US20210228727A1 - 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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Publication number
US20210228727A1
US20210228727A1 US17/193,923 US202117193923A US2021228727A1 US 20210228727 A1 US20210228727 A1 US 20210228727A1 US 202117193923 A US202117193923 A US 202117193923A US 2021228727 A1 US2021228727 A1 US 2021228727A1
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Prior art keywords
seq
sulfur atom
conjugate
optionally substituted
pharmaceutically acceptable
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US17/193,923
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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 US17/193,923 priority Critical patent/US20210228727A1/en
Priority to US17/236,722 priority patent/US11833213B2/en
Publication of US20210228727A1 publication Critical patent/US20210228727A1/en
Assigned to CIDARA THERAPEUTICS, INC. reassignment CIDARA THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BALKOVEC, JAMES M., BENSEN, Daniel C., CHEN, Zhi-yong, JIANG, WANLONG, BRADY, THOMAS P., DO, QUYEN-QUYEN THUY, LAM, THANH, COLE, JASON, NONCOVICH, ALAIN, BORCHARDT, ALLEN, DOEHRMANN, Simon, TARI, LESLIE W.
Priority to US18/464,421 priority patent/US20240156975A1/en
Abandoned legal-status Critical Current

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    • 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
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    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • 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
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
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    • 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
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
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    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
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    • C07C2601/00—Systems containing only non-condensed rings
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    • C07K2319/00—Fusion polypeptide
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    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16211—Influenzavirus B, i.e. influenza B virus
    • C12N2760/16271—Demonstrated in vivo effect

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.
  • neuraminidase inhibitors used to reduce viral spread have been identified, including oseltamivir (TamifluTM), zanamivir (RelenzaTM), and peramivir (RapivabTM).
  • 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 ⁇ Rs (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 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):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68);
  • 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.
  • 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-I)-(A-V):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68);
  • 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.
  • 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):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68);
  • 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.
  • 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):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68); 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
  • the invention features a conjugate described by formula (2):
  • each A 1 is independently selected from any one of formulas (A-I)-(A-V):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68); 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
  • the invention features a conjugate described by formula (2):
  • each A 1 is independently selected from any one of formulas (A-VI)-(A-IX):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl; each E comprises an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68); 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
  • each E includes an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-68.
  • 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: 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, Cys 30 and Cys18 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and Cys 36 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and Cys 38 in SEQ ID NO: 10 or SEQ ID NO: 11, and/or Cys 36 and Cys 38 in SEQ ID NO: 10 or SEQ ID NO: 11.
  • 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, Cys 30 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 Cys 36 and Cys 38 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.
  • 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: 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 invention also features a population of conjugates described in any of the previous aspects, in which the average value of T is 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20). In some embodiments, the average value of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the invention features a conjugate described by formula (3):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-I)-(A-VII):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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 ;
  • 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
  • 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 (3):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-I)-(A-V):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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 ;
  • 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
  • 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 (3):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-VI)-(A-IX):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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 ;
  • 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
  • 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 E includes an Fc domain monomer having the sequence of any one of SEQ ID Nos: 1-68.
  • 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: 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, Cys 30 and Cys18 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and Cys 36 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and Cys 38 in SEQ ID NO: 10 or SEQ ID NO: 11, and/or Cys 36 and Cys 38 in SEQ ID NO: 10 or SEQ ID NO: 11.
  • 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, Cys 30 and Cys18 in SEQ ID NO: 10 or SEQ ID NO: 11, Cys13 and
  • 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 and Cys 36 and Cys 38 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.
  • 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: 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 s 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 invention features a conjugate described by formula (4):
  • each A 1 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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 ;
  • 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.
  • the invention features a conjugate described by formula (4):
  • each A 1 is independently selected from any one of formulas (A-I)-(A-V):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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 ;
  • 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.
  • the invention features a conjugate described by formula (4):
  • each A 1 is independently selected from any one of formulas (A-VI)-(A-IX):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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 ;
  • 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.
  • each E includes an Fc domain monomer having the sequence of any one of SEQ ID Nos: 1-68.
  • each E comprises the sequence
  • each E comprises the sequence
  • At least one of the 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 sulfur atoms is the sulfur atom corresponding to (e.g., the sulfur atom of) Cys10 in SEQ ID NO: 4 or SEQ ID NO: 33.
  • 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 invention features a population of conjugates, wherein the average value of T is 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20). In some embodiments, the average value of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the invention features a conjugate described by formula (3):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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 ;
  • 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
  • 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 (3):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-I)-(A-V):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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 ;
  • 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
  • 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 (3):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-VI)-(A-IX):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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 ;
  • 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
  • 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 (4):
  • each A 1 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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 ;
  • 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
  • the invention features, a conjugate described by formula (4):
  • each A 1 is independently selected from any one of formulas (A-I)-(A-V):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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 ;
  • 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
  • the invention features, a conjugate described by formula (4):
  • each A 1 is independently selected from any one of formulas (A-VI)-(A-IX):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises 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: 1-68);
  • 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;
  • 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
  • the invention features a conjugate described by formula (5):
  • each Int is independently selected from anyone of the intermediates of Table 1;
  • E comprises an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer having, independently, the sequence of any one of SEQ ID NOs: 1-68);
  • L in each L-Int is a linker covalently attached to a nitrogen atom of a surface exposed lysine in E and to Int;
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), the squiggly line connected to E indicates that each L-Int is covalently attached (e.g., by way of a covalent bond or a linker) to 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.
  • T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7,
  • the conjugate (e.g., a conjugate described by formula (5)) comprises E, wherein E is an Fc domain monomer or an Fc domain (e.g., an Fc domain monomer or an Fc domain, each Fc domain monomer having, independently, the sequence of any one of SEQ ID NOs: 1-68).
  • 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 1).
  • E is conjugated to a linker functionalized with an azido group and the Int (e.g., an Int of Table 1) 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 1) is functionalized with an azido group.
  • Conjugation (e.g., by click chemistry) of the linker-alkyne of E and linker-azido of the Int forms a conjugate of the invention, for example a conjugate described by formula (5).
  • each E includes an Fc domain monomer having the sequence of any one of SEQ ID Nos: 1-68.
  • E includes the sequence
  • each E includes the sequence
  • E includes the sequence
  • each E comprises the sequence
  • 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 invention features a population of conjugates described in any of the previous aspects, wherein the average value of T is 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20). In some embodiments, the average value of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • 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 formula (3):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 69-71), 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 ;
  • 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),
  • 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 (3):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-I)-(A-V):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 69-71), 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 ;
  • 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),
  • 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 (3):
  • each A 1 and each A 2 is independently selected from any one of formulas (A-VI)-(A-IX):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 69-71), 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 ;
  • 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),
  • 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 (4):
  • each A 1 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 69-71), 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 ;
  • 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
  • the invention features a conjugate described by formula (4):
  • each A 1 is independently selected from any one of formulas (A-I)-(A-V):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 69-71), 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 ;
  • 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
  • the invention features a conjugate described by formula (4):
  • each A 1 is independently selected from any one of formulas (A-VI)-(A-IX):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl;
  • E comprises an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 69-71), 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 ;
  • 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
  • the invention features a conjugate described by formula (5):
  • each Int is independently selected from anyone of the intermediates of Table 1;
  • E comprises an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 69-71), an albumin protein-binding peptide, or an Fc-binding peptide;
  • L in each L-Int 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 Int;
  • T is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and the squiggly line connected to E indicates that each L-Int 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.
  • T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8,
  • the conjugate (e.g., a conjugate described by formula (5)) comprises E, wherein E is an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 69-71), an albumin protein-binding peptide, or an Fc-binding peptide.
  • E is an albumin protein (e.g., an albumin protein having the sequence of any one of SEQ ID NOs: 69-71), an albumin protein-binding peptide, or an Fc-binding peptide.
  • 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 1).
  • E is conjugated to a linker functionalized with an azido group and the Int (e.g., an Int of Table 1) 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 1) is functionalized with an azido group.
  • Conjugation (e.g., by click chemistry) of the linker-alkyne of E and linker-azido of the Int forms a conjugate of the invention, for example a conjugate described by formula (5).
  • each E includes an albumin protein having the sequence of any one of SEQ ID NOs: 69-71.
  • T is 1 and L-A is covalently attached to the sulfur atom corresponding to Cys34 of SEQ ID NO: 69.
  • the invention features a population of conjugates described in any of the previous aspects, wherein the average value of T is 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20). In some embodiments, the average value of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • 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):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl, or a pharmaceutically acceptable salt thereof.
  • 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-V):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl, or a pharmaceutically acceptable salt thereof.
  • 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-VI)-(A-IX):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl, or a pharmaceutically acceptable salt thereof.
  • 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 Intis independently selected from anyone of the intermediates of Table 1.
  • 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):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl, or a pharmaceutically acceptable salt thereof.
  • 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
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl, or a pharmaceutically acceptable salt thereof.
  • 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-VI)-(A-IX):
  • 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;
  • R 4 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 8 is selected from C3-C20 heterocycloalkyl, C5-C15 aryl, and C2-C15 heteroaryl, or a pharmaceutically acceptable salt thereof.
  • 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):
  • 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;
  • R 4 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
  • 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-I)-(A-V):
  • 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;
  • R 4 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
  • 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):
  • 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;
  • R 4 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
  • 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.
  • 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 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-IV-1):
  • 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-V-1):
  • 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-X-1):
  • 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, NR i , P, carbonyl, thiocarbonyl, O, S, NR i , P, carbon
  • the backbone of L or L′ consists of one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thi
  • 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-I):
  • L A is described by formula G A1 -(Z A1 ) g1 -(Y A1 ) h1 -(Z A2 ) i1 -(Y A2 ) j1 -(Z A3 ) k1 -(Y A3 ) l1 -(Z A4 ) m1 -(Y A4 ) n1 -(Z A5 ) o1 -G A2 ;
  • 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 ) i2 -(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 CF 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-X)).
  • a polyethlylene 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-X)).
  • a polyethylene glycol linker may covalently joining a neuraminidase inhibitor dimer and E (e.g., in a conjugate of any one of formulas (D-I)-(D-X)).
  • a polyethylene glycol linker may 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):
  • 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;
  • R 4 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
  • 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):
  • 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;
  • R 4 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
  • 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):
  • 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;
  • R 4 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
  • 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.
  • 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
  • y1 is an integer from 1-20 (e.g., y1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), or a pharmaceutically acceptable salt thereof.
  • 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-IV-1):
  • 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-X-1):
  • 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, NR i , P, carbonyl, thiocarbonyl, O, S, NR i , P, carbon
  • the backbone of L or L′ consists of one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15 heteroarylene, O, S, NR i , P, carbonyl, thi
  • 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-X)).
  • a polyethlylene 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-X)).
  • 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-X)).
  • a polyethylene glycol linker may 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.
  • n 2
  • each E is an Fc domain monomer
  • each E dimerizes to form an Fc domain
  • the conjugate is described by formula (M-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.
  • E has the sequence of any one of SEQ ID NOs: 1-68.
  • 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: 69-71.
  • 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-X), (D′-I), (M-I)-(M-X), or (M′-I)), wherein the average value of T is 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, or 15 to 20). In some embodiments, the average value of T is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • 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):
  • 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):
  • 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), Of (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):
  • each A 2 is independently selected from any one of formulas (A-I), (A-II), (A-VI), (A-VII), (A-VIII), and (A-IX):
  • 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;
  • R 4 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
  • 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):

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ECSP21023859A (es) 2021-06-30
MX2021002569A (es) 2021-06-08
PH12021550822A1 (en) 2021-10-04
EP3846846A4 (de) 2022-08-03
MA53558A (fr) 2021-09-15
AU2023278077A1 (en) 2024-01-18
WO2020051498A1 (en) 2020-03-12
TW202104176A (zh) 2021-02-01
CN113194983A (zh) 2021-07-30
JP2021536483A (ja) 2021-12-27
CA3111803A1 (en) 2020-03-12
CR20210166A (es) 2021-07-27
IL281277A (en) 2021-04-29
SG11202103313RA (en) 2021-04-29
US20240156975A1 (en) 2024-05-16
AU2019336230A1 (en) 2021-04-15
US11833213B2 (en) 2023-12-05
BR112021004266A2 (pt) 2021-08-03
US20220257787A1 (en) 2022-08-18
KR20210079278A (ko) 2021-06-29
EP3846846A1 (de) 2021-07-14

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