US20210220478A1 - Compositions and methods for the treatment of viral infections - Google Patents

Compositions and methods for the treatment of viral infections Download PDF

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US20210220478A1
US20210220478A1 US17/194,093 US202117194093A US2021220478A1 US 20210220478 A1 US20210220478 A1 US 20210220478A1 US 202117194093 A US202117194093 A US 202117194093A US 2021220478 A1 US2021220478 A1 US 2021220478A1
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seq
amino acid
acid sequence
conjugate
optionally substituted
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Inventor
James M. Balkovec
Daniel C. BENSEN
Allen Borchardt
Thomas P. Brady
Zhi-Yong CHEN
Jason Cole
Quyen-Quyen Thuy Do
Simon DOEHRMANN
Wanlong Jiang
Thanh Lam
Alain Noncovich
Leslie W. Tari
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Cidara Therapeutics Inc
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Cidara Therapeutics Inc
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Priority to US17/194,093 priority Critical patent/US20210220478A1/en
Priority to US17/236,745 priority patent/US11510992B1/en
Publication of US20210220478A1 publication Critical patent/US20210220478A1/en
Assigned to CIDARA THERAPEUTICS, INC. reassignment CIDARA THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BENSEN, Daniel C., TARI, LESLIE W., DOEHRMANN, Simon, BALKOVEC, JAMES M., BORCHARDT, ALLEN, BRADY, THOMAS P., COLE, JASON, DO, QUYEN-QUYEN THUY, LAM, THANH, NONCOVICH, ALAIN, CHEN, Zhi-yong, JIANG, WANLONG
Priority to US17/887,776 priority patent/US20230398226A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • Influenza virus the causative agent of influenza, or the flu
  • influenza is responsible for three to five million cases of severe illness annually, and approximately 500,000 deaths worldwide. While most people recover completely from influenza in about one to two weeks, others develop life-threatening complications, such as pneumonia. Thus, influenza can be deadly, especially for the young, old, or chronically ill.
  • People with weak or compromised immune systems such as people with advanced HIV infection or transplant patients, whose immune systems are medically suppressed to prevent transplant organ rejection, are at greater risk for complications relating to influenza. Pregnant women and young children are also at a high risk for complications.
  • influenza antiviral agents have been approved for use in the clinic, and these agents play important roles in modulating disease severity and controlling pandemics while vaccines are prepared.
  • drug-resistant strains have emerged to the most commonly used inhibitors.
  • Influenza antiviral agents largely target proteins presented on the surface of the influenza virus particle.
  • the envelope of the influenza virus contains two immunodominant glycoproteins, hemagglutinin and neuraminidase, that play key roles in viral infection and spread. Hemagglutinin effects attachment of the virus to the host cell through its interaction with surface sialic acids, thereby initiating entry.
  • Neuraminidase is an exo-glycosidase enzyme that cleaves sialic acids (terminal neuraminic acid residues) from glycan structures on the surface of infected host cells, releasing progeny viruses and allowing the spread of the virus from the host cell to uninfected surrounding cells. Inhibition of neuraminidase therefore serves as a pharmacological target for antiviral drugs. Viral neuraminidase inhibitors used to reduce viral spread have been identified, including oseltamivir (TamifluTM), zanamivir (RelenzaTM), and peramivir (RapivabTM).
  • TamifluTM oseltamivir
  • RelenzaTM zanamivir
  • RapivabTM peramivir
  • influenza in transplant recipients remains characterized by prolonged viral shedding, increasing the likelihood of developing drug resistant strains.
  • New, more effective therapies for treating influenza are needed.
  • conjugates contain monomers or dimers of a moiety that inhibits influenza virus neuraminidase (e.g., zanamivir, peramivir, or analogs thereof) conjugated to Fc monomers, Fc domains, Fc-binding peptides, albumin proteins, or albumin protein-binding peptides.
  • influenza virus neuraminidase e.g., zanamivir, peramivir, or analogs thereof
  • the neuraminidase inhibitor e.g., zanamivir, peramivir, or analogs thereof
  • the Fc monomers or Fc domains in the conjugates bind to Fc ⁇ R 5 (e.g., FcRn, Fc ⁇ RI, Fc ⁇ RIIa, Fc ⁇ RIIc, Fc ⁇ RIIIa, and Fc ⁇ RIIIb) on immune cells, e.g., neutrophils, to activate phagocytosis and effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), thus leading to the engulfment and destruction of viral particles by immune cells and further enhancing the antiviral activity of the conjugates.
  • the albumin or albumin-binding peptide may extend the half-life of the conjugate, for example, by binding of albumin to the recycling neonatal Fc receptor.
  • Such compositions are useful in methods for the inhibition of viral growth and in methods for the treatment of viral infections, such as those caused by an influenza virus A, influenza virus B and influenza virus C.
  • the invention features a conjugate described by any one of formulas (D-I), (M-I), (1), or (2):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-I)-(A-XII):
  • R 1 is selected from —OH, —NH 2 , —NHC( ⁇ NH)NH 2 , and —NHC( ⁇ NH)NHR 6 ;
  • R 2 and R 3 are each independently selected from —H, —OH, —F, —Cl, and —Br;
  • Ra is selected from —CO 2 H, —P( ⁇ O)(OH) 2 , —SO 3 H;
  • R 5 is selected from —COCH 3 , —COCF 3 , —SO 2 CH 3 ;
  • X is selected from —O— and —S—;
  • Y is selected from
  • R 6 is 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 5 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • n 1 or 2;
  • each E comprises an Fc domain monomer, an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide;
  • L is a linker covalently attached to E and to each Y of each A 1 or each A 1 and A 2 ;
  • T is an integer from 1 to 20
  • each squiggly line in formulas (D-I), (M-I), (1), or (2) indicates that L is covalently attached to each E;
  • n is 1 and each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide;
  • Fc domain monomer e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138
  • an albumin protein e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141
  • an albumin protein-binding peptide e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141
  • an albumin protein-binding peptide e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141
  • albumin protein-binding peptide e
  • n is 2 and each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), wherein the Fc domain monomers dimerize to form and Fc domain;
  • Fc domain monomer e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138
  • L is a linker covalently attached to each E and to each Y or each A 1 and/or A 2 ;
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and each squiggly line in formulas (D-I), (M-I), (1), or (2) indicates that L is covalently attached (e.g., by way of a covalent bond or linker) to each E; or a pharmaceutically acceptable salt thereof.
  • T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20)
  • each A 1 -L or each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L or A 1 -L-A 2 structures described herein).
  • n is 2 and each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138).
  • Fc domain monomers e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138.
  • a conjugate having two Fc domain monomers e.g., a conjugate of formula (1), formula (2), formula (D-I) where n equals 2, or (M-I) where n equals 2
  • the Fc domain monomers dimerize to form an Fc domain.
  • the invention features a conjugate described by formula (D-I):
  • each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138);
  • L in each A 1 -L-A 2 is a linker covalently attached to a sulfur atom of a hinge cysteine in E and to each of A 1 and A 2 ;
  • n is 1 or 2 (e.g., when n is 2, the two Fc domain monomers dimerize to form and Fc domain);
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the squiggly line connected to the E indicates that each A 1 -L-A 2 is covalently attached (e.g., by way of a covalent bond or linker) to a sulfur atom of a hinge cysteine in E, or a pharmaceutically acceptable salt thereof.
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • the invention features a conjugate described by formula (D-I):
  • each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138);
  • L in each A 1 -L-A 2 is a linker covalently attached to a nitrogen atom of a surface exposed lysine in E and to each of A 1 and A 2 ;
  • n is 1 or 2 (e.g., when n is 2, the two Fc domain monomers dimerize to form and Fc domain);
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the squiggly line connected to the E indicates that each A 1 -L-A 2 is covalently attached (e.g., by way of a covalent bond or linker) to the nitrogen atom of a surface exposed lysine in E, or a pharmaceutically acceptable salt thereof.
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • each of A 1 and A 2 may be independently selected from any one of formulas (A-I), (A-II), (A-VI), or (A-VII).
  • each of A 1 and A 2 may be independently selected from formula (A-I).
  • the invention features a conjugate described by formula (M-I):
  • each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138);
  • L in each L-A 1 is a linker covalently attached to a sulfur atom of a hinge cysteine in E and to A 1 ;
  • n is 1 or 2 (e.g., when n is 2, the two Fc domain monomers dimerize to form and Fc domain);
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and the squiggly line connected to E indicates that each L-A 1 is covalently attached (e.g., by way of a covalent bond or linker) to the sulfur atom of the hinge cysteine in E, or a pharmaceutically acceptable salt thereof.
  • each A 1 may be independently selected from any structure described by formula (A-I)-(A-XII). In some embodiments, each A 1 may be independently selected from any one of formulas (A-I), (A-II), (A-VI), or (A-VII). In other embodiments, each A 1 may be independently selected from formula (A-I).
  • the invention features a conjugate described by formula (M-I):
  • each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138);
  • L in each L-A 1 is a linker covalently attached to a nitrogen atom of a surface exposed lysine in E and to A 1 ;
  • n is 1 or 2 (e.g., when n is 2, the two Fc domain monomers dimerize to form and Fc domain);
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), the squiggly line connected to E indicates that each L-A 1 is covalently attached (e.g., by way of a covalent bond or linker) to the nitrogen atom of a surface exposed lysine in E, or a pharmaceutically acceptable salt thereof.
  • each A 1 may be independently selected from any structure described by formula (A-I)-(A-XII). In some embodiments, each A 1 may be independently selected from any one of formulas (A-I), (A-II), (A-VI), or (A-VII). In other embodiments, each A 1 may be independently selected from formula (A-I).
  • the disclosure features a conjugate described by formula (1):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-I)-(A-XII); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138); L in each A 1 -L-A 2 is a linker covalently attached to a sulfur atom of a hinge cysteine in each E and to each of A 1 and A 2 ; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two squiggly lines connected to the two Es indicate that each A 1 -L-A 2 is covalently attached (e.g., by way of a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in the two Es, or a pharmaceutically acceptable salt thereof.
  • each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • each of A 1 and A 2 may be independently selected from any one of formulas (A-I), (A-II), (A-VI), or (A-VII).
  • each of A 1 A 2 may be independently selected from formula (A-I).
  • the disclosure features a conjugate described by formula (1):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-I)-(A-V); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138); L in each A 1 -L-A 2 is a linker covalently attached to a sulfur atom of a hinge cysteine in each E and to each of A 1 and A 2 ; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two squiggly lines connected to the two Es indicate that each A 1 -L-A 2 is covalently attached (e.g., by way of a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in the two Es, or a pharmaceutically acceptable salt thereof.
  • each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • the disclosure features a conjugate described by formula (1):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-VI)-(A-IX); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138); L in each A 1 -L-A 2 is a linker covalently attached to a sulfur atom of a hinge cysteine in each E and to each of A 1 and A 2 ; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two squiggly lines connected to the two Es indicate that each A 1 -L-A 2 is covalently attached (e.g., by way of a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in the two Es, or a pharmaceutically acceptable salt thereof.
  • each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • the invention features a conjugate described by formula (2):
  • each A 1 is independently selected from any one of formulas (A-I)-(A-XII); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138); L in each L-A 1 is a linker covalently attached to a sulfur atom in a hinge cysteine in E and to A 1 ; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two squiggly lines connected to the two sulfur atoms indicate that each L-A 1 is covalently (e.g., by way of a covalent bond or a linker) attached to a pair of sulfur atoms of two hinge cysteines in the two Es, or a pharmaceutically acceptable salt thereof.
  • each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138); L in
  • each A 1 may be independently selected from any one of formulas (A-I)-(A-XII).
  • each of A 1 and A 2 may be independently selected from any one of formulas (A-I), (A-II), (A-VI), or (A-VII).
  • each of A 1 A 2 may be independently selected from formula (A-I).
  • the invention features a conjugate described by formula (2):
  • each A 1 is independently selected from any one of formulas (A-I)-(A-V); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138); L in each L-A 1 is a linker covalently attached to a sulfur atom in a hinge cysteine in E and to A 1 ; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two squiggly lines connected to the two sulfur atoms indicate that each L-A 1 is covalently attached (e.g., by way of a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in the two Es, or a pharmaceutically acceptable salt thereof.
  • T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20)
  • each A 1 may be
  • the invention features a conjugate described by formula (2):
  • each A 1 is independently selected from any one of formulas (A-VI)-(A-IX); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138); L in each L-A 1 is a linker covalently attached to a sulfur atom in a hinge cysteine in E and to A 1 ; T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the two squiggly lines connected to the two sulfur atoms indicate that each L-A 1 is covalently attached (e.g., by way of a covalent bond or a linker) to a pair of sulfur atoms of two hinge cysteines in the two Es, or a pharmaceutically acceptable salt thereof.
  • T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20)
  • each A 1 may
  • each E includes an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138.
  • At least one of the pair of sulfur atoms is the sulfur atom corresponding to (e.g., the sulfur atom of) a hinge cysteine of SEQ ID NO: 10 or SEQ ID NO: 11, i.e., Cys10, Cys13, Cys16, or Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11.
  • the pair of sulfur atoms are the sulfur atoms corresponding to (e.g., the sulfur atoms of) Cys10 and Cys13 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys10 and Cys16 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys30 and Cys18 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and Cys36 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and Cys38 in SEQ ID NO: 10 or SEQ ID NO: 11, and/or Cys36 and Cys38 in SEQ ID NO: 10 or SEQ ID NO: 11.
  • the sulfur atoms are the sulfur atoms corresponding to (e.g., the sulfur atoms of) Cys10 and Cys13 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys10 and Cys16 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys30 and Cys18 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and
  • the pair of sulfur atoms are (e.g., the sulfur atoms corresponding to) 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.
  • the pair of sulfur atoms include one sulfur atom of a cysteine from each E, i.e., L-A along with the sulfur atoms to which it is attached forms a bridge between two Fc domains (e.g., two Fc domains comprising the sequence of SEQ ID NO: 10 or SEQ ID NO: 11).
  • the pair of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.
  • the pair of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.
  • the pair of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.
  • the pair of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E.
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E;
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E;
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E;
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys18 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E;
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E; the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys16 of SEQ ID NO: 10 or SEQ ID NO: 11 from another E;
  • the conjugate has the structure:
  • each of a, b, c, and d is, independently, 0 or 1 and wherein when a, b, c, or d is 0, the two sulfur atoms form a disulfide bond.
  • 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 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 is 0. In some embodiments, c and d are 1 and
  • each E comprises the sequence
  • each E comprises the sequence
  • At least one of the pair of sulfur atoms is the sulfur atom corresponding to (e.g., the sulfur atom of) a hinge cysteine of SEQ ID NO: 4 or SEQ ID NO: 33, i.e., Cys10 and/or Cys13.
  • the pair of sulfur atoms are the sulfur atoms corresponding to (e.g., the sulfur atoms of) Cys10 and Cys13 in SEQ ID NO: 4 or SEQ ID NO: 33.
  • the pair of sulfur atoms include one sulfur atom of a cysteine from each E, i.e., L-A along with the sulfur atoms to which it is attached forms a bridge between two Fc domains (e.g., two Fc domains comprising the sequence of SEQ ID NO: 4 or SEQ ID NO: 33).
  • the pair of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 4 or SEQ ID NO: 33 from another E.
  • the pair of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 4 or SEQ ID NO: 33 from another E.
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 4 or SEQ ID NO: 33 from another E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 4 or SEQ ID NO: 33 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 4 or SEQ ID NO: 33 from another E.
  • the conjugate has the structure:
  • each of a and b is, independently, 0 or 1 and wherein when a or b is 0, the two sulfur atoms form a disulfide bond.
  • a is 1 and b is 0.
  • a is 0 and b is 1.
  • a and b are 1.
  • At least one of the pair of sulfur atoms is the sulfur atom corresponding to (e.g., the sulfur atom of) a hinge cysteine of SEQ ID NO: 8, i.e., Cys10 and/or Cys13.
  • the pair of sulfur atoms are the sulfur atoms corresponding to (e.g., the sulfur atoms of) Cys10 and Cys13 in SEQ ID NO: 8.
  • the pair of sulfur atoms include one sulfur atom of a cysteine from each E, i.e., L-A along with the sulfur atoms to which it is attached forms a bridge between two Fc domains (e.g., two Fc domains comprising the sequence of SEQ ID NO: 8).
  • the pair of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 8 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 8 from another E.
  • the pair of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 8 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 8 from another E.
  • the pairs of sulfur atoms are the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 8 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 of SEQ ID NO: 8 from another E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 8 from one E and the sulfur atom corresponding to (e.g., the sulfur atom of) Cys13 of SEQ ID NO: 8 from another E.
  • the conjugate has the structure:
  • each of a and b is, independently, 0 or 1 and wherein when a or b is 0, the two sulfur atoms form a disulfide bond.
  • a is 1 and b is 0.
  • a is 0 and b is 1.
  • a and b are 1.
  • the conjugate has the structure:
  • each of a and b is, independently, 0 or 1 and wherein when a or b is 0, the two sulfur atoms form a disulfide bond.
  • a is 1 and b is 0.
  • a is 0 and b is 1.
  • a and b are 1.
  • the conjugate has the structure:
  • each of a and b is, independently, 0 or 1 and wherein when a or b is 0, the two sulfur atoms form a disulfide bond.
  • a is 1 and b is 0.
  • a is 0 and b is 1.
  • a and b are 1.
  • the conjugate has the structure:
  • each of a and b is, independently, 0 or 1 and wherein when a or b is 0, the sulfur atoms is a thiol.
  • a is 1 and b is 0.
  • a is 0 and b is 1.
  • a and b are 1.
  • the nitrogen atom is the nitrogen of a surface exposed lysine, e.g., the nitrogen atom corresponding to (e.g., the nitrogen atom of) Lys35, Lys63, Lys77, Lys79, Lys106, Lys123, Lys129, Lys181, Lys203, Lys228, or Lys236 of SEQ ID NO: 10 or SEQ ID NO: 11.
  • the nitrogen atom is the nitrogen atom corresponding to (e.g., the nitrogen atom of) Lys65, Lys79, Lys108, Lys230, and/or Lys238 of SEQ ID NO: 10 or SEQ ID NO: 11.
  • the conjugate has the structure:
  • each of a, b, c, d, and e is, independently, 0 or 1 and wherein when a, b, c, d, or e is 0, the two nitrogen atom is NH 2 .
  • a is 1 and b, c, d, and e are 0.
  • b is 1 and a, c, d, and e are 0.
  • c is 1 and a, b, d, and e are 0.
  • d is 1 and a, b, c, and e are 0.
  • e is 1 and a, b, c, and d are 0.
  • a and b are 1 and c, d, and e are 0. In some embodiments, a and c are 1 and b, d, and e are 0. In some embodiments, a and d are 1 and b, c, and e are 0. In some embodiments, a and e are 1 and b, c, and d are 0. In some embodiments, b and c are 1 and a, d, and e are 0. In some embodiments, b and d are 1 and a, c, and e are 0. In some embodiments, b and e are 1 and a, c, and d are 0. In some embodiments, c and d are 1 and a, b, and e are 0. In some embodiments, c and d are 1 and a, b, and e are 0. In some embodiments, c and d are 1 and a, b, and e are 0.
  • c and e are 1 and a, b, and d are 0. In some embodiments, d and e are 1 and a, b, and c are 0. In some embodiments, a, b, and c are 1 and d and e are 0. In some embodiments, a, b, and d are 1 and c and e are 0. In some embodiments, a, b, and e are 1 and c and d are 0. In some embodiments, a, c, and d are 1 and b and e are 0. In some embodiments, a, c, and e are 1 and b and d are 0. In some embodiments, a, d, and e are 1 and b and d are 0. In some embodiments, a, d, and e are 1 and b and c are 0.
  • b, c, and d are 1 and a and e are 0. In some embodiments, b, d, and e are 1 and a and c are 0. In some embodiments, c, d, and e are 1 and a and b are 0.
  • the conjugate forms a homodimer including an Fc domain.
  • E homodimerizes with another E to form an Fc domain.
  • the invention features a conjugate described by (D-I):
  • E includes an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide;
  • L in each A 1 -L-A 2 is a linker independently covalently attached to a sulfur atom of a surface exposed cysteine or a nitrogen atom of a surface exposed lysine in E and to each of A 1 and A 2 ;
  • n is 1;
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and the squiggly line connected to the E indicates that each A 1 -L-A 2 is independently covalently attached to the sulfur atom of a solvent-exposed cysteine or the nitrogen atom of a solvent-exposed lysine in E, or a pharmaceutically acceptable salt thereof.
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • each of A 1 A 2 may be independently selected from any one of formulas (A-I), (A-II), (A-VI), or (A-VII).
  • each of A 1 A 2 may be independently selected from formula (A-I).
  • x is 2.
  • the invention features a conjugate described by formula (M-I):
  • E includes an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide;
  • L in each L-A 1 is a linker independently covalently attached to a sulfur atom of a surface exposed cysteine or a nitrogen atom of a surface exposed lysine in E and to A 1 ;
  • n is 1;
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and the squiggly line connected to E indicates that each L-A 1 is independently covalently attached to the sulfur atom of the solvent-exposed cysteine or the nitrogen atom of the solvent-exposed lysine in E, or a pharmaceutically acceptable salt thereof.
  • each A 1 may be independently selected from any structure described by formula (A-I)-(A-XII). In some embodiments, each A 1 may be independently selected from any one of formulas (A-I), (A-II), (A-VI), or (A-VII). In other embodiments, each A 1 may be independently selected from formula (A-I). In a preferred embodiment of the above, x is 2.
  • each E includes an albumin protein having the sequence of any one of SEQ ID NOs: 139-141.
  • T is 1 and L-A 1 is covalently attached to the sulfur atom corresponding to Cys34 of SEQ ID NO: 139.
  • the conjugate (e.g., a conjugate described by any one of formulas (1), (2), (D-I)-(D-XI), or (M-I)-(M-XI)) includes E, wherein E is an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer having, independently, the sequence of any one of SEQ ID NOs: 1-138).
  • 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 is covalently conjugated to a linker (e.g., a PEG 2 -PEG 20 linker).
  • the linker conjugated to E may be functionalized such that it may react to form a covalent bond with any of the Ints described herein (e.g., an Int of Table 1a).
  • E is conjugated to a linker functionalized with an azido group and the Int (e.g., an Int of Table 1a) is functionalized with an alkyne group.
  • Conjugation (e.g., by click chemistry) of the linker-azido of E and linker-alkyne of the Int forms a conjugate of the invention, for example a conjugate described by formula (5).
  • E is conjugated to a linker functionalized with an alkyne group and the Int (e.g., an Int of Table 1a) is functionalized with an azido group.
  • Conjugation e.g., by click chemistry; see, e.g., FIG.
  • the invention features conjugates of Table 1 b.
  • Each conjugate of Table 1 b corresponds to a conjugate of either formula (M-I) or formula (D-I), as indicated.
  • Conjugates of Table 1b include conjugates formed by the covalent reaction of an Int of Table 1a with a linker which is in turn conjugated to E (e.g., an Fc domain monomer, an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide).
  • the reactive moiety of the Int reacts with a corresponding reactive group (e.g., an alkyne or azido group) of a linker (represented by L′) covalently attached to E, such that an Int of Table 1a is covalently attached to E.
  • L′ corresponds to the remainder of L as defined in (M-I) or (D-I) (e.g., L′ is a linker that covalently joins the Int and E).
  • L′ may include a triazole (formed by the click chemistry reaction between the Int and a linker conjugated to E) and a linker (e.g., a PEG 2 -PEG 20 linker) which in turn is conjugated to an amino acid side chain of E (see, e.g., FIG. 103 ).
  • a linker e.g., a PEG 2 -PEG 20 linker
  • n is 1 or 2.
  • each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having a sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide.
  • each E includes an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), and the Fc domain monomers dimerize to form an Fc domain.
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • the disclosure also provides a population of any of the conjugates of Table 2 wherein the average value of T is 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5).
  • 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.
  • the average T is 1 to 10 (e.g., 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10). In certain embodiments, the average T is 1 to 5 (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5).
  • the average T is 1 to 10 (e.g., 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10). In certain embodiments, the average T is 1 to 5 (e.g., 1, 1.1,
  • the average T is 5 to 10 (e.g., 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10).
  • the average T is 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).
  • each L′-Int is covalently attached to an amino acid side chain in E (e.g., the nitrogen atom of a surface exposed lysine or the sulfur atom of a surface exposed cysteine in E), or a pharmaceutically acceptable salt thereof.
  • each E includes an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138. In other embodiments, each E includes an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64. In other embodiments, each E includes an Fc domain monomer having the amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 64. In other embodiments, each E includes an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 67 or SEQ ID NO: 68. In other embodiments, each E includes an Fc domain monomer having the amino acid sequence of SEQ ID NO: 67 or SEQ ID NO: 68.
  • each E includes an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 72 or SEQ ID NO: 73. In other embodiments, each E includes an Fc domain monomer having the amino acid sequence of SEQ ID NO: 72 or SEQ ID NO: 73. In other embodiments, each E includes an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 76 or SEQ ID NO: 77. In other embodiments, each E includes an Fc domain monomer having the amino acid sequence of SEQ ID NO: 76 or SEQ ID NO: 77.
  • each E includes an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 82. In other embodiments, each E includes an Fc domain monomer having the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 82. In other embodiments, each E includes an Fc domain monomer having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 85 or SEQ ID NO: 86. In other embodiments, each E includes an Fc domain monomer having the amino acid sequence of SEQ ID NO: 85 or SEQ ID NO: 86.
  • the invention features a conjugate including (i) a first moiety, A 1 ; (ii) a second moiety, A 2 ; (iii) an Fc domain monomer or an Fc domain; and (iv) a linker covalently attached to A 1 and A 2 , and to the Fc domain monomer or the Fc domain; wherein each A 1 and each A 2 is independently selected from any one of formulas (A-I)-(A-XII). In some embodiments, each of A 1 and A 2 may be independently selected from any one of formulas (A-I), (A-II), (A-VI), or (A-VII). In other embodiments, each of A 1 and A 2 may be independently selected from formula (A-I). In a preferred embodiment of the above, x is 2.
  • the invention features a conjugate including (i) a first moiety, Int; (ii) an Fc domain monomer or an Fc domain; and (iv) a linker covalently attached to Int, and to the Fc domain monomer or the Fc domain; wherein each Int is independently selected from any one of the intermediates of Table 1a.
  • the invention features a conjugate including (i) a first moiety, A 1 ; (ii) a second moiety, A 2 ; (iii) an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide; and (iv) a linker covalently attached to A 1 and A 2 , and to the albumin protein, the albumin protein-binding peptide, or the Fc-binding peptide; wherein each A 1 and each A 2 is independently selected from any one of formulas (A-I)-(A-XII).
  • each of A 1 and A 2 may be independently selected from any one of formulas (A-I), (A-II), (A-VI), or (A-VII). In other embodiments, each of A 1 and A 2 may be independently selected from formula (A-I). In a preferred embodiment of the above, x is 2.
  • the invention features a conjugate described by formula (D-I):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-I)-(A-XII); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and Lis a linker covalently attached to each of E, A 1 , and A 2 , or a pharmaceutically acceptable salt thereof.
  • Fc domain monomer e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138
  • an albumin protein e.g., an albumin protein having the sequence of any
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • each of A 1 and A 2 may be independently selected from any one of formulas (A-I), (A-II), (A-VI), or (A-VII).
  • each of A 1 and A 2 may be independently selected from formula (A-I).
  • the invention features a conjugate described by formula (D-I):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-I)-(A-V); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and Lis a linker covalently attached to each of E, A 1 , and A 2 , or a pharmaceutically acceptable salt thereof.
  • Fc domain monomer e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138
  • an albumin protein e.g., an albumin protein having the sequence of any one of
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • the invention features a conjugate described by formula (D-I):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-VI)-(A-IX); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and L is a linker covalently attached to each of E, A 1 , and A 2 , or a pharmaceutically acceptable salt thereof.
  • Fc domain monomer e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138
  • an albumin protein e.g., an albumin protein having the sequence of any one
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • the conjugate is described by formula (D-II):
  • the conjugate is described by formula (D-II-1):
  • the conjugate is described by formula (D-II-2):
  • the conjugate is described by formula (D-II-3):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate has the structure selected from:
  • the conjugate is described by formula (D-II-4):
  • the conjugate is described by formula (D-II-5):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate has the structure selected from:
  • the conjugate has the structure selected from:
  • the conjugate is described by formula (D-II-6):
  • R 7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl, and C2-C15 heteroaryl; or a pharmaceutically acceptable salt thereof.
  • R 7 is selected from C1-C20 alkyl (e.g., methyl, ethyl, propyl, or butyl).
  • the conjugate is described by formula (D-II-7):
  • the conjugate is described by formula (D-II-8):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate has the structure
  • the conjugate has the structure
  • the conjugate has the structure
  • the conjugate has the structure
  • the conjugate is described by formula (D-II-9):
  • the conjugate is described by formula (D-II-10):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate has the structure
  • the conjugate has the structure of
  • the conjugate is described by formula (D-III):
  • the conjugate is described by formula (D-III-1):
  • the conjugate is described by formula (D-III-2):
  • the conjugate is described by formula (D-III-3):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate is described by formula (D-III-4):
  • the conjugate is described by formula (D-III-5):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate is described by formula (D-III-6):
  • the conjugate is described by formula (D-III-7):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate is described by formula (D-III-8):
  • the conjugate is described by formula (D-III-9):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate is described by formula (D-IV):
  • the conjugate is described by formula (D-IV1):
  • the conjugate is described by formula (D-IV-2):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate is described by formula (D-V):
  • the conjugate is described by formula (D-VI):
  • the conjugate is described by formula (D-V-2):
  • the conjugate is described by formula (D-V-3):
  • L′ is the remainder of L
  • y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • y 1 and y 2 are each 1, y 1 and y 2 are each 2, or y 1 and y 2 are each 3.
  • the conjugate is described by formula (D-V-4):
  • the conjugate is described by formula (D-V-5):
  • L′ is the remainder of L
  • y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • y 1 and y 2 are each 1, y 1 and y 2 are each 2, or y 1 and y 2 are each 3.
  • the conjugate is described by formula (D-V-6):
  • the conjugate is described by formula (D-V-7):
  • the conjugate is described by formula (D-V-8):
  • L′ is the remainder of L
  • y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • y 1 and y 2 are each 1, y 1 and y 2 are each 2, or y 1 and y 2 are each 3.
  • the conjugate is described by formula (D-V-9):
  • the conjugate is described by formula (D-V-10):
  • L′ is the remainder of L
  • y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • y 1 and y 2 are each 1, y 1 and y 2 are each 2, or y 1 and y 2 are each 3.
  • the conjugate is described by formula (D-VI):
  • the conjugate is described by formula (D-VI-1):
  • the conjugate is described by formula (D-VI-2):
  • the conjugate is described by formula (D-VI-3):
  • L′ is the remainder of L
  • y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • y 1 and y 2 are each 1, y 1 and y 2 are each 2, or y 1 and y 2 are each 3.
  • the conjugate is described by formula (D-VI-4):
  • the conjugate is described by formula (D-VI-5):
  • L′ is the remainder of L
  • y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • y 1 and y 2 are each 1, y 1 and y 2 are each 2, or y 1 and y 2 are each 3.
  • the conjugate is described by formula (D-VI-6):
  • the conjugate is described by formula (D-VI-7):
  • L′ is the remainder of L
  • y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • y 1 and y 2 are each 1, y 1 and y 2 are each 2, or y 1 and y 2 are each 3.
  • the conjugate is described by formula (D-VI-8):
  • the conjugate is described by formula (D-VI-9):
  • L′ is the remainder of L
  • y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • y 1 and y 2 are each 1, y 1 and y 2 are each 2, or y 1 and y 2 are each 3.
  • the conjugate is described by formula (D-VII):
  • R 1 is OH. In some embodiments of any of the aspects described herein, R 1 is NH 2 . In some embodiments of any of the aspects described herein, R 1 is —NHC( ⁇ NH)NH 2 .
  • the conjugate is described by formula (D-VIII):
  • the conjugate is described by formula (D-VIII-1):
  • the conjugate is described by formula (D-VIII-2):
  • the conjugate is described by formula (D-VIII-3):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate has the structure selected from
  • the conjugate is described by formula (D-VIII-4):
  • the conjugate is described by formula (D-VIII-5):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate has the structure selected from:
  • the conjugate is described by the structure
  • the conjugate is described by formula (D-VIII-6):
  • the conjugate is described by formula (D-VIII-7):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate is described by formula (D-VIII-8):
  • the conjugate is described by formula (D-VIII-9):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate is described by formula (D-VIII-10):
  • the conjugate is described by formula (D-VIII-11):
  • L′ is the remainder of L, and y 1 and y 2 are each independently an integer from 1-20 (e.g., y 1 and y 2 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.
  • L′ is a nitrogen atom.
  • the conjugate is described by formula (D-IX):
  • the conjugate is described by formula (D-IX-1):
  • the conjugate is described by formula (D-IX-2):
  • the conjugate is described by formula (D-IX-3):
  • the conjugate is described by formula (D-IX-4):
  • the conjugate is described by formula (D-IX-5):
  • the conjugate is described by formula (D-IX-6):
  • the conjugate is described by formula (D-X):
  • the conjugate is described by formula (D-XI):
  • the conjugate is described by formula (D-X-2):
  • the conjugate is described by formula (D-X-3):
  • L or L′ includes 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, P, carbonyl, thiocarbonyl, sulfonyl
  • 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, P, carbonyl, thiocarbonyl, a compound that is optionally substituted C8-C
  • L or L′ is oxo substituted.
  • the backbone of L or L′ comprises no more than 250 atoms.
  • L or L′ is capable of forming an amide, a carbamate, a sulfonyl, or a urea linkage.
  • L or L′ is a bond.
  • L or L′ is an atom.
  • each L is described by formula (D-L-1):
  • L A is described by formula G A1 -(Z A1 ) g1 -(Y A1 ) h1 -(Z A2 ) i1 -(Z A3 ) j1 -(Z A3 ) k1 -(Y A3 ) l1 -(Z A4 ) m1 -(Y A4 ) n1 -(Z A5 ) o1 -G A2 ;
  • L B is described by formula G B1 -(Z B1 ) g2 -(Y B1 ) h2 -(Z B2 ) i2 -(Y B2 ) j2 -(Z B3 ) k2 -(Y B3 ) l2 -(Z B4 ) m2 -(Y B4 ) n2 - (Z B5 ) o2 -G B2 ;
  • L C is described by formula G C1 -(Z C1 ) g3
  • L C may have two points of attachment to the Fc domain, Fc-binding peptide, albumin protein, or albumin protein-binding peptide (e.g., two G C2 ).
  • L includes a polyethylene glycol (PEG) linker.
  • a PEG linker includes a linker having the repeating unit structure (—CH 2 CH 2 O—) n , wherein n is an integer from 2 to 100.
  • a polyethylene glycol linker may covalently join a neuraminidase inhibitor and E (e.g., in a conjugate of any one of formulas (M-I)-(M-XI)).
  • a polyethylene glycol linker may covalently join a first neuraminidase inhibitor and a second neuraminidase inhibitor (e.g., in a conjugate of any one of formulas (D-I)-(D-XI)).
  • a polyethylene glycol linker may covalently join a neuraminidase inhibitor dimer and E (e.g., in a conjugate of any one of formulas (D-I)-(D-XI)).
  • a polyethylene glycol linker may be selected any one of PEG 2 to PEG 100 (e.g., PEG 2 , PEG 3 , PEG 4 , PEG 5 , PEG 5 -PEG 10 , PEG 10 -PEG 20 , PEG 20 -PEG 30 , PEG 30 -PEG 40 , PEG 50 -PEG 60 , PEG 60 -PEG 70 , PEG 70 -PEG 80 , PEG 80 -PEG 90 , PEG 90 -PEG 100 ).
  • L c includes a PEG linker, where L C is covalently attached to each of Q and E.
  • L is N
  • z 1 and z 2 are each, independently, and integer from 1 to 20; and R 9 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl, and C2-C15 heteroaryl.
  • L is N
  • R* is a bond or includes one or more of optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thiocarbonyl, sulfonyl,
  • Y is:
  • Y is:
  • Y is:
  • Y is:
  • the invention features a conjugate described by formula (M-I):
  • each A 1 is independently selected from any one of formulas (A-I)-(A-XII); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and L is a linker covalently attached to each of E and A 1 , or a pharmaceutically acceptable salt thereof.
  • Fc domain monomer e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138
  • an albumin protein e.g., an albumin protein having the sequence of any one of SEQ ID NOs:
  • each A 1 may be independently selected from any one of formulas (A-I)-(A-XII). In some embodiments, each A 1 may be independently selected from any one of formulas (A-I), (A-II), (A-VI), or (A-VII). In other embodiments, each A 1 may be independently selected from formula (A-I).
  • the invention features a conjugate described by formula (M-I):
  • each A 1 is independently selected from any one of formulas (A-I)-(A-V); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and Lis a linker covalently attached to each of E and A 1 , or a pharmaceutically acceptable salt thereof.
  • T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20)
  • each A 1 may be independently selected from any one of formulas (A-I)-(A-V).
  • the invention features a conjugate described by formula (M-I):
  • each A 1 is independently selected from any one of formulas (A-VI)-(A-IX); each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide; n is 1 or 2; T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and Lis a linker covalently attached to each of E and A 1 , or a pharmaceutically acceptable salt thereof. When T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A 1 may be independently selected from any one of formulas (A-VI)-(A-IX).
  • each E comprises
  • the conjugate is described by formula (M-II):
  • the conjugate is described by formula (M-II-1):
  • the conjugate is described by formula (M-II-2):
  • the conjugate is described by formula (M-II-3):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-II-4):
  • the conjugate is described by formula (M-II-5):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate has the structure
  • the conjugate is described by formula (M-II-6):
  • R 7 is selected from H, C1-C20 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl; C5-C15 aryl, and C2-C15 heteroaryl; or a pharmaceutically acceptable salt thereof.
  • R 7 is selected from C1-C20 alkyl (e.g., methyl, ethyl, propyl, or butyl).
  • the conjugate is described by formula (M-II-7):
  • the conjugate is described by formula (M-II-8):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate has the structure:
  • the conjugate is described by formula (M-II-9):
  • the conjugate is described by formula (M-II-10):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate has the structure
  • the conjugate is described by formula (M-III):
  • the conjugate is described by formula (M-III-1):
  • the conjugate is described by formula (M-III-2):
  • the conjugate is described by formula (M-III-3):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-III-4):
  • the conjugate is described by formula (M-III-5):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-III-6):
  • the conjugate is described by formula (M-III-7):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-III-8):
  • the conjugate is described by formula (M-III-9):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-IV):
  • the conjugate is described by formula (M-IV1):
  • the conjugate is described by formula (M-IV-2):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-V):
  • the conjugate is described by formula (M-V-1):
  • the conjugate is described by formula (M-V-2):
  • the conjugate is described by formula (M-V-3):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-V-4):
  • the conjugate is described by formula (M-V-5):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-V-6):
  • the conjugate is described by formula (M-V-7):
  • the conjugate is described by formula (M-V-8):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-V-9):
  • the conjugate is described by formula (M-V-10):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-VI):
  • the conjugate is described by formula (M-VI-1):
  • the conjugate is described by formula (M-VI-2):
  • the conjugate is described by formula (M-VI-3):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-VI-4):
  • the conjugate is described by formula (M-VI-5):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-VI-6):
  • the conjugate is described by formula (M-VI-7):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-VI-8):
  • the conjugate is described by formula (M-VI-9):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-VII):
  • R 1 is OH. In some embodiments of any of the aspects described herein, R 1 is NH 2 . In some embodiments of any of the aspects described herein, R 1 is —NHC( ⁇ NH)NH 2 .
  • the conjugate is described by formula (M-VIII):
  • the conjugate is described by formula (M-VIII-1):
  • the conjugate is described by (M-VIII-2):
  • the conjugate is described by formula (M-VIII-3):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-VIII-4):
  • the conjugate is described by formula (M-VIII-5):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20, or a pharmaceutically acceptable salt thereof.
  • the conjugate has the structure of
  • the conjugate is described by formula (M-VIII-6):
  • the conjugate is described by formula (M-VIII-7):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-VIII-8):
  • the conjugate is described by formula (M-VIII-9):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-VIII-10):
  • the conjugate is described by formula (M-VIII-11):
  • L′ is the remainder of L
  • y 1 is an integer from 1-20 (e.g., y 1 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.
  • the conjugate is described by formula (M-IX):
  • the conjugate is described by formula (M-IX-1):
  • the conjugate is described by formula (M-IX-2):
  • the conjugate is described by formula (M-IX-3):
  • the conjugate is described by formula (M-IX-4):
  • the conjugate is described by formula (M-IX-5):
  • the conjugate is described by formula (M-IX-6):
  • the conjugate is described by formula (M-X):
  • the conjugate is described by formula (M-XI):
  • the conjugate is described by formula (M-X-2):
  • the conjugate is described by formula (M-X-3):
  • L or L′ comprises one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, P, carbonyl, thiocarbonyl, sulfonyl
  • 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, P, carbonyl, thiocarbonyl, a compound that is optionally substituted C8-C
  • L or L′ is oxo substituted.
  • the backbone of L or L′ comprises no more than 250 atoms.
  • L or L′ is capable of forming an amide, a carbamate, a sulfonyl, or a urea linkage.
  • L or L′ is a bond.
  • L or L′ is an atom.
  • L′ is a nitrogen atom.
  • each L is described by formula (M-L-1):
  • J 2 may have two points of attachment to the Fc domain, Fc-binding peptide, albumin protein, or albumin protein-binding peptide (e.g., two J 2 ).
  • L is N
  • d is an integer from 1 to 20 (e.g., d is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • L is N
  • each of d and e is, independently, an integer from 1 to 26; or a pharmaceutically acceptable salt thereof.
  • L includes a polyethylene glycol (PEG) linker.
  • a PEG linker includes a linker having the repeating unit structure (—CH 2 CH 2 O—) n , wherein n is an integer from 2 to 100.
  • a polyethylene glycol linker may covalently join a neuraminidase inhibitor and E (e.g., in a conjugate of any one of formulas (M-I)-(M-XI)).
  • a polyethylene glycol linker may covalently join a first neuraminidase inhibitor and a second neuraminidase inhibitor (e.g., in a conjugate of any one of formulas (D-I)-(D-XI)).
  • a polyethylene glycol linker may covalently join a neuraminidase inhibitor dimer and E (e.g., in a conjugate of any one of formulas (D-I)-(D-XI)).
  • a polyethylene glycol linker may be selected any one of PEG 2 to PEG 100 (e.g., PEG 2 , PEG 3 , PEG 4 , PEG 5 , PEG 5 -PEG 10 , PEG 10 -PEG 20 , PEG 20 -PEG 30 , PEG 30 -PEG 40 , PEG 50 -PEG 60 , PEG 60 -PEG 70 , PEG 70 -PEG 80 , PEG 80 -PEG 90 , PEG 90 -PEG 100 ).
  • L c includes a PEG linker, where L C is covalently attached to each of Q and E.
  • R 1 is —NHC( ⁇ NH)NH 2 .
  • R 2 is —F.
  • R 3 is —F.
  • R 4 is —CO 2 H.
  • R 5 is —COCH 3 .
  • L is covalently attached to the nitrogen atom of a surface exposed lysine of E or L is covalently attached to the sulfur atom of a surface exposed cysteine of E.
  • E is an Fc domain monomer. In some embodiments, n is 2 and each E dimerizes to form an Fc domain.
  • n 2
  • each E is an Fc domain monomer
  • each E dimerizes to form an Fc domain
  • the conjugate is described by formula (D-I-1):
  • J is an Fc domain
  • T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • the conjugate has the structure of
  • n 2
  • each E is an Fc domain monomer
  • each E dimerizes to form an Fc domain
  • the conjugate is described by formula (M-II):
  • J is an Fc domain
  • T is an integer from 1 to 20 (e.g., T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • E has the sequence of any one of SEQ ID NOs: 1-138.
  • E is an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide. In some embodiments, where E is an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide, n is 1.
  • n is 1
  • E is an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide and the conjugate is described by formula (D-I-2):
  • E is an albumin protein, an albumin protein-binding peptide, or Fc-binding peptide; and T is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.
  • n is 1
  • E is an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide, and the conjugate is described by formula (M-I-2):
  • E is an albumin protein, an albumin protein-binding peptide, or an Fc-binding peptide; and T is an integer from 1 to 20, or a pharmaceutically acceptable salt thereof.
  • E is an albumin protein having the sequence of any one of SEQ ID NOs: 139-141.
  • T is 1, 2, 3, 4, or 5.
  • the invention provides a population of conjugates having the structure of any of the conjugates described herein (e.g., a population of conjugates having the formula of any one of formulas (1)-(5), (D-I)-(D-XI), (D′-I), (M-I)-(M-XI), or (M′-I)), wherein the average value of T is 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5).
  • the average value of T is 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 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,
  • 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.
  • each A 1 -L-A 2 may be independently selected (e.g., independently selected from any of the A 1 -L-A 2 structures described herein).
  • E may be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different A 1 -L-A 2 , moieties.
  • E is conjugated to a first A 1 -L-A 2 moiety, and a second A 1 -L-A 2 , moiety.
  • a 1 and A 2 of the first A 1 -L-A 2 moiety are independently selected from any one of formulas (A-III)-(A-V), and A 1 and A 2 of the second A 1 -L-A 2 moiety are independently selected from any one of formulas (A-I), (A-II), (A-VI), (A-VII), (A-VIII), and (A-IX).
  • each of the first A 1 -L-A 2 moieties is conjugated specifically to a lysine residue of E (e.g., the nitrogen atom of a surface exposed lysine residue of E), and each of the second A 1 -L-A 2 moieties is conjugated specifically to a cysteine residue of E (e.g., the sulfur atom of a surface exposed cysteine residue of E).
  • E e.g., the nitrogen atom of a surface exposed lysine residue of E
  • cysteine residue of E e.g., the sulfur atom of a surface exposed cysteine residue of E
  • each of the first A 1 -L-A 2 moieties is conjugated specifically to a cysteine residue of E (e.g., the sulfur atom of a surface exposed cysteine residue of E), and each of the second A 1 -L-A 2 moieties is conjugated specifically to a lysine residue of E (e.g., the nitrogen atom of a surface exposed lysine residue of E).
  • E e.g., the sulfur atom of a surface exposed cysteine residue of E
  • a lysine residue of E e.g., the nitrogen atom of a surface exposed lysine residue of E
  • the number of first A 1 -L-A 2 moieties conjugated to E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the number of second A 1 -L-A 2 moieties conjugated to E is an integer from 1 to 10 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).
  • each A 1 -L may be independently selected (e.g., independently selected from any of the A 1 -L structures described herein).
  • E may be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different A 1 -L moieties.
  • E is conjugated to a first A 1 -L moiety, and a second A 1 -L, moiety.
  • a 1 of the first A 1 -L moiety is selected from any one of formulas (A-III)-(A-V), and A 1 of the second A 1 -L moiety is selected from any one of formulas (A-I), (A-II), (A-VI), (A-VII), (A-VIII), or (A-IX).
  • each of the first A 1 -L moieties is conjugated specifically to a lysine residue of E (e.g., the nitrogen atom of a surface exposed lysine residue of E), and each of the second A 1 -L moieties is conjugated specifically to a cysteine residue of E (e.g., the sulfur atom of a surface exposed cysteine residue of E).
  • E e.g., the nitrogen atom of a surface exposed lysine residue of E
  • cysteine residue of E e.g., the sulfur atom of a surface exposed cysteine residue of E
  • each of the first A 1 -L moieties is conjugated specifically to a cysteine residue of E (e.g., the sulfur atom of a surface exposed cysteine residue of E), and each of the second A 1 -L moieties is conjugated specifically to a lysine residue of E (e.g., the nitrogen atom of a surface exposed lysine residue of E).
  • E e.g., the sulfur atom of a surface exposed cysteine residue of E
  • each of the second A 1 -L moieties is conjugated specifically to a lysine residue of E (e.g., the nitrogen atom of a surface exposed lysine residue of E).
  • the number of first A 1 -L moieties conjugated to E is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the number of second A 1 -L moieties conjugated to E is an integer from 1 to 10 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).
  • the invention features a conjugate described by formula (D′-I):
  • each A 1 is independently selected from any one of formulas (A-III)-(A-V); wherein each A 2 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 the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide; n is 1 or 2; T 1 is an integer from 1 to 10 (e.g., T 1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L 1 is a linker covalently conjugated to E and to each A 1 ; T 1 is an integer from 1 to 10 (e.g., T 1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L 2 is a
  • each A 1 -L-A 1 is conjugated specifically to a lysine residue of E (e.g., the nitrogen atom of a surface exposed lysine residue of E), and each the A 2 -L-A 2 is conjugated specifically to a cysteine residue of E (e.g., the sulfur atom of a surface exposed cysteine residue of E).
  • E e.g., the nitrogen atom of a surface exposed lysine residue of E
  • cysteine residue of E e.g., the sulfur atom of a surface exposed cysteine residue of E
  • each A 1 -L-A 1 moiety is conjugated specifically a cysteine residue of E (e.g., the sulfur atom of a surface exposed cysteine residue of E), and each A 2 -L-A 2 moiety is conjugated specifically to a lysine residue of E (e.g., the nitrogen atom of a surface exposed lysine residue of E).
  • E e.g., the sulfur atom of a surface exposed cysteine residue of E
  • each A 2 -L-A 2 moiety is conjugated specifically to a lysine residue of E (e.g., the nitrogen atom of a surface exposed lysine residue of E).
  • the invention features a conjugate described by formula (M′-I):
  • each A 1 is independently selected from any one (M-IX) of formulas (A-III)-(A-V); wherein each A 2 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 the sequence of any one of SEQ ID NOs: 1-138), an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 139-141), an albumin protein-binding peptide, or an Fc-binding peptide; n is 1 or 2; T 1 is an integer from 1 to 10 (e.g., T 1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); L 1 is a linker covalently conjugated to E and A 1 ; T 1 is an integer from 1 to 10 (e.g., T 1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10);
  • each A 1 -L is conjugated specifically to a lysine residue of E (e.g., the nitrogen atom of a surface exposed lysine residue of E), and each the A 2 -L is conjugated specifically to a cysteine residue of E (e.g., the sulfur atom of a surface exposed cysteine residue of E).
  • each A 1 -L moiety is conjugated specifically a cysteine residue of E (e.g., the sulfur atom of a surface exposed cysteine residue of E), and each A 2 -L moiety is conjugated specifically to a lysine residue of E (e.g., the nitrogen atom of a surface exposed lysine residue of E).
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the conjugates described herein (e.g., a conjugate of any one of formulas (1)-(5), (D-I)-(D-XI), (D′-I), (M-I)-(M-XI), or (M′-I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the invention provides a method for the treatment of a subject having a viral infection or presumed to have a viral infection, the method comprising administering to the subject an effective amount of any of the conjugates or compositions described herein (e.g., a conjugate of any one of formulas (1)-(5), (D-I)-(D-XI), (D′-I), (M-I)-(M-XI), or (M′-I)).
  • any of the conjugates or compositions described herein e.g., a conjugate of any one of formulas (1)-(5), (D-I)-(D-XI), (D′-I), (M-I)-(M-XI), or (M′-I)).
  • the invention provides a method for the prophylactic treatment of a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the conjugates or compositions described herein (e.g., a conjugate of any one of formulas (1)-(5), (D-I)-(D-XI), (D′-I), (M-I)-(M-XI), or (M′-I)).
  • any of the conjugates or compositions described herein e.g., a conjugate of any one of formulas (1)-(5), (D-I)-(D-XI), (D′-I), (M-I)-(M-XI), or (M′-I)).
  • the viral infection is caused by influenza virus or parainfluenza virus. In some embodiments, the viral infection is influenza virus A, B, or C, or parainfluenza virus.
  • the subject is immunocompromised.
  • the subject has been diagnosed with humoral immune deficiency, T cell deficiency, neutropenia, asplenia, or complement deficiency.
  • the subject is being treated or is about to be treated with an immunosuppressive therapy.
  • the subject has been diagnosed with a disease which causes immunosuppression.
  • the disease is cancer or acquired immunodeficiency syndrome.
  • the cancer is leukemia, lymphoma, or multiple myeloma.
  • the subject has undergone or is about to undergo hematopoietic stem cell transplantation.
  • the subject has undergone or is about to undergo an organ transplant.
  • the subject has or is at risk of developing a secondary infection.
  • 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.
  • MRSA methicillin-resistant Staphylococcus aureus
  • Streptococcus pneumoniae Streptococcus pneumoniae
  • Pseudomonas aeruginosa and/or Haemophilus influenzae
  • the secondary infection is MRSA.
  • the secondary infection is S. pneumoniae .
  • the secondary infection is a respiratory infection (e.g., an infection of the respiratory tract).
  • the secondary infection is associated with (e.g., causes) pneumonia (e.g., bacterial or viral pneumonia).
  • the subject has or is at risk of developing pneumonia.
  • the disclosure features a method of preventing a secondary infection in a subject diagnosed with an influenza infection, wherein the method includes administering to the subject a conjugate or composition described herein. In some embodiments, the method includes administering to the subject conjugate 45 or a pharmaceutical composition including conjugate 45.
  • administering a conjugate or composition of the present invention to a subject diagnosed with an influenza infection decreases the likelihood of developing a secondary infection, e.g., by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500% or more (e.g., as compared to a subject suffering from influenza not treated with the conjugate or composition).
  • administering a conjugate or composition of the present invention to a subject diagnosed with an influenza infection decreases the likelihood of developing a secondary bacterial infection (e.g., MRSA, Streptococcus pneumoniae, Pseudomonas aeruginosa , and/or Haemophilus influenzae ), e.g., by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500% or more.
  • a secondary bacterial infection e.g., MRSA, Streptococcus pneumoniae, Pseudomonas aeruginosa , and/or Haemophilus influenzae
  • the conjugate or composition is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, locally, by inhalation, by injection, or by infusion.
  • the subject is treated with a second therapeutic agent.
  • the second therapeutic agent is an antiviral agent.
  • the antiviral agent is selected from pimovidir, oseltamivir, zanamivir, peramivir, laninamivir, amantadine, or rimantadine.
  • the second therapeutic agent is pimovidir.
  • the second therapeutic agent is a viral vaccine.
  • the viral vaccine elicits an immune response in the subject against influenza virus A, B, or C, or parainfluenza virus.
  • the conjugate is administered in combination with an antiviral agent, where the antiviral agent is baloxavir.
  • the conjugate is described by formula (D-II-6).
  • the conjugate is described by formula (D-II-7).
  • each E includes an Fc domain that has an amino acid sequence at least 95% identical to the sequence of any one of SEQ ID NOs: 63-138.
  • each E includes an Fc domain that has an amino acid sequence at least 95% identical to the sequence of any one of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85, or SEQ ID NO: 86.
  • each E includes an Fc domain that has the amino acid sequence of any one of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85, or SEQ ID NO: 86.
  • the conjugate is conjugate 45 (e.g., conjugate 45a or 45b) or conjugate 46.
  • the conjugate and baloxavir are administered sequentially. In other embodiments, the conjugate and baloxavir are administered simultaneously.
  • the disclosure provides a method for treating or preventing a viral infection in subject by administering to the subject: a) an effective amount of a conjugate or composition of any one of claims 1 - 215 ; and b) a second therapeutic agent.
  • the conjugate is administered to the subject after the subject has a viral infection, is presumed to have a viral infection, or has been exposed to a virus.
  • the conjugate is administered to the subject prophylactically.
  • the second therapeutic agent is administered to the subject after the subject has a viral infection, is presumed to have a viral infection, or has been exposed to the virus.
  • the second therapeutic agent is administered to the subject prophylactically.
  • the second therapeutic agent is administered within 30 days, within 14 days, within 7 days, within 2 days, or within 24 hours days of the conjugate. In particular embodiments, the second therapeutic agent is administered within 2 days of the conjugate.
  • 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).
  • the antiviral agent is baloxavir marboxil, baloxavir acid, or a pharmaceutically acceptable salt thereof.
  • the baloxavir marboxil is administered in an amount between 20 mg and 90 mg (e.g., between 25 mg and 50 mg, between 45 mg and 70 mg, or between 65 and 90 mg). In some embodiments, the baloxavir marboxil is administered orally. In certain embodiments, the baloxavir marboxil is administered as a single dose. In other embodiments, the baloxavir marboxil is administered as more than one dose. In particular embodiments, the baloxavir marboxil is administered in an amount between 20 mg and 40 mg. In other embodiments, the baloxavir marboxil is administered in an amount between 30 and 80 mg. In certain embodiments, conjugate is described by formula (D-II-6).
  • each E has a sequence at least 95% identical to the sequence of any one of SEQ ID NOs: 63-138.
  • each E includes an Fc domain that has an amino acid sequence at least 95% identical to the sequence of any one of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85, or SEQ ID NO: 86.
  • each E includes an Fc domain that has the amino acid sequence of any one of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 85, or SEQ ID NO: 86.
  • the conjugate is conjugate 45 (e.g., conjugate 45a or conjugate 45b) or conjugate 46.
  • the conjugate is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, locally, by inhalation, by injection, or by infusion.
  • the conjugate is administered intravenously.
  • the conjugate is administered intramuscularly.
  • the viral infection is caused by an influenza virus or a parainfluenza virus.
  • the virus is influenza virus A, B, or C, or parainfluenza virus.
  • an Fc-domain-containing composition may be substituted for an Fc domain and an Fc-domain-monomer-containing composition may be substituted for an Fc domain monomer in any one of formulas (1)-(5), (D-I)-(D-XI), (D′-I), (M-I)-(M-XD, or (M′-I) (e.g., any one of 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-
  • any of the formulas described herein e.g., any one of formulas (1)-(5), (D-I)-(D-XI), (D-I), (M-I)-(M-XI), or (M′-I)
  • E is an Fc-domain-monomer-containing composition
  • any of the formulas described herein e.g., any one of formulas (1)-(5), (D-I)-(D-XI), (D′-I), (M-I)-(M-XI), or (M′-I)
  • E is an Fc-domain-containing composition.
  • the Fc-domain-containing composition is an antibody or an antibody fragment.
  • An antibody may include any form of immunoglobulin, heavy chain antibody, light chain antibody, LRR-based antibody, or other protein scaffold with antibody-like properties, as well as any other immunological binding moiety known in the art, including antibody fragments (e.g., a Fab, Fab′, Fab′2, F(ab′)2, Fd, Fv, Feb, scFv, or SMIP).
  • the subunit structures and three-dimensional configurations of different classes of antibodies are known in the art.
  • An antibody fragment may include a binding moiety that includes a portion derived from or having significant homology to an antibody, such as the antigen-determining region of an antibody. Exemplary antibody fragments include Fab, Fab′, Fab′2, F(ab′)2, Fd, Fv, Feb, scFv, and SMTP.
  • the antibody or antibody fragment is a human, mouse, camelid (e.g., llama, alpaca, or camel), goat, sheep, rabbit, chicken, guinea pig, hamster, horse, or rat antibody or antibody fragment.
  • the antibody is an IgG, IgA, IgD, IgE, IgM, or intrabody.
  • the antibody fragment includes an scFv, sdAb, dAb, Fab, Fab′, Fab′2, F(ab′)2, Fd, Fv, Feb, or SMTP.
  • the Fc-domain-containing composition confers binding specificity to a one or more targets (e.g., an antigen).
  • the one or more targets (e.g., an antigen) bound by the Fc-domain-containing composition is a viral (e.g., influenza) protein such as neuraminidase or hemagglutinin.
  • the antibody or antibody fragment recognizes a viral surface antigen.
  • the antibody or antibody fragment targets hemagglutinin.
  • Hemagglutinin-targeting antibodies include monoclonal antibodies, such as CR6261, CR8020, MEDI8852, MHAA4549A, and VIS410.
  • the antibody or antibody fragment is a broadly neutralizing antibody or antibody fragment targeting influenza hemagglutinin (e.g., an antibody or antibody fragment described in Wu et al., J. Mol, Biol. 429:2694-2709 (2017)).
  • the antibody or antibody fragment targets a viral matrix protein (e.g., matrix 2 protein).
  • TCN032 is a matrix 2 protein targeting monoclonal antibody.
  • the Fc-domain-containing composition (e.g., an antibody or antibody fragment) includes one or more single-domain antibodies (sdAbs).
  • the Fc-domain-containing composition is an antibody or antibody fragment including a sdAb with influenza A reactivity, such as a sdAb that binds to hemagglutinin of influenza A (e.g., SD36 or SD38, described in Laursen et al. Science, 362:598-602 (2018)).
  • the Fc-domain-containing composition is an antibody or antibody fragment including a sdAb with influenza B reactivity, such as a sdAb that binds to hemagglutinin of influenza B (e.g., SD83 or SD84, described in Laursen et al. Science. 362:598-602 (2016)).
  • a sdAb with influenza B reactivity such as a sdAb that binds to hemagglutinin of influenza B (e.g., SD83 or SD84, described in Laursen et al. Science. 362:598-602 (2018)).
  • the Fc-domain-containing composition is a multidomain antibody (MDAb) or Multidomain antibody fragment including 2 or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more) sdAbs.
  • the MDAb or fragment thereof includes one or more sdABs that binds to hemagglutinin of influenza A, and one or more sdAbs that binds to hemagglutinin of influenza B.
  • the MDAb is JNJ-7445 (also known as MD3606), which is described in Laursen et al. Science.
  • JNJ-7445 is an MDAb that includes two sdAbs that bind to hemagglutinin of influenza A (SD36 and SD38) and two sdAbs that bind to hemagglutinin of influenza B (SD83 and SD84), which are linked to an Fc domain (IgG1).
  • the sdAbs were produced by immunizing llamas with influenza vaccine and H7 and H2 recombinant hemagglutinin.
  • the invention includes a conjugate described by any one of formulas (1)-(5), (D-I)-(D-XI), (D′-D, (M-I)-(M-XI), or (M′-I) (e.g., any one of 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-IV1), (D-IV-2), (D-V), (D-VI), (D-V-2),
  • n is 1.
  • the antibody or antibody fragment includes any antibody or antibody fragment described herein, such as a monoclonal antibody that binds to viral hemagglutinin CR6261, CR8020, MED18852, MHAA4549A, or VIS410); a broadly neutralizing antibody or antibody fragment targeting viral hemagglutinin (e.g., antibodies or antibody fragments described in Wu et al., J. Md. Biol.
  • a sdAb targeting viral hemagglutinin e.g., SD36, SD38, SD83, or SD84
  • a MDAb or fragment thereof targeting viral hemagglutinin e.g., JNJ-7445
  • E includes the amino acid sequence of SEQ ID NO: 1.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 2.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 3.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 4.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino add sequence of SEQ ID NO: 4.
  • E includes the amino add sequence of SEQ ID NO: 5.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 5.
  • E includes the amino acid sequence of SEQ ID NO: 6.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 6.
  • E includes the amino acid sequence of SEQ ID NO: 7.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 8.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 9.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 9.
  • E includes the amino acid sequence of SEQ ID NO: 10.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 10.
  • E includes the amino acid sequence of SEQ ID NO: 11.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 12.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 13.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 14.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino add sequence of SEQ ID NO: 14.
  • E includes the amino add sequence of SEQ ID NO: 15.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 15.
  • E includes the amino acid sequence of SEQ ID NO: 16.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 16.
  • E includes the amino acid sequence of SEQ ID NO: 17.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 18.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 19.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 19.
  • E includes the amino acid sequence of SEQ ID NO: 20.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 20.
  • E includes the amino acid sequence of SEQ ID NO: 21.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 22.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 23.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 24.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino add sequence of SEQ ID NO: 24.
  • E includes the amino add sequence of SEQ ID NO: 25.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 26.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 27.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 28.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 29.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 30.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 31.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 32.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 33.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 34.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino add sequence of SEQ ID NO: 34.
  • E includes the amino add sequence of SEQ ID NO: 35.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 36.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 37.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 38.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 39.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 40.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 41.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 42.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 43.
  • E includes an amino add sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 44.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino add sequence of SEQ ID NO: 45.
  • E includes the amino add sequence of SEQ ID NO: 46.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 46.
  • E includes the amino acid sequence of SEQ ID NO: 47.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 47.
  • E includes the amino acid sequence of SEQ ID NO: 48.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 49.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 50.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 51.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 52.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 51.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 54.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 55.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino add sequence of SEQ ID NO: 55.
  • E includes the amino add sequence of SEQ ID NO: 56.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 56.
  • E includes the amino acid sequence of SEQ ID NO: 57.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 57.
  • E includes the amino acid sequence of SEQ ID NO: 58.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 59.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 60.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 61.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 62.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 63.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 64.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 65.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino add sequence of SEQ ID NO: 65.
  • E includes the amino add sequence of SEQ ID NO: 66.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 66.
  • E includes the amino acid sequence of SEQ ID NO: 67.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 67.
  • E includes the amino acid sequence of SEQ ID NO: 68.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 69.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 70.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 71.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 72.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 71.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 74.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 75.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino add sequence of SEQ ID NO: 75.
  • E includes the amino add sequence of SEQ ID NO: 76.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 76.
  • E includes the amino acid sequence of SEQ ID NO: 77.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 77.
  • E includes the amino acid sequence of SEQ ID NO: 78.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 79.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 80.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 81.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 82.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 83.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 84.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 85.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 85.
  • E includes the amino add sequence of SEQ ID NO: 86.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 86.
  • E includes the amino acid sequence of SEQ ID NO: 87.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 87.
  • E includes the amino acid sequence of SEQ ID NO: 88.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 89.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 90.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 90.
  • E includes the amino acid sequence of SEQ ID NO: 91.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 92.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 93.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 94.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 95.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino add sequence of SEQ ID NO: 95.
  • E includes the amino add sequence of SEQ ID NO: 96.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 96.
  • E includes the amino acid sequence of SEQ ID NO: 97.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 97.
  • E includes the amino acid sequence of SEQ ID NO: 98.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 99.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 100.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 101.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 102.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 103.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 104.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 105.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 105.
  • E includes the amino acid sequence of SEQ ID NO: 106.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 106.
  • E includes the amino acid sequence of SEQ ID NO: 107.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 108.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 109.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 110.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 111.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 112.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 113.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 114.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 115.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 115.
  • E includes the amino acid sequence of SEQ ID NO: 116.
  • E includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 01100% identical to the amino acid sequence of SEQ ID NO: 116.
  • E includes the amino acid sequence of SEQ ID NO: 117.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 118.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 119.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 120.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 121.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 122.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 123.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 124.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 125.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 126.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 127.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 128.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 129.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 130.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 131.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 132.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 133.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 134.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 135.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 136.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 137.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 138.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 139.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 140.
  • E includes an amino acid sequence that is 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.
  • E includes the amino acid sequence of SEQ ID NO: 145.
  • E includes an amino acid sequence that is 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.
  • the Fc domain monomer (e.g., the Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138) includes a triple mutation corresponding to M252Y/S254T/T256E (YTE).
  • YTE M252Y/S254T/T256E
  • an amino acid “corresponding to” a particular amino acid residue should be understood to include any amino acid residue that one of skill in the art would understand to align to the particular residue (e.g., of the particular sequence).
  • any one of SEQ ID NOs: 1-138 may be mutated to include a YTE mutation.
  • the Fc domain monomer (e.g., the Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138) includes a double mutant corresponding to M428UN434S (LS).
  • an amino acid “corresponding to” a particular amino acid residue e.g., of a particular SEQ ID NO.
  • any one of SEQ ID NOs: 1-138 may be mutated to include a LS mutation.
  • the Fc domain monomer (e.g., the Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138) includes a mutant corresponding to N434H.
  • an amino acid “corresponding to” a particular amino acid residue e.g., of a particular SEQ ID NO.
  • any one of SEQ ID NOs: 1-138 may be mutated to include an N434H mutation.
  • the Fc domain monomer (e.g., the Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138) includes a mutant corresponding to C220S.
  • an amino acid “corresponding to” a particular amino acid residue e.g., of a particular SEQ ID NO.
  • any one of SEQ ID NOs: 1-138 may be mutated to include a C220S mutation.
  • the Fc domain monomer (e.g., the Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-95) includes a triple mutation corresponding to V309D/Q311H/N434S (DHS).
  • DHS V309D/Q311H/N434S
  • an amino acid “corresponding to” a particular amino acid residue should be understood to include any amino acid residue that one of skill in the art would understand to align to the particular residue (e.g., of the particular sequence).
  • any one of SEQ ID NOs: 1-95 may be mutated to include a DHS mutation.
  • the Fc domain monomer (e.g., the Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-138) is a fragment of the Fc domain monomer (e.g., a fragment of at least 25 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more), at least 50 (e.g., 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 or more), at least 75 (e.g., 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86
  • 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 is covalently conjugated to a linker (e.g., a PEG 2 -PEG 20 linker).
  • the linker conjugated to E may be functionalized such that it may reacts to form a covalent bond with the L of any A 1 -L or any A 2 -L-A 1 described herein.
  • E is conjugated to a linker functionalized with an azido group and the L of A 1 -L or any A 2 -L-A 1 is functionalized with an alkyne group.
  • Conjugation e.g., by click chemistry
  • linker-azido of E and linker-alkyne of A 1 -L or A 2 -L-A 1 forms a conjugate of the invention, for example a conjugate described by any one of formulas (1)-(5).
  • E is conjugated to a linker functionalized with an alkyne group and L of any A 1 -L or of any A 2 -L-A 1 is functionalized with an azido group.
  • Conjugation e.g., by click chemistry, see, e.g., FIG. 103
  • linker-alkyne of E and linker-azido of A 1 -L or A 2 -L-A 1 forms a conjugate of the invention, for example a conjugate described by formula (1)-(5), (D-I)-(D-XI), (D′-I), (M-I)-(M-XI), or (M′-I).
  • the squiggly line of any one of formulas (1)-(5), (D-I)-(D-XI), (D′-I), (M-I)-(M-XI), or (M′-I) may represent a covalent bond between E and the L of A 1 -L or A 2 -L-A 1 .
  • the squiggly line of any one of formulas (1)-(5), (D-I)-(D-XI), (D′-I), (M-I)-(M-XI), or (M′-I) may represent that one or more amino acid side chains of E (e.g., one or more nitrogen atoms of one or more surface exposed lysine residues of E or one or more sulfur atoms of one or more surface exposed cysteines in E) have been conjugated to a linker (e.g., a PEG 2 -PEG 20 linker) wherein the linker has been functionalized with a reactive moiety, such that the reactive moiety forms a covalent bond with the L of any A 1 -L or any A 2 -L-A 1 described herein (e.g., by click chemistry between an azido functionalized linker and an alkyne functionalized linker, as described above; see, e.g., FIG. 103 ).
  • a linker e.g., a
  • a 1 and/or A 2 have the structure described by (A-I):
  • a 1 and/or A 2 have the structure described by (A-I):
  • R 1 is —NHC( ⁇ NH)NH 2
  • R 4 is —CO 2 H
  • R 5 is —COCH 3
  • X is —O—.
  • a 1 and/or A 2 have the structure of zanamivir described by:
  • a 1 and/or A 2 have the structure described by (A-II):
  • a 1 and/or A 2 have the structure described by (A-II):
  • R 1 is —NHC( ⁇ NH)NH 2
  • R 2 is H or F
  • R 3 is H or F
  • R 4 is —CO 2 H
  • R 5 is —COCH 3
  • X is —O—.
  • a 1 and/or A 2 have the structure described by:
  • a 1 and/or A 2 have the structure described by (A-III):
  • a 1 and/or A 2 have the structure described by (A-III):
  • R 1 is —NHC( ⁇ NH)NH 2
  • R 4 is —CO 2 H
  • R 5 is —COCH 3 .
  • a 1 and/or A 2 have the structure of peramivir described by:
  • a 1 and/or A 2 have the structure described by (A-IV):
  • a 1 and/or A 2 have the structure described by (A-IV):
  • R 1 is —NHC( ⁇ NH)NH 2
  • R 4 is —CO 2 H
  • R 5 is —COCH 3 .
  • a 1 and/or A 2 have the structure described by:
  • a 1 and/or A 2 have the structure described by (A-V):
  • a 1 and/or A 2 have the structure described by (A-V):
  • R 1 is —NHC( ⁇ NH)NH 2
  • R 4 is —CO 2 H
  • R 5 is —COCH 3 .
  • a 1 and/or A 2 have the structure described by:
  • a 1 and/or A 2 have the structure described by (A-VI):
  • a 1 and/or A 2 have the structure described by (A-VI):
  • R 1 is —NHC( ⁇ NH)NH 2
  • R 4 is —CO 2 H
  • R 5 is —COCH 3
  • X is —O—.
  • a 1 and/or A 2 have the structure of zanamivir described by:
  • a 1 and/or A 2 have the structure described by (A-VII):
  • a 1 and/or A 2 have the structure described by (A-VII):
  • R 1 is —NHC( ⁇ NH)NH 2
  • R 2 is H or F
  • R 3 is H or F
  • R 4 is —CO 2 H
  • R 5 is —COCH 3
  • X is —O—.
  • a 1 and/or A 2 have the structure described by:
  • a 1 and/or A 2 have the structure described by (A-VIII):
  • a 1 and/or A 2 have the structure described by (A-VIII):
  • R 1 is —NHC( ⁇ NH)NH 2
  • R 5 is —COCH 3
  • X is —O—.
  • a 1 and/or A 2 have the structure described by:
  • a 1 and/or A 2 have the structure described by (A-IX):
  • a 1 and/or A 2 have the structure described by (A-IX):
  • R 1 is —NHC( ⁇ NH)NH 2
  • R 2 is H or F
  • R 3 is H or F
  • R 5 is —COCH 3
  • X is —O—.
  • a 1 and/or A 2 have the structure described by:
  • a 1 and/or A 2 have the structure described by (A-X):
  • a 1 and/or A 2 have the structure described by (A-X):
  • R 1 is —NHC( ⁇ NH)NH 2
  • R 3 is H
  • R 5 is —COCH 3
  • X is —O—.
  • a 1 and/or A 2 have the structure of sulfozanamivir described by:
  • a 1 and/or A 2 have the structure described by (A-XI):
  • a 1 and/or A 2 have the structure described by (A-XI): R 4 is —CO 2 H, and/or R 5 is —COCH 3 .
  • the alkene is (E), (Z), or a racemic mixture of (E)/(Z).
  • a 1 and/or A 2 have the structure of A-315675 (Abbott) described by:
  • a 1 and/or A 2 have the structure described by (A-XII):
  • a 1 and/or A 2 have the structure described by (A-XII):
  • R 4 is —CO 2 H.
  • a 1 and/or A 2 have the structure of A-315675 (Abbott) described by:
  • the conjugate is conjugate 1, or any regioisomer thereof, and the drug-to-antibody ratio (DAR) (e.g., T) is between 0.5 and 10.0, e.g., 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,
  • DAR
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 1, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 2, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 2, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 3, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 3, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 4, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 4, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 5, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 5, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 6, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 6, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 7, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 7, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 8, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 8, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 9, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 9, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 10, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 10, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 11, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 11, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 12, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 12, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 13, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 13, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 14, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 14, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 15, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 15, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 16, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 16, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 17, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 17, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 18, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 18, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 19, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 19, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 20, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 20, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 21, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 21, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 22, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 22, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 23, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 23, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 24, or any regioisomer thereof, and the DAR (e.g., T) is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 24, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 25, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 25, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 26, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 26, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 27, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 27, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 28, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.
  • the DAR is between 0.5 and 2.0, between 2.0 and 4.0, between 4.0 and 6.0, between 6.0 and 8.0, or between 8.0 and 10.0.
  • the invention provides a population of conjugates, each conjugate having the structure of conjugate 28, wherein the average DAR (e.g., T) of the population of conjugates is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 15 to 20, 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, 7.5 to 9.5, or 8.5 to 10.5.
  • the conjugate is conjugate 29, or any regioisomer thereof
  • the DAR e.g., T
  • the DAR is between 0.5 and 10.0, e.g., about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.

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