 is an integer from 1 to 20 (for example, y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) represented by or a pharmaceutically acceptable salt thereof.

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

[0173] In some embodiments, the complex is of formula (M-III): [Chemical formula] represented by or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the complex is of formula (M-III-1): [Chemical formula] represented by or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the complex is of formula (M-III-2): [Chemical formula] represented by or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the complex is of formula (M-III-3):

[0177]

Chem.

[0178] In some embodiments, the complex is of formula (M-III-4):

Chem.

[0179] In some embodiments, the complex is of formula (M-III-5):

Chem.

[0180] In some embodiments, the complex is of formula (M-III-6):

Chem.

[0181] In some embodiments, the complex is of formula (M-III-7):

Chem.

[0182] In some embodiments, the complex is of formula (M-III-8):

Chemical formula

[0183] In some embodiments, the complex is of formula (M-III-9):

Chemical formula

[0184] In some embodiments, the complex is of formula (M-IV):

Chemical formula

[0185] In some embodiments, the complex is of formula (M-IV-1):

Chemical formula

[0186] In some embodiments, the complex is of formula (M-IV-2):

Chemical formula

[0187] In some embodiments, the complex is of formula (M-V):

Chemical formula

[0188] In some embodiments, the complex is of formula (M-V-1):

Chemical formula

[0189] In some embodiments, the complex is of formula (M-V-2):

Chemical formula

[0190] In some embodiments, the complex is of formula (M-V-3):

Chemical formula

[0191] In some embodiments, the complex is of formula (M-V-4):

Chemical formula

[0192] In some embodiments, the complex is of formula (M-V-5):

Chemical formula

[0193] In some embodiments, the complex is of formula (M-V-6):

Chemical formula

[0194] In some embodiments, the complex is of formula (M-V-7):

Chemical formula

[0195] In some embodiments, the complex is of formula (M-V-8):

Chemical formula

[0196] In some embodiments, the complex is of formula (M-V-9):

Chemical formula

[0197] In some embodiments, the complex is of formula (M-V-10):

Chemical formula

[0198] In some embodiments, the complex is of formula (M-VI):

Chemical formula

[0199] In some embodiments, the complex is of formula (M-VI-1):

Chemical formula

[0200] In some embodiments, the complex is of formula (M-VI-2):

Chemical formula

[0201] In some embodiments, the complex is of formula (M-VI-3):

Chemical formula

[0202] In some embodiments, the complex is of formula (M-VI-4):

Chemical formula

[0203] In some embodiments, the complex is of formula (M-VI-5):

Chemical formula

[0204] In some embodiments, the complex is of formula (M-VI-6):

Chemical formula

[0205] In some embodiments, the complex is of formula (M-VI-7):

Chemical formula

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

[0207] In some embodiments, the complex has the formula (M-VI-9): [Chemical formula] [wherein, L' is the remainder of L, and y1 is an integer from 1 to 20 (for example, y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20)] or a pharmaceutically acceptable salt thereof.

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

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

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

[0211] In some embodiments, the complex has the formula (M-VIII-1): [Chemical formula] is represented by, or is a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the complex is of formula (M-VIII-2): [Chemical formula] is represented by, or is a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the complex is of formula (M-VIII-3): [Chemical formula] [wherein, L’ is the remainder of L, and y1 is an integer from 1 to 20 (for example, y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20)] is represented by, or is a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the complex is of formula (M-VIII-4): [Chemical formula] is represented by, or is a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the complex is of formula (M-VIII-5): [Chemical formula] [wherein, L’ is the remainder of L, and y1 is an integer from 1 to 20] is represented by, or is a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the complex is [Chemical formula] has the structure of or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the complex has the formula (M-VIII-6):

Chemical formula

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

Chemical formula

[0219] In some embodiments, the complex has the formula (M-VIII-8):

Chemical formula

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

Chemical formula

[0221] In some embodiments, the complex has the formula (M-VIII-10):

Chemical formula

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

Chemical formula

[0223] In some embodiments, the complex has the formula (M-IX):

Chemical formula

[0224] In some embodiments, the complex has the formula (M-IX-1):

Chemical formula

[0225] In some embodiments, the complex has the formula (M-IX-2):

Chemical formula

[0226] In some embodiments, the complex has the formula (M-IX-3):

Chemical formula

[0227] In some embodiments, the complex has the formula (M-IX-4):

Chemical formula

[0228] In some embodiments, the complex is of formula (M-IX-5):

Chemical formula

[0229] In some embodiments, the complex is of formula (M-IX-6):

Chemical formula

[0230] In some embodiments, the complex is of formula (M-X):

Chemical formula

[0231] In some embodiments, the complex is of formula (M-X-1):

Chemical formula

[0232] In some embodiments, the complex is of formula (M-X-2):

Chemical formula

[0233] In some embodiments, the complex is of formula (M-X-3):

Chemical formula

[0234] In some embodiments of any of the aspects described herein, L or L' is one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino, and R i is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

[0235] In some embodiments of any of the aspects described herein, the main chain of L or L’ is one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocyclocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino, where R i is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocyclocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

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

[0237] In some embodiments, each L is of formula (M-L-1): J 1 -(Q 1 ) g -(T 1 ) h -(Q 2 ) i -(T 2 ) j -(Q 3 ) k -(T 3 ) l -(Q 4 ) m -(T 4 ) n -(Q 5 ) o -J 2 [Wherein, J 1 is a bond with A1, J 2 is a bond with E, or a functional group capable of reacting with a functional group that is complexed with E (e.g., maleimide and cysteine, amine and active carboxylic acid, thiol and maleimide, active sulfonic acid and amine, isocyanate and amine, azide and alkyne, and alkene and tetrazine), Q 1 , Q 2 , Q 3 , Q 4 and Q 5Each of which is independently optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene, T 1 、T 2 、T 3 、T 4 Each of which is independently O, S, NR i 、P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino, R i is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl, and each of g, h, i, j, k, l, m, n and o is independently 0 or 1〕 represented by, or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, J 2 may have two binding sites for an Fc domain, an Fc-binding peptide, an albumin protein, or an albumin protein-binding peptide (e.g., two J 2 ).

[0239] In some embodiments, L is

Chemical formula

[0240] In some embodiments, L is

Chemical formula

[0241] In some embodiments of any of the aspects described herein, L comprises a polyethylene glycol (PEG) linker. The PEG linker includes a linker having a repeating unit structure (-CH2CH2O-) n wherein n is an integer from 2 to 100. The polyethylene glycol linker can covalently link a neuraminidase inhibitor and E (e.g., in any one of the complexes of formulas (M-I) to (M-XI)). The polyethylene glycol linker can covalently link a first neuraminidase inhibitor and a second neuraminidase inhibitor (e.g., in any one of the complexes of formulas (D-I) to (D-XI)). The polyethylene glycol linker can covalently link a neuraminidase inhibitor dimer and E (e.g., in any one of the complexes of formulas (D-I) to (D-XI)). The polyethylene glycol linker is PEG2 to PEG 100 (e.g., PEG2, PEG3, PEG4, PEG5, PEG5 to PEG10 , PEG 10 ~PEG 20 , PEG 20 ~PEG 30 , PEG 30 ~PEG 40 , PEG 50 ~PEG 60 , PEG 60 ~PEG 70 , PEG 70 ~PEG 80 , PEG 80 ~PEG 90 , PEG 90 ~PEG 100 ) can be selected from any one of them. In some embodiments, L c includes a PEG linker, and L C is covalently bonded to each of Q and E.

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

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

[0244] In some embodiments of any of the aspects described herein, E is an Fc domain monomer. In some embodiments, n is 2, and each E dimerizes to form an Fc domain.

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

[0246] [Chemical formula] [wherein, J is an Fc domain, and T is an integer from 1 to 20 (for example, T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20)] represented thereby, or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the complex is [Chemical formula] having the structure of or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, n is 2, each E is an Fc domain monomer, each E dimerizes to form an Fc domain, and the complex is of formula (M-I-1): [Chemical formula] [wherein, J is an Fc domain, and T is an integer from 1 to 20 (for example, T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20)] represented thereby, or a pharmaceutically acceptable salt thereof.

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

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

[0251] In some embodiments, n is 1, E is an albumin protein, an albumin protein-binding peptide or an Fc-binding peptide, and the complex is of formula (D-I-2):

Chemical formula

[0252] In some embodiments, n is 1, E is an albumin protein, an albumin protein-binding peptide or an Fc-binding peptide, and the complex is of formula (M-I-2):

Chemical formula

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

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

[0255] In another aspect, the present invention provides a population of complexes having the structure of any of the complexes described herein (e.g., a population of complexes having any one of the formulas (1)-(5), (D-I)-(D-XI), (D'-I), (M-I)-(M-XI), or (M'-I)), where the average value of T is from 1 to 20 (e.g., the average value of T is from 1 to 2, from 1 to 3, from 1 to 4, from 1 to 5, from 5 to 10, from 10 to 15, from 15 to 20, from 1.5 to 3.5, from 2.5 to 4.5, from 3.5 to 5.5, from 4.5 to 6.5, from 5.5 to 7.5, from 6.5 to 8.5, from 7.5 to 9.5, or from 8.5 to 10.5). In some embodiments, the average value of T is about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 or 20.

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

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

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

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

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

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

[0262] In another aspect, the present invention provides a complex represented by formula (D'-I):

Chemical formula

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

[0264] In another aspect, the present invention provides a complex represented by formula (M’-I): [Chemical formula] wherein each A1 is independently selected from any one of formulas (A-III) to (A-V) of (M-IX), each A2 is independently selected from any one of formulas (A-I), (A-II), (A-VI), (A-VII), (A-VIII), and (A-IX), each E comprises an Fc domain monomer (e.g., an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138), an albumin protein (e.g., an albumin protein having any one of the sequences of SEQ ID NOs: 139 to 141), an albumin protein-binding peptide, or an Fc-binding peptide, n is 1 or 2, 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 attached 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 attached to E and A2, and 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.

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

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

[0267] In another aspect, the present invention provides a method of treating a subject having or suspected of having a viral infection, the method comprising administering to the subject an effective amount of any one of the complexes or compositions described herein (e.g., any one of the complexes of formulas (1)-(5), (D-I)-(D-XI), (D'-I), (M-I)-(M-XI), or (M'-I)).

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

[0269] 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 virus type A, B, or C, or a parainfluenza virus.

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

[0271] In some embodiments, the subject is diagnosed with humoral immunodeficiency, T-cell deficiency, neutropenia, asplenia, or complement deficiency.

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

[0273] In some embodiments, the subject is 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.

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

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

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

[0277] In another aspect, the present disclosure features a method for preventing secondary infections in a subject diagnosed with influenza infection, the method comprising administering to the subject the complex or composition described herein. In some embodiments, the method comprises administering to the subject complex 45, or a pharmaceutical composition comprising complex 45.

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

[0279] In some embodiments, the subject is treated with a second therapeutic agent. In some embodiments, the second therapeutic agent is an antiviral agent. In some embodiments, the antiviral agent is selected from pimovidir, oseltamivir, zanamivir, peramivir, laninamivir, amantadine or rimantadine. In certain embodiments, the second therapeutic agent is pimovidir. In some embodiments, the second therapeutic agent is a viral vaccine. In some embodiments, the viral vaccine induces an immune response against influenza virus type A, B or C, or parainfluenza virus in the subject.

[0280] In some embodiments, the complex is administered in combination with an antiviral agent, which is baloxavir. In one embodiment, the complex is represented by formula (D-II-6). In other embodiments, the complex is represented by formula (D-II-7). In one embodiment, each E comprises an Fc domain having an amino acid sequence that is at least 95% identical to any one of the sequences of SEQ ID NOs: 63 to 138. In certain embodiments, each E comprises an Fc domain having an amino acid sequence that is at least 95% identical to any one of the sequences of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85 or SEQ ID NO: 86. In certain embodiments, each E comprises an Fc domain having any one of the amino acid sequences of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85 or SEQ ID NO: 86. In a preferred embodiment, the complex is complex 45 (e.g., complex 45a or 45b) or complex 46.

[0281] In one embodiment, the complex and baloxavir are administered sequentially. In other embodiments, the complex and baloxavir are administered simultaneously.

[0282] In one aspect, the present disclosure provides a method for treating or preventing a viral infection in a subject by administering to the subject a) an effective amount of the complex or composition according to any one of claims 1 to 215, and b) a second therapeutic agent. In certain embodiments, the complex is administered to the subject after the subject has, is presumed to have, or has been exposed to a viral infection. In some embodiments, the complex is administered prophylactically to the subject. In certain embodiments, the second therapeutic agent is administered to the subject after the subject has, is presumed to have, or has been exposed to a viral infection. In some embodiments, the second therapeutic agent is administered prophylactically to the subject. In some embodiments, the second therapeutic agent is administered within 30 days, within 14 days, within 7 days, within 2 days, or within 24 hours of the complex. In certain embodiments, the second therapeutic agent is administered within 2 days of the complex. In certain embodiments, the second therapeutic agent is an antiviral agent (e.g., pimovidir, oseltamivir, zanamivir, peramivir, laninamivir, amantadine, baloxavir marboxil, baloxavir acid, rimantadine, or a pharmaceutically acceptable salt thereof). In certain embodiments, the antiviral agent is baloxavir marboxil, baloxavir acid, or a pharmaceutically acceptable salt thereof. In certain embodiments, baloxavir marboxil is administered in an amount of 20 to 90 mg (e.g., 25 to 50 mg, 45 to 70 mg, or 65 to 90 mg). In some embodiments, baloxavir marboxil is administered orally. In certain embodiments, baloxavir marboxil is administered as a single dose. In other embodiments, baloxavir marboxil is administered as multiple doses more than once. In certain embodiments, baloxavir marboxil is administered in an amount of 20 to 40 mg. In other embodiments, baloxavir marboxil is administered in an amount of 30 to 80 mg. In certain embodiments, the complex is represented by formula (D-II-6). In other embodiments, the complex is represented by formula (D-II-7). In certain embodiments, each E has a sequence that is at least 95% identical to any one of the sequences of SEQ ID NOs: 63 to 138.In certain embodiments, each E comprises an Fc domain having an amino acid sequence that is at least 95% identical to any one of the sequences of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85, or SEQ ID NO: 86. In certain embodiments, each E comprises an Fc domain having any one of the amino acid sequences of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85, or SEQ ID NO: 86. In some embodiments, the complex is complex 45 (e.g., complex 45a or 45b) or complex 46. In certain embodiments, the complex is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subcutaneously, subconjunctivally, intracapsularly, transmucosally, pericardially, intraumbilically, intraocularly, orally, topically, by inhalation, by injection, or by infusion. In some embodiments, the complex is administered intravenously. In some embodiments, the complex is administered intramuscularly. In some embodiments, the viral infection is caused by an influenza virus or a parainfluenza virus. In some embodiments, the virus is an influenza A, B, or C virus, or a parainfluenza virus.

[0283] In some embodiments, any one of formulas (1) to (5), (D-I) to (D-XI), (D’-I), (M-I) to (M-XI), or (M’-I) (for example, formulas (1), (2), (3), (4), (5), (D-I), (D-II), (D-II-1), (D-II-2), (D-II-3), (D-II-4), (D-II-5), (D-II-6), (D-II-7), (D-II-8), (D-II-9), (D-II-10), (D-III), (D-III-1), (D-III-2), (D-III-3), (D-III-4), (D-III-5), (D-III-6), (D-III-7), (D-III-8), (D-III-9), (D-IV), (D-IV-1), (D-IV-2), (D-V), (D-V-1), (D-V-2), (D-V-3), (D-V-4), (D-V-5), (D-V-6), (D-V-7), (D-V-8), (D-V-9), (D-V-10), (D-VI), (D-VI-1), (D-VI-2), (D-VI-3), (D-VI-4), (D-VI-5), (D-VI-6), (D-VI-7), (D-VI-8), (D-VI-9), (D-VII), (D-VIII), (D-VIII-1), (D-VIII-2), (D-VIII-3), (D-VIII-4), (D-VIII-5), (D-VIII-6), (D-VIII-7), (D-VIII-8), (D-VIII-9), (D-VIII-10), (D-VIII-11), (D-IX), (D-IX-1), (D-IX-2), (D-IX-3), (D-IX-4), (D-IX-5), (D-IX-6), (D-X), (D-X-1), (D-X-2), (D-X-3), (D-XI), (D-XI-1), (D’-I), (M-I), (M-II), (M-II-1), (M-II-2), (M-II-3), (M-II-4), (M-II-5), (M-II-6), (M-II-7), (M-II-8), (M-II-9), (M-II-10), (M-III), (M-III-1), (M-III-2), (M-III-3), (M-III-4), (M-III-5), (M-III-6), (M-III-7), (M-III-8), (M-III-9), (M-IV), (M-IV-1), (M-IV-2), (M-V), (M-V-1), (M-V-2)((M-V-3), (M-V-4), (M-V-5), (M-V-6), (M-V-7), (M-V-8), (M-V-9), (M-V-10), (M-VI), (M-VI-1), (M-VI-2), (M-VI-3), (M-VI-4), (M-VI-5), (M-VI-6), (M-VI-7), (M-VI-8), (M-VI-9), (M-VII), (M-VIII), (M-VIII-1), (M-VIII-2), (M-VIII-3), (M-VIII-4), (M-VIII-5), (M-VIII-6), (M-VIII-7), (M-VIII-8), (M-VIII-9), (M-VIII-10), (M-VIII-11), (M-IX), (M-IX-1), (M-IX-2), (M-IX-3), (M-IX-4), (M-IX-5), (M-IX-6), (M-X), (M-X-1), (M-X-2), (M-X-3), (M-XI), (M-XI-1) or (M’-I)), a Fc domain-containing composition may be used instead of the Fc domain, and a Fc domain monomer-containing composition may be used instead of the Fc domain monomer. In any of the formulas described herein (for example, any one of formulas (1) to (5), (D-I) to (D-XI), (D’-I), (M-I) to (M-XI) or (M’-I)), when n is 1, E is a Fc domain monomer-containing composition. In any of the formulas described herein (for example, any one of formulas (1) to (5), (D-I) to (D-XI), (D’-I), (M-I) to (M-XI), or (M’-I)), when n is 2, E is a Fc domain-containing composition.,

[0284] In certain embodiments, the Fc domain-containing composition is an antibody or an antibody fragment. The antibody can be any form of immunoglobulin, heavy chain antibody, light chain antibody, LRR-based antibody, or other protein scaffold having antibody-like properties, and further any other immunological binding moiety known in the art, such as antibody fragments (e.g., Fab, Fab’, Fab’2, F(ab’)2, Fd, Fv, Feb, scFv or SMIP). The subunit structures and three-dimensional arrangements of various classes of antibodies are known in the art. The antibody fragment can include a binding moiety derived from or highly homologous to an antibody, such as the antigen-determining region of the antibody. Exemplary antibody fragments include Fab, Fab’, Fab’2, F(ab’)2, Fd, Fv, Feb, scFv and SMIP.

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

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

[0287] In some embodiments, one or more targets (e.g., antigens) to which the Fc domain-containing construct (e.g., an antibody or antibody fragment) binds 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. Examples of hemagglutinin-directed antibodies include monoclonal antibodies, such as CR6261, CR8020, MEDI8852, MHAA4549A, and VIS410. In some embodiments, the antibody or antibody fragment is an antibody or antibody fragment that broadly neutralizes influenza hemagglutinin as a target (e.g., the antibody or antibody fragment described in Wu et al., J. Mol. Biol. 429:2694-2709 (2017)). In some embodiments, the antibody or antibody fragment targets a viral matrix protein (e.g., matrix 2 protein). TCN032 is a monoclonal antibody directed against the matrix 2 protein.

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

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

[0290] In another aspect, the present invention is any one of formulas (1) to (5), (D-I) to (D-XI), (D'-I), (M-I) to (M-XI), 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-XI), (D-XI-1), (D'-I), (M-I), (M-II), (M-II-1), (M-II-2), (M-II-3), (M-II-4), (M-II-5), (M-II-6), (M-II-7), (M-II-8), (M-II-9), (M-II-10), (M-III), (M-III-1), (M-III-2), (M-III-3), (M-III-4), (M-III-5), (M-III-6), (M-III-7), (M-III-8), (M-III-9), (M-IV), (M-IV-1), (M-IV-2), (M-V), (M-V-1),(M-V-2), (M-V-3), (M-V-4), (M-V-5), (M-V-6), (M-V-7), (M-V-8), (M-V-9), (M-V-10), (M-VI), (M-VI-1), (M-VI-2), (M-VI-3), (M-VI-4), (M-VI-5), (M-VI-6), (M-VI-7), (M-VI-8), (M-VI-9), (M-VII), (M-VIII), (M-VIII-1), (M-VIII-2), (M-VIII-3), (M-VIII-4), (M-VIII-5), (M-VIII-6), (M-VIII-7), (M-VIII-8), (M-VIII-9), (M-VIII-10), (M-VIII-11), (M-IX), (M-IX-1), (M-IX-2), (M-IX-3), (M-IX-4), (M-IX-5), (M-IX-6), (M-X), (M-X-1), (M-X-2), (M-X-3) or (M'-I), and contains a complex represented by any one of them, and E is an antibody or an antibody fragment. In a preferred embodiment, when E is an antibody or an antibody fragment, n is 1. In some embodiments, the antibody or antibody fragment is any antibody or antibody fragment described herein, for example, a monoclonal antibody that binds to viral hemagglutinin (e.g., CR6261, CR8020, MEDI8852, MHAA4549A or VIS410); an antibody or antibody fragment that broadly neutralizes targeting viral hemagglutinin (e.g., the antibody or antibody fragment described in Wu et al., J. Mol. Biol. 429:2694-2709 (2017)); an sdAb that targets viral hemagglutinin (e.g., SD36, SD38, SD83 or SD84); or an MDAb or its fragment that targets viral hemagglutinin (e.g., JNJ-7445).

[0291] In some embodiments of any of the aspects described herein, E (e.g., each E) contains the amino acid sequence of SEQ ID NO: 1. In some embodiments, E contains an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 1.

[0292] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 2.

[0293] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 3. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 3.

[0294] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 4.

[0295] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 5.

[0296] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 6.

[0297] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 7. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7.

[0298] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8.

[0299] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 9.

[0300] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10.

[0301] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 11.

[0302] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 12.

[0303] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 13. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 13.

[0304] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 14.

[0305] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 15.

[0306] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 16.

[0307] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17.

[0308] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 18. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18.

[0309] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 19. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19.

[0310] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20.

[0311] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 21. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 21.

[0312] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 22. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 22.

[0313] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23.

[0314] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 24. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 24.

[0315] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 25. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 25.

[0316] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 26. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26.

[0317] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 27. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 27.

[0318] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 28. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 28.

[0319] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 29. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 29.

[0320] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 30. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 30.

[0321] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 31. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 31.

[0322] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 32. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 32.

[0323] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 33. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 33.

[0324] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 34. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 34.

[0325] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 35. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 35.

[0326] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 36. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 36.

[0327] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 37. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 37.

[0328] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 38. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38.

[0329] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 39. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 39.

[0330] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 40. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 40.

[0331] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 41. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 41.

[0332] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 42. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 42.

[0333] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 43. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 43.

[0334] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 44. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 45.

[0335] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 46. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 46.

[0336] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 47. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 47.

[0337] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 48.

[0338] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 49. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 49.

[0339] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 50. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 50.

[0340] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 51. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 51.

[0341] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 52.

[0342] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 53. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 53.

[0343] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 54. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 54.

[0344] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 55. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 55.

[0345] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 56. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 56.

[0346] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 57. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 57.

[0347] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 58. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 58.

[0348] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 59. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 59.

[0349] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 60. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 60.

[0350] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 61.

[0351] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 62. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 62.

[0352] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 63. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 63.

[0353] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 64. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 64.

[0354] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 65. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 65.

[0355] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 66. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 66.

[0356] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 67. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 67.

[0357] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 68. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 68.

[0358] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 69. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 69.

[0359] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 70. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 70.

[0360] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 71. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 71.

[0361] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 72. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 72.

[0362] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 73. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 73.

[0363] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 74. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 74.

[0364] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 75. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 75.

[0365] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 76. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 76.

[0366] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 77. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 77.

[0367] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 78. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 78.

[0368] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 79. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 79.

[0369] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 80. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 80.

[0370] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 81. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 81.

[0371] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 82. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 82.

[0372] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 83. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 83.

[0373] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 84. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 84.

[0374] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 85. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 85.

[0375] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 86. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 86.

[0376] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 87. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 87.

[0377] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 88. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 88.

[0378] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 89.

[0379] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 90. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 90.

[0380] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 91. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 91.

[0381] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 92. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 92.

[0382] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 93. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 93.

[0383] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 94. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 94.

[0384] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 95. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 95.

[0385] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 96. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 96.

[0386] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 97. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 97.

[0387] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 98. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 98.

[0388] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 99. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 99.

[0389] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 100. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 100.

[0390] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 101. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 101.

[0391] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 102. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 102.

[0392] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 103. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 103.

[0393] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 104. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 104.

[0394] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 105. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 105.

[0395] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 106. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 106.

[0396] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 107. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 107.

[0397] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 108. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 108.

[0398] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 109. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 109.

[0399] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 110. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 110.

[0400] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 111. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 111.

[0401] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 112. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 112.

[0402] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 113. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 113.

[0403] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 114. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 114.

[0404] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 115.

[0405] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 116. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 116.

[0406] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 117.

[0407] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 118. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 118.

[0408] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 119. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 119.

[0409] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 120. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 120.

[0410] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 121. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 121.

[0411] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 122. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 122.

[0412] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 123. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 123.

[0413] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 124. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 124.

[0414] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 125. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 125.

[0415] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 126. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 126.

[0416] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 127. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 127.

[0417] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 128. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 128.

[0418] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 129. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 129.

[0419] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 130. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 130.

[0420] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 131. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 131.

[0421] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 132. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 132.

[0422] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 133. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 133.

[0423] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 134. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 134.

[0424] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 135. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 135.

[0425] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 136. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 136.

[0426] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 137. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 137.

[0427] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 138. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 138.

[0428] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 139. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 139.

[0429] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 140. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 140.

[0430] In some embodiments of any of the aspects described herein, E (e.g., each E) comprises the amino acid sequence of SEQ ID NO: 145. In some embodiments, E comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 141.

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

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

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

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

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

[0436] In some embodiments of any of the aspects described herein, E comprises an Fc domain monomer, and the Fc domain monomer (e.g., an Fc domain monomer having any one of the sequences of SEQ ID NOs: 1 to 138) is a fragment of the Fc domain monomer (e.g., at least 25 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more), at least 50 (e.g., 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 or more), at least 75 (e.g., 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more) consecutive amino acids in length).

[0437] In some embodiments of any of the aspects described herein (e.g., any one complex of formulas (1)-(5), (D-I)-(D-XI), (D'-I), (M-I)-(M-XI), or (M'-I)), one or more nitrogen atoms of one or more surface-exposed lysine residues of E, or one or more sulfur atoms of one or more surface-exposed cysteines in E, are covalently linked to a linker (e.g., PEG2 to PEG 20It is complexed with a linker). The linker complexed with E can be functionalized so as to be able to react to form a covalent bond with any L of A1-L or any A2-L-A1 described herein. In a preferred embodiment, E is complexed with a linker functionalized with an azide group, and L of A1-L or any A2-L-A1 is functionalized with an alkyne group. The complex of the present invention, for example, a complex represented by any one of formulas (1) to (5), (D-I) to (D-XI), (D’-I), (M-I) to (M-XI), or (M’-I) is formed by the complexation (e.g., by click chemistry) of the linker-azide of E and the linker-alkyne of A1-L or A2-L-A1. In still other embodiments, E is complexed with a linker functionalized with an alkyne group, and L of any A1-L or any A2-L-A1 is functionalized with an azide group. The complex of the present invention, for example, a complex represented by formula (1) to (5), (D-I) to (D-XI), (D’-I), (M-I) to (M-XI), or (M’-I) is formed by the complexation (e.g., by click chemistry, e.g., referring to FIG. 103) of the linker-alkyne of E and the linker-azide of A1-L or A2-L-A1. In some embodiments of any of the aspects described herein, the wavy line of any one of formulas (1) to (5), (D-I) to (D-XI), (D’-I), (M-I) to (M-XI), or (M’-I) can represent a covalent bond between E and L of A1-L or A2-L-A1.

[0438] In some embodiments of any of the aspects described herein, the wavy line of any one of formulas (1) to (5), (D-I) to (D-XI), (D’-I), (M-I) to (M-XI), or (M’-I) is a linker (e.g., PEG2 to PEG 20a linker) that is functionalized with a reactive moiety, such that the reactive moiety forms a covalent bond with an L of any A1-L or any A2-L-A1 described herein (e.g., by click chemistry between an azide-functionalized linker and an alkyne-functionalized linker, as described above, e.g., with reference to FIG. 103), and one or more amino acid side chains of E (e.g., one or more nitrogen atoms of one or more surface-exposed lysine residues of E, or one or more sulfur atoms of one or more surface-exposed cysteines in E) are complexed therewith, which may be represented.

[0439] In some embodiments of any of the aspects described herein, A1 and / or A2 has a structure represented by (A-I):

Chemical formula

[0440] In preferred embodiments, A1 and / or A2 has a structure represented by (A-I), R1 is -NHC(=NH)NH2, R4 is -CO2H, R5 is -COCH3, and / or X is -O-. In preferred embodiments, A1 and / or A2

Chemical formula

[0441] In some embodiments of any of the aspects described herein, A1 and / or A2 is (A-II):

Chemical formula

[0442] In a preferred embodiment, A1 and / or A2 has a structure represented 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 is [Chemical Formula] has a structure represented by.

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

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

[0445] In some embodiments of any of the aspects described herein, A1 and / or A2 is (A-IV): [Chemical Formula] has a structure represented by.

[0446] In a preferred embodiment, A1 and / or A2 has a structure represented by (A-IV), R1 is -NHC(=NH)NH2, R4 is -CO2H, and / or R5 is -COCH3. In a preferred embodiment, A1 and / or A2 is [Chemical Formula] It has a structure represented by

[0447] In some embodiments of any of the aspects described herein, A1 and / or A2 is (A-V):

[0448]

Chemical formula

[0449] In a preferred embodiment, A1 and / or A2 has a structure represented by (A-V), R1 is -NHC(=NH)NH2, R4 is -CO2H, and / or R5 is -COCH3. In a preferred embodiment, A1 and / or A2 is

[0450]

Chemical formula

[0451] In some embodiments of any of the aspects described herein, A1 and / or A2 is (A-VI):

Chemical formula

[0452] In a preferred embodiment, A1 and / or A2 has a structure represented 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 is

Chemical formula

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

[0454] In a preferred embodiment, A1 and / or A2 has a structure represented 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 is [Chemical formula] It has a structure represented by

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

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

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

[0458] In a preferred embodiment, A1 and / or A2 have a structure represented 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 are

Chemical formula

[0459] In some embodiments of any of the aspects described herein, A1 and / or A2 are (A-X):

Chemical formula

[0460] In a preferred embodiment, A1 and / or A2 have a structure represented by (A-X), R1 is -NHC(=NH)NH2, R3 is H, R5 is -COCH3, and / or X is -O-. In a preferred embodiment, A1 and / or A2 are

Chemical formula

[0461] In some embodiments of any of the aspects described herein, A1 and / or A2 are (A-XI):

Chemical formula

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

Chemical formula

[0463] In some embodiments of any of the aspects described herein, A1 and / or A2 is (A-XII):

Chemical formula

[0464] In a preferred embodiment, A1 and / or A2 has the structure represented by (A-XII) and R4 is -CO2H. In a preferred embodiment, A1 and / or A2 is

Chemical formula

[0465] In some embodiments, the conjugate is conjugate 1 or any of its positional isomers, and the drug-to-antibody ratio (DAR) (e.g., T) is from 0.5 to 10.0, for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 1, and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0466] In some embodiments, the conjugate is conjugate 2 or any positional isomer thereof, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 2 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0467] In some embodiments, the conjugate is conjugate 3 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 3 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0468] In some embodiments, the conjugate is conjugate 4 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 4 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0469] In some embodiments, the conjugate is conjugate 5 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 5 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0470] In some embodiments, the conjugate is conjugate 6 or any positional isomer thereof, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, from 2.0 to 4.0, from 4.0 to 6.0, from 6.0 to 8.0, or from 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 6 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, from 1 to 3, from 1 to 4, from 1 to 5, from 5 to 10, from 10 to 15, from 15 to 20, from 1.5 to 3.5, from 2.5 to 4.5, from 3.5 to 5.5, from 4.5 to 6.5, from 5.5 to 7.5, from 6.5 to 8.5, from 7.5 to 9.5, or from 8.5 to 10.5.

[0471] In some embodiments, the conjugate is conjugate 7 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 7 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0472] In some embodiments, the conjugate is conjugate 8 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 8 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0473] In some embodiments, the conjugate is conjugate 9 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 9 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0474] In some embodiments, the conjugate is conjugate 10 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 10 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0475] In some embodiments, the conjugate is conjugate 11 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 11 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0476] In some embodiments, the conjugate is conjugate 12 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 12 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0477] In some embodiments, the conjugate is conjugate 13 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 13 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0478] In some embodiments, the conjugate is conjugate 14 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 14 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0479] In some embodiments, the conjugate is conjugate 15 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, for example, about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 15 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0480] In some embodiments, the conjugate is conjugate 16 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 16 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0481] In some embodiments, the conjugate is conjugate 17 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 17 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0482] In some embodiments, the conjugate is conjugate 18 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 18 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0483] In some embodiments, the conjugate is conjugate 19 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 19 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0484] In some embodiments, the conjugate is conjugate 20 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 20 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0485] In some embodiments, the conjugate is conjugate 21 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 21 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0486] In some embodiments, the conjugate is conjugate 22 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 22 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0487] In some embodiments, the conjugate is conjugate 23 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 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, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 23 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0488] In some embodiments, the conjugate is conjugate 24 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 24 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0489] In some embodiments, the conjugate is conjugate 25 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 25 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0490] In some embodiments, the conjugate is conjugate 26 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 26 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0491] In some embodiments, the conjugate is conjugate 27 or any positional isomer thereof, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 27 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0492] In some embodiments, the conjugate is conjugate 28 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 28 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0493] In some embodiments, the conjugate is conjugate 29 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 29 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0494] In some embodiments, the conjugate is conjugate 30 or any of its regioisomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 30 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0495] In some embodiments, the conjugate is conjugate 31 or any positional isomer thereof, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 31 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0496] In some embodiments, the conjugate is conjugate 32 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 32 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0497] In some embodiments, the conjugate is conjugate 33 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 33 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0498] In some embodiments, the conjugate is conjugate 34 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 34 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0499] In some embodiments, the conjugate is conjugate 35 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 35 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0500] In some embodiments, the conjugate is conjugate 36 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 36 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0501] In some embodiments, the conjugate is conjugate 37 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 37 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0502] In some embodiments, the conjugate is conjugate 38 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 38 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0503] In some embodiments, the conjugate is conjugate 39 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 39 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0504] In some embodiments, the conjugate is conjugate 40 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 40 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0505] In some embodiments, the conjugate is conjugate 41 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 41 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0506] In some embodiments, the conjugate is conjugate 42 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 42 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0507] In some embodiments, the conjugate is conjugate 43 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 43 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0508] In some embodiments, the conjugate is conjugate 44 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 44 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0509] In some embodiments, the conjugate is conjugate 45 (e.g., conjugate 45a or conjugate 45b) or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 45 (e.g., conjugate 45a or conjugate 45b), and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0510] In some embodiments, the conjugate is conjugate 46 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 46 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0511] In some embodiments, the conjugate is conjugate 47 or any positional isomer thereof, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 47 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0512] In some embodiments, the conjugate is conjugate 48 or any of its positional isomers, and the DAR (e.g., T) is from 0.5 to 10.0, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In some embodiments, the DAR is from 0.5 to 2.0, 2.0 to 4.0, 4.0 to 6.0, 6.0 to 8.0, or 8.0 to 10.0. In another aspect, the present invention provides a population of conjugates, wherein each conjugate has the structure of conjugate 48 and the average DAR (e.g., T) of the population of conjugates is from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.

[0513] In some embodiments of any of the aspects described herein, the present invention features a conjugate represented by any one of formula (D-I), (M-I), (1) or (2), or a pharmaceutically acceptable salt thereof, wherein each A1 and each A2 in the formula are independently of formula (A-XIII):

Chemical formula

[0514] In some embodiments, each A1 and each A2 are of formula (A-XIII-1):

Chemical formula

[0515] In some embodiments, each A1 and each A2 are independently of formula (A-XIII-1a) to (A-XIII-1d):

Chemical formula

[0516] In some embodiments, the complex is of formula (D-XI):

Chemical formula

[0517] In some embodiments, the complex is of formula (D-XI-1):

Chemical formula

[0518] In some embodiments, the complex is of formula (M-XI):

Chemical formula

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

[0520] Definition To facilitate the understanding of the present invention, some terms are defined below. The terms defined herein have the meanings generally understood by those skilled in the art to which the present invention pertains. Terms such as "a", "an", and "the" are not intended to refer only to singular entities, but include general classes for which specific examples may be used for illustration. The technical terms herein are used to describe specific embodiments of the present invention, but their usage does not limit the present invention, except when defined within the claims.

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

[0522] As used herein, the term "inhibiting neuraminidase activity" means an IC 50 of 1,000 nM or less when measured according to, for example, the neuraminidase inhibition assay in Example 2 herein. Specifically, IC 50 represents the concentration of an influenza virus neuraminidase inhibitor required for 50% inhibition in vitro. In some embodiments, an IC 50 by the neuraminidase inhibition assay of 100 nM or less or 10 nM or less suggests that the compound is inhibiting neuraminidase activity.

[0523] "Viral infectious disease" means the growth of a virus (e.g., influenza virus) that is pathogenic in a host organism (e.g., a human subject). A viral infectious disease can be any situation where the presence of a virus population (multiple possible) is damaging to the host's body. Thus, a subject is "suffering from" a viral infectious disease when an excessive amount of virus population is present in or on the subject's body, or when the presence of the virus population (multiple possible) is damaging to the subject's cells or other tissues.

[0524] As used herein, the term "Fc domain monomer" refers to at least the hinge domain and the second and third antibody constant domains (C H 2 and C H3) or a polypeptide chain comprising such functional fragments thereof (e.g., (i) fragments capable of dimerizing with another Fc domain monomer to form an Fc domain and (ii) fragments capable of binding to an Fc receptor). The Fc domain monomer can be any immunoglobulin antibody isotype including IgG, IgE, IgM, IgA or IgD (e.g., IgG). In addition, the Fc domain monomer can be an IgG subtype (e.g., IgG1, IgG2a, IgG2b, IgG3 or IgG4) (e.g., IgG1). The Fc domain monomer does not contain any portion of an immunoglobulin that can act as an antigen recognition region, such as a variable domain or a complementarity determining region (CDR). The Fc domain monomer in the complexes described herein can contain one or more alterations (e.g., 1-10, 1-8, 1-6, 1-4 amino acid substitutions, additions or deletions) from the wild-type Fc domain monomer sequence that alter the interaction between the Fc domain and the Fc receptor. Examples of suitable alterations are known in the art. In certain embodiments, the human Fc domain monomer (e.g., an IgG heavy chain, e.g., IgG1) includes the region extending from any of Asn208, Glu216, Asp221, Lys222 or Cys226 to the carboxy terminus of the heavy chain at Lys447. The C-terminal Lys447 of the Fc region may or may not be present without affecting the structure or stability of the Fc region. The C-terminal Lys447 can be proteolytically cleaved during polypeptide expression. In some embodiments of any of the Fc domain monomers described herein, the C-terminal Lys447 is optionally present or absent. The present disclosure specifically contemplates any of SEQ ID NOs: 1-4, 11, 16, 19, 20, 32-37, 48-53, and 60-68 that do not include a C-terminal Lys corresponding to Lys447. The N-terminal N (Asn) of the Fc region (e.g., any one of SEQ ID NOs: 60-77) may or may not be present without affecting the structure or stability of the Fc region. The N-terminal Asn can be deamidated during polypeptide expression. In some embodiments of any of the Fc domain monomers described herein, the N-terminal Asn is optionally present or absent.The present disclosure contemplates, in particular, any of SEQ ID NOs: 60-77 that do not contain an N-terminal Asn. Unless otherwise specified herein, the numbering of amino acid residues in an IgG or Fc domain monomer follows the EU numbering system for antibodies, also referred to as the Kabat EU index, as described, for example, in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0525] As used herein, the term "Fc domain" refers to a dimer of two Fc domain monomers that can bind to an Fc receptor. In the wild-type Fc domain, the two Fc domain monomers dimerize by interaction between the two C H 3 antibody constant domains, and in some embodiments, one or more disulfide bonds are formed between the hinge domains of the two dimerized Fc domain monomers. The term "covalently bound" means that the two parts of the complex are connected to each other by a covalent bond formed between two atoms in the two parts of the complex.

[0526] As used herein, the term "Fc-binding peptide" refers to a polypeptide having an amino acid sequence of 5 to 50 (e.g., 5 to 40, 5 to 30, 5 to 20, 5 to 15, 5 to 10, 10 to 50, 10 to 30, or 10 to 20) amino acid residues that has an affinity and binding function for an Fc domain, such as any of the Fc domains described herein. The Fc-binding peptide can be of various origins, for example, it can be of synthetic, human, mouse, or rat origin. The Fc-binding peptides of the present invention include Fc-binding peptides engineered to contain one or more (e.g., 2, 3, 4, or 5) solvent-exposed cysteine or lysine residues that can provide a site for complexation with a compound of the present invention (e.g., complexation with a neuraminidase inhibitor monomer or dimer, including cases with a linker). It would be most preferred that the Fc-binding peptide contains a single solvent-exposed cysteine or lysine, thereby enabling site-specific complexation of the compound of the present invention. The Fc-binding peptide may contain only naturally occurring amino acid residues or may contain one or more non-naturally occurring amino acid residues. Non-naturally occurring amino acid residues (e.g., side chains of non-naturally occurring amino acid residues), when included, can be used as a binding point for a compound of the present invention (e.g., a neuraminidase inhibitor monomer or dimer, including cases with a linker). The Fc-binding peptides of the present invention may be linear or cyclic. The Fc-binding peptides of the present invention include any Fc-binding peptides known to those skilled in the art.

[0527] As used herein, the term "albumin protein" refers to a polypeptide comprising the amino acid sequence corresponding to a naturally occurring albumin protein (e.g., human serum albumin) or a variant thereof, such as an engineered variant of a naturally occurring albumin protein. Variants of albumin protein include polymorphisms, fragments such as domains and subdomains, and fusion proteins (e.g., albumin protein fused at the C-terminus or N-terminus, e.g., having a polypeptide linker). Preferably, the albumin protein has the amino acid sequence of human serum albumin (HSA), or a variant or fragment thereof, most preferably a functional variant or fragment thereof. The albumin proteins of the present invention include proteins having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with any one of SEQ ID NOs: 139-141. The albumin proteins of the present invention include albumin proteins engineered to contain one or more (e.g., 2, 3, 4 or 5) solvent-exposed cysteine or lysine residues that can provide a site for complexation with a compound of the present invention (e.g., complexation with a neuraminidase inhibitor monomer or dimer, including by means of a linker). Most preferably, the albumin protein contains a single solvent-exposed cysteine or lysine, thereby enabling site-specific complexation of the compounds of the present invention. The albumin protein may contain only naturally occurring amino acid residues or may contain one or more non-naturally occurring amino acid residues. Non-naturally occurring amino acid residues (e.g., side chains of non-naturally occurring amino acid residues), if included, can be used as attachment points for the compounds of the present invention (e.g., neuraminidase inhibitor monomers or dimers, including by means of a linker).

[0528] As used herein, the term "albumin protein binding peptide" refers to a polypeptide having an amino acid sequence of 5 to 50 (e.g., 5 to 40, 5 to 30, 5 to 20, 5 to 15, 5 to 10, 10 to 50, 10 to 30, or 10 to 20) amino acid residues that has an affinity and binding function for an albumin protein, such as any of the albumin proteins described herein. Preferably, the albumin protein binding peptide binds to a naturally occurring serum albumin, most preferably human serum albumin. The albumin protein binding peptide can be of various origins, for example, it can be of synthetic, human, mouse, or rat origin. The albumin protein binding peptides of the present invention include those that have been engineered to contain one or more (e.g., 2, 3, 4, or 5) solvent-exposed cysteine or lysine residues that can provide a site for complexation with a compound of the present invention (e.g., complexation with a neuraminidase inhibitor monomer or dimer, including when by a linker). Most preferably, the albumin protein binding peptide contains a single solvent-exposed cysteine or lysine, thereby enabling site-specific complexation of the compound of the present invention. The albumin protein binding peptide may contain only naturally occurring amino acid residues, or may contain one or more non-naturally occurring amino acid residues. Non-naturally occurring amino acid residues (e.g., side chains of non-naturally occurring amino acid residues), when included, can be used as a point of attachment for a compound of the present invention (e.g., a neuraminidase inhibitor monomer or dimer, including when by a linker). The albumin protein binding peptides of the present invention may be linear or cyclic. The albumin protein binding peptides of the present invention include any albumin protein binding peptides known to those skilled in the art, examples of which are provided herein. Further exemplary albumin protein binding peptides are shown in U.S. Patent Application Publication No. 2005 / 0287153, which is hereby incorporated by reference in its entirety.

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

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

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

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

[0533] In some embodiments, the linker may include a synthetic group derived from, for example, a synthetic polymer (such as a polyethylene glycol (PEG) polymer). In some embodiments, the linker may include one or more amino acid residues, such as D- or L-amino acid residues. In some embodiments, the linker may be a residue of an amino acid sequence (e.g., a 1-25 amino acid, 1-10 amino acid, 1-9 amino acid, 1-8 amino acid, 1-7 amino acid, 1-6 amino acid, 1-5 amino acid, 1-4 amino acid, 1-3 amino acid, 1-2 amino acid, or 1 amino acid sequence). In some embodiments, the linker may be one or more, e.g., 1-100, 1-50, 1-25, 1-10, 1-5, or 1-3 optionally substituted alkylene, optionally substituted heteroalkylene (such as a PEG unit), optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted cycloalkenylene, optionally substituted heterocycloalkenylene, optionally substituted cycloalkynylene, optionally substituted heterocycloalkynylene, optionally substituted arylene, optionally substituted heteroarylene (such as pyridine), O, S, NR i (R iis H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkenyl, optionally substituted cycloalkynyl, optionally substituted heterocycloalkynyl, optionally substituted aryl, or optionally substituted heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino. For example, the linker may comprise one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene (e.g., PEG units), optionally substituted C2-C20 alkenylene (e.g., C2 alkenylene), optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene (e.g., C6 arylene), optionally substituted C2-C15 heteroarylene (e.g., imidazole, pyridine), O, S, NR i (R iis H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl), P, and may contain carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl or imino.

[0534] As used herein, the terms "alkyl", "alkenyl" and "alkynyl" include straight-chain and branched-chain monovalent substituents and combinations thereof that contain only C and H when unsubstituted. When an alkyl group contains at least one carbon-carbon double bond or carbon-carbon triple bond, the alkyl group can be referred to as an "alkenyl" or "alkynyl" group, respectively. The fact that an alkyl, alkenyl or alkynyl group is monovalent does not include the case where an optional substituent is attached to the alkyl, alkenyl or alkynyl group. For example, when an alkyl, alkenyl or alkynyl group is bonded to a compound, the fact that the alkyl, alkenyl or alkynyl group is monovalent means that it is bonded to the compound and does not contain any additional substituents that may be present on the alkyl, alkenyl or alkynyl group. In some embodiments, an alkyl or heteroalkyl group can contain, for example, 1 to 20, 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, an alkenyl, heteroalkenyl, alkynyl or heteroalkynyl group can contain, for example, 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-propenyl, and 3-butynyl.

[0535] As used herein, the term "cycloalkyl" refers to a monovalent saturated or unsaturated non-aromatic cyclic alkyl group. Cycloalkyl can have, for example, 3 to 20 carbons (e.g., C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. When a cycloalkyl group contains at least one carbon-carbon double bond, the cycloalkyl group can be referred to as a "cycloalkenyl" group. Cycloalkenyl can have, for example, 4 to 20 carbons (e.g., C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. When a cycloalkyl group contains at least one carbon-carbon triple bond, the cycloalkyl group can be referred to as a "cycloalkynyl" group. Cycloalkynyl can have, for example, 8 to 20 carbons (e.g., C8-C9, C8-C10, C8-C11, C8-C12, C8-C14, C8-C16, C8-C18, or C8-C20 cycloalkynyl). The term "cycloalkyl" also includes cyclic compounds having a bridged polycyclic structure in which one or more carbons bridge two non-adjacent constitutive members of a monocyclic ring, such as bicyclo[2.2.1]heptyl and adamantane. The term "cycloalkyl" also includes bicyclic, tricyclic, and tetracyclic fused ring structures, such as decalin and spirocyclic compounds.

[0536] As used herein, the term "aryl" refers to any monocyclic or fused bicyclic or tricyclic system having aromatic characteristics with respect to the electron distribution throughout the ring system, such as phenyl, naphthyl or phenanthrene. In some embodiments, the ring system contains 5 to 15 ring member atoms or 5 to 10 ring member atoms. An aryl group can have, for example, 5 to 15 carbons (e.g., C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C11, C5-C12, C5-C13, C5-C14, or C5-C15 aryl). The term "heteroaryl" also refers to such monocyclic or fused bicyclic systems containing one or more selected from O, S and N, for example, 1 to 4, 1 to 3, 1, 2, 3 or 4 heteroatoms. A heteroaryl group can have, for example, 2 to 15 carbons (e.g., C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C2-C11, C2-C12, C2-C13, C2-C14, or C2-C15 heteroaryl). By including heteroatoms, it becomes possible to consider a 5-membered ring including a 6-membered ring as aromatic as well. Thus, typical heteroaryl systems include, for example, pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolinyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl and imidazolyl. Groups such as phthalimide are also considered heteroaryl because of the possibility of tautomers. In some embodiments, an aryl or heteroaryl group optionally containing 1 to 2 nitrogen atoms is a 5- or 6-membered aromatic ring system. In some embodiments, the aryl or heteroaryl group is optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl or imidazopyridinyl. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group can be optionally substituted with substituents such as aryl substituents, for example biphenyl.

[0537] The term "alkaryl" refers to an aryl group linked to an alkylene, alkenylene or alkynylene group. When a compound is attached to an alkaryl group, generally, the alkylene, alkenylene or alkynylene portion of the alkaryl is attached to the compound. In some embodiments, the alkaryl is C6-C35 alkaryl (e.g., C6-C16, C6-C14, C6-C12, C6-C10, C6-C9, C6-C8, C7 or C6 alkaryl), where the number of carbons represents the total number of carbons of both the aryl portion of the alkaryl and the alkylene, alkenylene or alkynylene portion. Examples of alkaryl include, but are not limited to, (C1-C8)alkylene(C6-C12)aryl, (C2-C8)alkenylene(C6-C12)aryl, or (C2-C8)alkynylene(C6-C12)aryl. In some embodiments, the alkaryl is benzyl or phenethyl. In heteroalkaryl, one or more heteroatoms selected from N, O and S may be present in the alkylene, alkenylene or alkynylene portion of the alkaryl group and / or in the aryl portion of the alkaryl group. In optionally substituted alkaryl, the substituents may be present on the alkylene, alkenylene or alkynylene portion of the alkaryl group and / or on the aryl portion of the alkaryl group.

[0538] The term "amino" as used herein represents -N(R x )2, or -N + (R x )3, wherein each R x is independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x combine to form a heterocycloalkyl. In some embodiments, the amino group is -NH2.

[0539] The term "alkamino" as used herein refers to an amino group in which the amino group is bonded to an alkylene (e.g., C1-C5 alkylene), alkenylene (e.g., C2-C5 alkenylene) or alkynylene group (e.g., C2-C5 alkynylene). When a compound is bonded to an alkanino group, generally, the alkylene, alkenylene or alkynylene moiety of the alkanino is bonded to the compound. The amino moiety of the alkanino is -N(R x )2, or -N + (R x )3, where each R x is independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, or two R x combine to form a heterocycloalkyl. In some embodiments, the amino moiety of the alkanino is -NH2. An example of an alkanino group is C1-C5 alkanino, such as C2 alkanino (e.g., CH2CH2NH2 or CH2CH2N(CH3)2). In a heteroalkanino group, one or more, e.g., 1 to 4, 1 to 3, 1, 2, 3 or 4 heteroatoms selected from N, O and S may be present in the alkylene, alkenylene or alkynylene moiety of the heteroalkanino group. In some embodiments, the alkanino group may be optionally substituted. In a substituted alkanino group, the substituent may be present in the alkylene, alkenylene or alkynylene moiety of the alkanino group and / or on the amino moiety of the alkanino group.

[0540] The term "alkanamide" as used herein refers to an amide group in which the amide group is bonded to an alkylene (e.g., C1-C5 alkylene), alkenylene (e.g., C2-C5 alkenylene) or alkynylene (e.g., C2-C5 alkynylene) group. When a compound is bonded to an alkanamide group, generally, the alkylene, alkenylene or alkynylene moiety of the alkanamide is bonded to the compound. The amide moiety of the alkanamide is -C(O)-N(R x )2, where each R xis independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, or two Rs x combine to form heterocycloalkyl. In some embodiments, the amide portion of the alkamide is -C(O)NH2. The alkamide group can be -(CH2)2-C(O)NH2 or -CH2-C(O)NH2. In the heteroalkamide group, one or more, for example, 1 to 4, 1 to 3, 1, 2, 3, or 4 heteroatoms selected from N, O, and S can be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkamide group. In some embodiments, the alkamide group may optionally be substituted. In the substituted alkamide group, the substituent may be present in the alkylene, alkenylene, or alkynylene portion of the alkamide group and / or on the amide portion of the alkamide group.

[0541] The terms "alkylene", "alkenylene", and "alkynylene", as used herein, refer to divalent groups having the specified size. In some embodiments, alkylene can contain, for example, 1 to 20, 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, alkenylene or alkynylene can contain, for example, 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Alkylene, alkenylene, and / or alkynylene include straight-chain and branched-chain forms and combinations thereof. The divalency of an alkylene, alkenylene, or alkynylene group does not include the presence of optional substituents on the alkylene, alkenylene, or alkynylene group. For example, two neuraminidase inhibitors may be linked to each other by a linker containing alkylene, alkenylene, and / or alkynylene or a combination thereof. Each alkylene, alkenylene, and / or alkynylene group in the linker is considered divalent with respect to the two bonds at both ends of the alkylene, alkenylene, and / or alkynylene group. For example, if the linker contains -(optionally substituted alkylene)-(optionally substituted alkenylene)-(optionally substituted alkylene)-, the alkenylene is considered divalent with respect to its bonds to the two alkylene groups at the ends of the linker. The presence of optional substituents on the alkenylene is not included in the alkenylene being divalent. The divalent nature of an alkylene, alkenylene, or alkynylene group (e.g., an alkylene, alkenylene, or alkynylene group in a linker) relates to both ends of the group and does not include any optional substituents that may be present in the alkylene, alkenylene, or alkynylene group.Since they are divalent, they can link together multiple (e.g., two) parts of a complex, such as a first neuraminidase inhibitor and a second neuraminidase inhibitor. The alkylene, alkenylene, and / or alkynylene groups can be substituted with groups typically suitable as substituents for the alkyl, alkenyl, and alkynyl groups shown herein. For example, C=O is a C1 alkylene substituted with oxo (=O). For example, -HCR-C≡C- can be regarded as an optionally substituted alkynylene and is regarded as a divalent group even if it has an optional substituent R. The heteroalkylene, heteroalkenylene, and / or heteroalkynylene groups refer to those in which the alkylene, alkenylene, and / or alkynylene groups contain one or more, for example, 1 to 4, 1 to 3, 1, 2, 3, or 4 heteroatoms, such as N, O, and S. For example, a polyethylene glycol (PEG) polymer or a PEG unit -(CH2)2-O- in a PEG polymer is regarded as a heteroalkylene containing one or more oxygen atoms.

[0542] As used herein, "combination therapy" or "administered in combination" means that a complex described herein (e.g., any one of the complexes of formulas (1)-(5), (D-I)-(D-XI), (D'-I), (M-I)-(M-XI), or (M'-I)) and one (or more) different agents or therapies are administered to a subject as part of a defined treatment plan for a viral infection. The treatment plan defines the dosage and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, delivery of the complex and one or more agents is performed simultaneously or concurrently, and the complex and one or more agents may be co-formulated. In some embodiments, the complex and one or more agents are not co-formulated and are administered in a sequential manner as part of a defined dosing schedule. In some embodiments, administering the complex in combination with one or more agents or therapies results in a greater reduction in symptoms or other parameters associated with a viral infection than is observed when one agent or therapy is delivered alone or in the absence of others. The effects of the complex and one or more agents can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissues. The therapeutic agents can be administered by the same route or by different routes. For example, the complex described herein can be administered by intravenous injection while a second therapeutic agent of the combination can be administered orally.

[0543] As used herein, the term "cycloalkylene" refers to a divalent cyclic group that joins two moieties of a compound. For example, one carbon in the cycloalkylene group can be connected to one moiety of the compound, while another carbon in the cycloalkylene group can be connected to another moiety of the compound. The cycloalkylene group can include a saturated or unsaturated non-aromatic cyclic group. Cycloalkylene can have, for example, 3 to 20 carbons in the ring portion of the cycloalkylene (e.g., C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkylene). When the cycloalkylene group contains at least one carbon-carbon double bond, the cycloalkylene group can be referred to as a "cycloalkenylene" group. Cycloalkenylene can have, for example, 4 to 20 carbons in the ring portion of the cycloalkenylene (e.g., C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl). When the cycloalkylene group contains at least one carbon-carbon triple bond, the cycloalkylene group can be referred to as a "cycloalkynylene" group. Cycloalkynylene can have, for example, 4 to 20 carbons in the ring portion of the cycloalkynylene (e.g., C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C8-C20 cycloalkynylene). The cycloalkylene group can be substituted with groups typically suitable as substituents for alkyl, alkenyl, and alkynyl groups shown herein. Heterocycloalkylene refers to a cycloalkylene group containing one or more, for example, 1 to 4, 1 to 3, 1, 2, 3, or 4 heteroatoms, such as N, O, and S. Examples of cycloalkylene include, but are not limited to, cyclopropylene and cyclobutylene. Tetrahydrofuran can be regarded as heterocycloalkylene.

[0544] As used herein, the term "arylene" refers to a polyvalent (e.g., divalent or trivalent) aryl group that links together multiple (e.g., two or three) moieties of a compound. For example, one carbon in the arylene group can be linked to one moiety of the compound, while another carbon in the arylene group can be linked to another moiety of the compound. Arylene can have, for example, 5 to 15 carbons in the aryl portion of the arylene (e.g., C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C11, C5-C12, C5-C13, C5-C14, or C5-C15 arylene). The arylene group can be substituted with groups typically suitable as substituents for the alkyl, alkenyl, and alkynyl groups shown herein. Heteroarylene refers to those in which the aromatic group contains one or more, for example, 1 to 4, 1 to 3, 1, 2, 3, or 4 heteroatoms, such as N, O, and S. The heteroarylene group can have, for example, 2 to 15 carbons (e.g., C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C2-C11, C2-C12, C2-C13, C2-C14, or C2-C15 heteroarylene).

[0545] The term "optionally substituted", as used herein, means having zero, one or more substituents, e.g., having from 0 to 25, 0 to 20, 0 to 10 or 0 to 5 substituents. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaralkyl, halogen, oxo, cyano, nitro, amino, alkylamino, hydroxy, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, ureido, amidinyl, any of the foregoing groups or moieties, and hetero forms of any of the foregoing groups or moieties. Substituents include, but are not limited to, F, Cl, methyl, phenyl, benzyl, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, SO3R, CONR2, SO2NR2, NRSO2NR2, CN, CF3, OCF3, SiR3 and NO2, wherein each R is independently H, alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl or heteroaryl, and two of the optionally selected substituents on the same or adjacent atoms may combine to form an optionally substituted aromatic or non-aromatic fused ring containing 3 to 8 ring members, or two of the optionally selected substituents on the same atom may combine to form an optionally substituted aromatic or non-aromatic, saturated or unsaturated ring containing 3 to 8 ring members.

[0546] An optionally substituted group or moiety refers to a group or moiety in which one of the atoms (e.g., a hydrogen atom) is optionally replaced by another substituent (e.g., any one of the above groups or moieties). For example, an optionally substituted alkyl can be an optionally substituted methyl in which the hydrogen atom of the methyl group is replaced by, for example, OH. As another example, the substituent attached to a heteroalkyl or its divalent counterpart, heteroalkylene, may replace the hydrogen attached to carbon or the hydrogen attached to a heteroatom such as N. For example, the hydrogen atom in the group -R-NH-R- may be replaced by an amide substituent, such as -R-N[(CH2C(O)N(CH3)2]-R.

[0547] Generally, optional substituents are non-interfering substituents. A "non-interfering substituent" refers to a substituent that leaves intact the ability of a complex described herein (e.g., any one of the complexes of formulas (1)-(5), (D-I)-(D-XI), (D'-I), (M-I)-(M-XI), or (M'-I)) to either bind to viral neuraminidase or inhibit the growth of influenza virus. Thus, in some embodiments, a substituent may alter the degree of such activity. However, as long as the complex retains its ability to bind to viral neuraminidase or inhibit virus growth, the substituent will be classified as "non-interfering". For example, a non-interfering substituent will leave intact the ability of a compound to provide antiviral efficacy based on an IC50 value of 10 μM or less in a viral plaque reduction assay, e.g., an IC50 value of 500 nM or less against influenza virus neuraminidase in Example 2. Thus, a substituent may alter the degree of inhibition based on plaque reduction or influenza virus neuraminidase inhibition. However, as long as the compounds herein, e.g., the compounds of formulas (A-I), (A-II), (A-III), (A-IV), (A-V), (A-VI), (A-VII), (A-VIII), (A-IX), (A-X), (A-XI), (A-XII), and (A-XIII) retain their ability to inhibit influenza virus neuraminidase activity, the substituent will be classified as "non-interfering". Multiple assays are available in the art for determining viral plaque reduction or the influenza virus neuraminidase inhibitory ability of any compound, and some are exemplified in the following examples.

[0548] When the term "hetero" is used to represent a chemical group or moiety, it means having at least one heteroatom other than carbon or hydrogen, such as N, O, and S. Any one of the above groups or moieties can be called hetero if it contains at least one heteroatom. For example, a heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl group refers to a cycloalkyl, cycloalkenyl, or cycloalkynyl group having one or more heteroatoms independently selected from, for example, N, O, and S. An example of a heterocycloalkenyl group is maleimide. For example, a heteroaryl group refers to an aromatic group having one or more heteroatoms independently selected from, for example, N, O, and S. One or more heteroatoms may be included in the substituents replacing the hydrogen atoms in the groups or moieties described herein. For example, an optionally substituted heteroaryl group may contain one or more heteroatoms in the substituent (e.g., methanol) when one of the hydrogen atoms in the heteroaryl group is replaced by a substituent (e.g., methyl).

[0549] As used herein, the term "acyl" has the structure: [Chemical Formula] [wherein, R Z is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aralkyl, alkamino, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaryl, heteroaralkyl, or heteroalkamino] refers to a group having.

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

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

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

[0553] The term "carbonyl", as used herein, refers to the structure:

Chem.

[0554] The term "thiocarbonyl", as used herein, refers to the structure:

Chem.

[0555] The term "phosphate", as used herein, refers to the structure:

Chem.

[0556] The term "phosphoryl", as used herein, refers to the structure:

Chem.

[0557] The term "sulfonyl", as used herein, refers to the structure:

Chem.

[0558] The term "imino", as used herein, has the structure:

Chemical formula

[0559] The term “N-protecting group,” as used herein, refers to a group that is intended to protect an amino group from unwanted reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 5th Edition (John Wiley & Sons, New York, 2014), which is hereby incorporated by reference into this specification.Examples of N-protecting groups include acyl, aryloyl, and carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, carboxybenzyl (CBz), 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D,L-amino acid residues such as alanine, leucine, phenylalanine; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (BOC), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; aralkyl groups such as benzyl, triphenylmethyl and benzyloxymethyl; and silyl groups such as trimethylsilyl.

[0560] As used herein, the term "amino acid" means naturally occurring amino acids and non-naturally occurring amino acids.

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

[0562] As used herein, the term "non-naturally occurring amino acid" means an alpha amino acid that is not naturally produced or found in mammals. Examples of non-naturally occurring amino acids include D-amino acids; amino acids having an acetylaminomethyl group attached to the sulfur atom of cysteine; pegylated amino acids; the formula NH2(CH2) nOmega amino acids of COOH [wherein n is 2 - 6], neutral non-polar amino acids, for example, sarcosine, t-butylalanine, t-butylglycine, N-methylisoleucine, and norleucine; oxy-methionine; phenylglycine; citrulline; methionine sulfoxide; cysteic acid; ornithine; diaminobutyric acid; 3-aminoalanine; 3-hydroxy-D-proline; 2,4-diaminobutyric acid; 2-aminopentanoic acid; 2-aminooctanoic acid, 2-carboxypiperazine; piperazine-2-carboxylic acid, 2-amino-4-phenylbutanoic acid; 3-(2-naphthyl)alanine, and hydroxyproline. Other amino acids are α-aminobutyric acid, α-amino-α-methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, aminonorbornyl-carboxylate, L-cyclohexylalanine, cyclopentylalanine, L-N-methylleucine, L-N-methylmethionine, L-N-methylnorvaline, L-N-methylphenylalanine, L-N-methylproline, L-N-methylserine, L-N-methyltryptophan, D-ornithine, L-N-methylethylglycine, L-norleucine, α-methyl-aminoisobutyrate, α-methylcyclohexylalanine, D-α-methylalanine, D-α-methylarginine, D-α-methylasparagine, D-α-methylaspartate, D-α-methylcysteine, D-α-methylglutamine, D-α-methylhistidine, D-α-methylisoleucine, D-α-methylleucine, D-α-methyllysine, D-α-methylmethionine, D-α-methylornithine, D-α-methylphenylalanine, D-α-methylproline, D-α-methylserine, D-N-methylserine, D-α-methylthreonine, D-α-methyltryptophan, D-α-methyltyrosine, D-α-methylvaline, D-N-methylalanine, D-N-methylarginine, D-N-methylasparagine, D-N-methylaspartate, D-N-methylcysteine, D-N-methylglutamine, D-N-methylglutamate, D-N-methylhistidine, D-N-methylisoleucine, D-N-methylleucine, D-N-methyllysine, N-methylcyclohexylalanine, D-N-methylornithine, N-methylglycine, N-methylaminoisobutyrate,N-(1-methylpropyl)glycine, N-(2-methylpropyl)glycine, D-N-methyltryptophan, D-N-methyltyrosine, D-N-methylvaline, γ-aminobutyric acid, L-t-butylglycine, L-ethylglycine, L-homophenylalanine, L-α-methylarginine, L-α-methylaspartate, L-α-methylcysteine, L-α-methylglutamine, L-α-methylhistidine, L-α-methyli...

Claims

1. A complex represented by any one of formulas (D-I), (M-I), (1), or (2): 【Chemical Formula 1】 [wherein each A １ and each A ２ is independently of the formula (A-I) to (A-XII): 【Chemical 2】 represented by R １ is selected from -OH, -NH ２ , -NHC(=NH)NH ２ , and -NHC(=NH)NHR ６ and is selected from R ２ and R ３ are each independently selected from -H, -OH, -F, -Cl, and -Br, R ４ is selected from -CO ２ H, -P(=O)(OH) ２ and -SO ３ H, and R ５ is selected from -COCH ３ , -COCF ３ , -SO ２ CH ３ and X is selected from -O- and -S- Y is 【Chemical Formula 3】 selected from R ６ is 【Chemical Formula 4】 selected from R ７ is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl, R ８ is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl, n is 1 or 2 each E contains an Fc domain monomer, an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide L is linked to E and to each A １ or A １ and A ２ by a linker that is covalently bound to each respective Y of each of them, T is an integer from 1 to 20 In each of formulas (D-I), (M-I), (1), or (2), each wavy line indicates that L is covalently bonded to each E], or a pharmaceutically acceptable salt thereof.

2. The complex is of formula (D-I): 【Chemical Formula 5】 [In the formula, each A １ and each A ２ is independently selected from any one of formulas (A-I) to (A-XII), each E contains an Fc domain monomer, an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide n is 1 or 2 T is an integer from 1 to 20 The wavy line connected to the E represents that the L in each A １ -L-A ２ is covalently bonded to the E. The complex according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The complex is of formula (D-II): 【Chemical Formula 6】 The complex according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof.

4. The complex is of formula (D-II-1): 【Chemical Formula 7】 The complex according to claim 3, or a pharmaceutically acceptable salt thereof.

5. The complex is of formula (D-II-6): 【Chemical Formula 8】 [wherein, R ７ is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl] The complex according to claim 4, or a pharmaceutically acceptable salt thereof.

6. R ７ The complex according to claim 5, wherein R is selected from C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl.

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

8. The complex is of formula (D-II-7): 【Chemical Formula 9】 The complex according to any one of claims 5 to 7, or a pharmaceutically acceptable salt thereof.

9. The complex is of formula (D-II-8): 【Chemical Formula 10】 [wherein L' is the remainder of L, y １ and y ２ are each independently an integer from 1 to 20) The complex according to claim 8, or a pharmaceutically acceptable salt thereof.

10. The complex is 【Chemical 11】 having the structure of The complex according to claim 9, or a pharmaceutically acceptable salt thereof.

11. 【Chemical Formula 12】 The complex is having the structure of The complex according to claim 10, or a pharmaceutically acceptable salt thereof. 【Chemical 13】 [In the formula, each A １ is independently selected from any one of formulas (A-I) to (A-XII), and each E contains an Fc domain monomer, an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide.

12. The complex is of formula (M-I): L is a linker that is covalently bonded to each of E and A １ and The wavy line connected to said E represents that L of each A １ -L is covalently bonded to E], the complex according to claim 1, n is 1 or 2 T is an integer from 1 to 20 or a pharmaceutically acceptable salt thereof. 【Chemical Formula 14】

13. The complex is of formula (M-II): The complex according to claim 12, or a pharmaceutically acceptable salt thereof. 【Chemical Formula 15】 [wherein, R ７ is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl]

14. The complex is of formula (M-II-6): The complex according to claim 13, R ７ The complex according to claim 14, wherein R is selected from C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl. or a pharmaceutically acceptable salt thereof. R ７ The complex according to claim 14 or claim 15, wherein R is selected from methyl, ethyl, propyl or butyl.

15.

16.

17. The wavy line connected to E represents each A １ -L or each A １ -L-A ２ wherein L of -L- or -L-A is covalently bonded to the nitrogen atom of the solvent-exposed lysine of E the complex according to any one of claims 1 to 16. **Claim 18** The wavy line connected to E represents Each A １ -L of L or each A １ -L-A ２ wherein L of is covalently bonded to the sulfur atom of the solvent-exposed cysteine of E the complex according to any one of claims 1 to 16. **Claim 19** The complex according to any one of claims 1 to 18, wherein each E is an Fc domain monomer. **Claim 20** The complex according to claim 19, wherein n is 2 and each E dimerizes to form an Fc domain. **Claim 21** n is 2, each E is an Fc domain monomer, each E dimerizes to form an Fc domain, and the complex has the formula (D-I-1): 【Chemical 16】 [wherein, J is an Fc domain, T is an integer from 1 to 20] The complex according to claim 2, or a pharmaceutically acceptable salt thereof. **Claim 22** The complex according to claim 21, having 【Chemical 17】 the structure of, or a pharmaceutically acceptable salt thereof. **Claim 23** n is 2, each E is an Fc domain monomer, each E dimerizes to form an Fc domain, and the complex has the formula (M-I-1): 【Chemical Formula 18】 [wherein, J is an Fc domain, T is an integer from 1 to 20] The complex according to claim 12, or a pharmaceutically acceptable salt thereof. **Claim 24** Each E contains an amino acid sequence that is at least 95% identical to any one of the sequences of SEQ ID NOs: 1 to 138, the complex according to any one of claims 19 to 23. **Claim 25** Each E contains an amino acid sequence that is at least 95% identical to any one of the sequences of SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 94, SEQ ID NO: 95 the complex according to claim 24. **Claim 26** The complex according to claim 25, wherein each E contains the amino acid sequence of SEQ ID NO:

72. **Claim 27** The complex according to claim 25, wherein each E contains the amino acid sequence of SEQ ID NO:

73. **Claim 28** The complex according to claim 25, wherein each E contains the amino acid sequence of SEQ ID NO:

76. **Claim 29** The complex according to claim 25, wherein each E contains the amino acid sequence of SEQ ID NO:

77. **Claim 30** The complex according to any one of claims 19 to 29, wherein T is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. **Claim 31** A population of complexes according to any one of claims 19 to 29, wherein the average value of T is 1 to 10, 5 to 10, 1 to 5, 3 to 7, or 3.5 to 5.

5.

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

5.

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

34. A method of treating a subject having or suspected of having a viral infection, comprising administering to the subject an effective amount of a complex, population of complexes or pharmaceutical composition according to any one of claims 1 to 33.

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

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

37. A method of preventing secondary infections in a subject diagnosed with influenza infection, comprising administering to the subject a complex, population of complexes or pharmaceutical composition according to any one of claims 1 to 33.

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

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

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

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

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

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

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

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

77.

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

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