CCR5 conjugates and uses thereof

Abstract

The disclosure provides conjugates including a polypeptide, Fc domain monomer, or Fc domain that binds to or inhibits PD-1 that is further covalently linked to a moiety that binds to or inhibits CCR5. The disclosure additionally provides conjugates including an albumin protein that is further covalently linked to a moiety that binds to or inhibits CCR5. The disclosure also provides pharmaceutical compositions including such conjugates and uses of such conjugates in the treatment of disorders that result from the dysregulation of CCR5, PD-L1, or PD-1.

Description

[0001] CCR5 CONJUGATES AND USES THEREOF

[0002] Background

[0003] C-C Chemokine Receptor 5 (CCR5) has been linked to various diseases and plays an important role in cancer, particularly tumor infiltration and metastasis. Increased CCR5 expression is an indicator of disease status in some cancers. Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of invasive breast and prostate cancer. Further, CCR5 also plays a crucial role in HIV-1 , graft-versus-host disease, and rheumatoid arthritis. There are various compounds that inhibit CCR5, but inhibition of CCR5 signaling can have an immunosuppressive effect. Accordingly, there is a need for novel inhibitors and methods of use for the CCR5 receptor with reduced intended side effects.

[0004] Summary

[0005] This disclosure relates to conjugates that bind to or inhibit CCR5 and optionally PD-1 . This disclosure also provides pharmaceutical compositions including such conjugates and uses of such conjugates in the treatment of disorders associated with dysregulation or overexpression of CCR5, PD- L1 , or PD-1 (e.g., cancer, HIV, graft-versus-host disease, and rheumatoid arthritis).

[0006] In an aspect, the disclosure features a conjugate, or a pharmaceutically acceptable salt thereof, described by formula (D-l) or (M-l): wherein each of A1and A2, independently, has the structure of formula (A-l) or (A-ll):

[0007] R1is H or phenyl optionally substituted with one or two fluorines;

[0008] R2is H or phenyl optionally substituted with one or two fluorines; wherein when R1is H, then R2is phenyl optionally substituted with one or two fluorines and when R1is phenyl optionally substituted with one or two fluorines, then R2is H;

[0009] R3is CF3, C3-C5carbocycle, C3-C4heteroaryl, or C1-C3alkyl optionally substituted with 1 to 2 oxygen atoms;

[0010] R4is C1-C3alkyl optionally substituted with -CO2H or C3-C5carbocycle optionally substituted with an O-benzyl group or a six-membered heterocycle substituted with one acetyl that forms a spirocycle with the carbocycle; X1is C3-C6heteroalkyl, C3heteroaryl, C3-C6heterocycle optionally substituted with sulfonyl or Ci acyl, or C3-C5carbocycle optionally substituted with 1 to 2 fluorines, trifluoromethyl, 1 to 2 methyl groups, or a six-membered heterocycle substituted with one methyl, that forms a spirocycle with the carbocycle, or C1-C3alkyl optionally substituted with 1 to 2 oxygen atoms;

[0011] X2is N or X2is C and X2and R4together, with the atoms to which each is attached, join to form a 5- to 7-membered aromatic or non-aromatic carbocycle or heterocycle that is optionally substituted with -C(O)OCH3;

[0012] Y is a first linker covalently attached to L or absent;

[0013] L is a second linker; n is 1 or 2; each E is a polypeptide including an Fc domain monomer or an albumin protein;

[0014] T is an integer from 1 to 20; and the squiggly line indicates that L is covalently attached to E.

[0015] In an aspect, the disclosure features a conjugate, or a pharmaceutically acceptable salt thereof, described by formula (D-l I) or (M-l I): wherein each of B1and B2, independently, has the structure of formula (B-l) or (B-l I):

[0016] R1is H or phenyl optionally substituted with one or two fluorines;

[0017] R2is H or phenyl optionally substituted with one or two fluorines;

[0018] R3is C1-C3alkyl or CF3; wherein when R1is H, then R2is phenyl optionally substituted with one or two fluorines and when R1is phenyl optionally substituted with one or two fluorines, then R2is H;

[0019] X1is C3-C6heteroalkyl, C3heteroaryl, C3-C6heterocycle optionally substituted with sulfonyl or Ci acyl, or C3-C5carbocycle optionally substituted with 1 to 2 fluorines, trifluoromethyl, 1 to 2 methyls, or a six-membered heterocycle substituted with one methyl that forms a spirocycle with the carbocycle, or C1- C3alkyl optionally substituted with 1 to 2 oxygen atoms;

[0020] Ring A is a 5- to 7-membered aromatic or non-aromatic carbocycle or heterocycle;

[0021] Y is a first linker covalently attached to L or absent;

[0022] L is a second linker; n is 1 or 2; each E is a polypeptide including an Fc domain monomer or an albumin protein; T is an integer from 1 to 20; and the squiggly line indicates that L is covalently attached to E.

[0023] In an aspect, the disclosure features conjugate, or a pharmaceutically acceptable salt thereof, described by formula (D-lll) or (M-lll): wherein each of C1and C2, independently, has the structure of formula (C):

[0024] R1is H or phenyl optionally substituted with one or two fluorines;

[0025] R2is H or phenyl optionally substituted with one or two fluorines; wherein when R1is H, then R2is phenyl optionally substituted with one or two fluorines and when R1is phenyl optionally substituted with one or two fluorines, then R2is H;

[0026] R3is CF3, C3-C5carbocycle, C3-C4heteroaryl, or C1-C3alkyl optionally substituted with 1 to 2 oxygen atoms;

[0027] X1is C3-C6heteroalkyl, C3 heteroaryl, C3-C6heterocycle optionally substituted with sulfonyl or Ci acyl, or C3-C5carbocycle optionally substituted with 1 or 2 fluorines, trifluoromethyl, 1 or 2 methyls, or a six-membered heterocycle substituted with one methyl that forms a spirocycle with the carbocycle, or C1- C3alkyl optionally substituted with 1 to 2 oxygen atoms;

[0028] Y is a first linker covalently attached to L or absent;

[0029] L is a second linker; n is 1 or 2; each E is a polypeptide including an Fc domain monomer or an albumin protein;

[0030] T is an integer from 1 to 20; and the squiggly line indicates that L is covalently attached to E.

[0031] In some embodiments, the conjugate, or a pharmaceutically acceptable salt thereof, is described by formula (D-l): In some embodiments, the conjugate, or a pharmaceutically acceptable salt thereof, conjugate is described by formula (M-l):

[0032] In some embodiments, the conjugate, or a pharmaceutically acceptable salt thereof, conjugate is described by formula (D-l I):

[0033] In some embodiments, the conjugate, or a pharmaceutically acceptable salt thereof, conjugate is described by formula (M-ll):

[0034] In some embodiments, the conjugate, or a pharmaceutically acceptable salt thereof, conjugate is described by formula (D-lll):

[0035] In some embodiments, the conjugate, or a pharmaceutically acceptable salt thereof, conjugate is described by formula (M-lll): In some embodiments, A1and A2have the structure of formula (A-la):

[0036] In some embodiments, A1and A2have the structure of formula (A-lb):

[0037] In some embodiments, A1and A2have the structure of formula (A-lc):

[0038] In some embodiments, A1and A2have the structure of formula (A-ld):

[0039] In some embodiments, A1and A2have the structure of formula (A-e):

[0040] In some embodiments, A1and A2have the structure of formula (A-lf): In some embodiments, A1and A2have the structure of formula (A-lg):

[0041] In some embodiments, A1and A2have the structure of formula (A-lh):

[0042] In some embodiments, A1and A2have the structure of formula (A-lla):

[0043] In some embodiments, A1and A2have the structure of formula (A-llb):

[0044] In some embodiments, B1and B2have the structure of formula (B-la):

[0045] In some embodiments, B1and B2have the structure of formula (B-lb): In some embodiments, B1and B2have the structure of formula (B-lc):

[0046] In some embodiments, B1and B2have the structure of formula (B-ld):

[0047] In some embodiments, B1and B2have the structure of formula (B-lla):

[0048] In some embodiments, C1and C2have the structure of formula (C-la):

[0049] In some embodiments, C1and C2have the structure of formula (C-lb):

[0050] In some embodiments, C1and C2have the structure of formula (C-lc): In some embodiments, C1and C2have the structure of formula (C-ld):

[0051] In some embodiments of any of the foregoing aspects, the tropane is in exo form:

[0052] In some embodiments, the tropane is in endo form:

[0053] In some embodiments of the foregoing aspects, R3is isopropyl.

[0054] In some embodiments, R3is methyl.

[0055] In some embodiments, R3is ethyl.

[0056] In some embodiments of the foregoing aspects, R4is methyl.

[0057] In some embodiments of the foregoing aspects, X1is methyl, ethyl, isopropyl, In some embodiments of the foregoing aspects, Y is: m is 1 , 2, 3, 4, or 5; p is 1 or 2; and r is 1 or 2.

[0058] In some embodiments of any of the foregoing aspects, L includes one or more optionally substituted C1-C40alkylene, optionally substituted C1-C40heteroalkylene, optionally substituted C1-C40alkoxylene, optionally substituted C3-C20cycloalkylene, optionally substituted C2-C20heterocycloalkylene, optionally substituted C5-C15arylene, optionally substituted C2-C15heteroarylene, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino, wherein R' is H, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C3-C20cycloalkyl, optionally substituted C2-C20heterocycloalkyl, optionally substituted C5-C15aryl, or optionally substituted C2-C15heteroaryl.

[0059] In some embodiments, L is oxo substituted.

[0060] In some embodiments, the backbone of L includes between 1 and 250 atoms.

[0061] In some embodiments, L is capable of forming an amide, a carbamate, a sulfonyl, or a urea linkage.

[0062] In some embodiments, L is described by the formula: wherein J1is a bond attached to Y;

[0063] J2is a bond attached to E or is a functional group capable of reacting with a functional group conjugated to E; each of Q1, Q2, Q3, Q4, and Q5is, independently, optionally substituted C1-C40alkylene, optionally substituted C1-C40heteroalkylene, optionally substituted C1-C40alkoxylene, optionally substituted C3-C20cycloalkylene, optionally substituted C2-C20heterocycloalkylene, optionally substituted C5-C15arylene, or optionally substituted C2-C15heteroarylene; each of T1, T2, T3, T4is, independently, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, imino, or oximo;

[0064] R' is H, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C3-C20cycloalkyl, optionally substituted C2-C20heterocycloalkyl, optionally substituted C5-C15aryl, or optionally substituted C2-C15heteroaryl; and each of g, h, i, j, k, I, m, n, and 0 is, independently, 0, 1 , or 2.

[0065] In some embodiments, Q1is

[0066] , optionally substituted C1-C40heteroalkylene, or optionally substituted C 3-C20cycloalkylene.

[0067] In some embodiments, Q2is optionally substituted C3-C20cycloalkyl, optionally substituted C1-C40alkylene, optionally substituted C1-C40heteroalkylene, optionally substituted C1-C40alkoxylene, or optionally substituted C2-C15heteroarylene. In some embodiments, Q3is optionally substituted C2-C15heteroarylene or optionally substituted C1-C40heteroalkylene.

[0068] In some embodiments, Q4is optionally substituted C1-C40alkylene, optionally substituted C1-C40heteroalkylene, optionally substituted C1-C40alkoxylene, or optionally substituted C2-C15heteroarylene.

[0069] In some embodiments, a conjugate, or a pharmaceutically acceptable salt thereof, is described by a formula of Table 2.

[0070] In some embodiments of any of the foregoing aspects, the squiggly line connected to E indicates that the L of each A1-L or each A1-L-A2is covalently attached to a nitrogen atom of a solvent-exposed lysine of E. In some embodiments, the squiggly line connected to E indicates that the L of each A1-L or each A1-L-A2is covalently attached to the sulfur atom of a solvent-exposed cysteine of E.

[0071] In some embodiments, the squiggly line connected to E indicates that the L of each B1-L or each B1-L-B2is covalently attached to a nitrogen atom of a solvent-exposed lysine of E. In some embodiments, the squiggly line connected to E indicates that the L of each B1-L or each B1-L-B2is covalently attached to the sulfur atom of a solvent-exposed cysteine of E.

[0072] In some embodiments, the squiggly line connected to E indicates that the L of each C1-L or each C1-L-C2is covalently attached to a nitrogen atom of a solvent-exposed lysine of E. In some embodiments, the squiggly line connected to E indicates that the L of each C1-L or each C1-L-C2is covalently attached to the sulfur atom of a solvent-exposed cysteine of E.

[0073] In some embodiments of any of the foregoing aspects, each E is an albumin protein (e.g., human serum albumin or bovine serum albumin). In some embodiments, each E includes an amino acid sequence having at least 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 273-276.

[0074] In some embodiments of any of the foregoing aspects, n is 2, and each E dimerizes to form an Fc domain.

[0075] In some embodiments of any of the foregoing aspects, each E is a polypeptide that includes a human IgG 1 Fc domain monomer. In some embodiments, each E includes a substitution mutation at N297 selected from N297A, N297G, or N297Q, wherein the amino acid numbering of each Fc domain monomer is according to the Kabat EU index. In some embodiments, each E includes a C220S substitution mutation, wherein the amino acid numbering of each Fc domain monomer is according to the Kabat EU index. In some embodiments, each E includes a M252Y, a S254T, and a T256E substitution mutation, wherein the amino acid numbering of each Fc domain monomer is according to the Kabat EU index.

[0076] In some embodiments, each E includes an amino acid sequence having at least 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 1-120 and 283. In some embodiments, each E includes the amino acid sequence of any one of SEQ ID NOs: 1-120 and 283.

[0077] In some embodiments, each E includes an amino acid sequence having at least 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, or SEQ ID NO: 18. In some embodiments, each E includes the amino acid sequence of any one of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, or SEQ ID NO: 18. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 13. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 14. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 17. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 18.

[0078] In some embodiments, each E includes an amino acid sequence having at least 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NO: 80, SEQ ID NO: 81 , SEQ ID NO: 82, or SEQ ID NO: 83. In some embodiments, each E includes the amino acid sequence of any one of SEQ ID NO: 80, SEQ ID NO: 81 , SEQ ID NO: 82, or SEQ ID NO: 83. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 80. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 81 . In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 82. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 83.

[0079] In some embodiments, each E includes an amino acid sequence having at least 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 113. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 113. In some embodiments, each E includes an amino acid sequence having at least 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 114. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 114. In some embodiments, each E includes an amino acid sequence having at least 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 115. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 115. In some embodiments, each E includes an amino acid sequence having at least 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 116. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 116. In some embodiments, each E includes an amino acid sequence having at least 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 117. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 117. In some embodiments, each E includes an amino acid sequence having at least 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 118. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 118. In some embodiments, each E includes an amino acid sequence having at least 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 283. In some embodiments, each E includes the amino acid sequence of SEQ ID NO: 283.

[0080] In some embodiments, the polypeptide of each E includes the structure, from N-terminal to C- terminal: VL-KI-VH-K2-G or VH-KI-VL-K2-G, wherein VL is an anti-PD-1 light chain variable region; VH is an anti-PD-1 heavy chain variable region; G is an Fc domain monomer of each E; and Ki and K2, are each, independently, a peptide linker.

[0081] In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 121 , 124, and 125; and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 126, 129, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 130, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 131 , and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 132, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 133, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 134, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 135, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs:

[0082] 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 136, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 130, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 131 , and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 132, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 133, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs:

[0083] 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 134, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 135, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 127, 136, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 130, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 131 , and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs:

[0084] 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 132, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 133, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 134, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 135, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 136, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs:

[0085] 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 130, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 131 , and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 132, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 133, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 134, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 135, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 128, 136, and 137. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 138, 139, and 140 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 141 , 142, and 143. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 122, 144, and 145 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 146, 147, and 148. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 149, 150, and 151 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 152, 153, and 154. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 155, 156, and 157 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 158, 159, and 160. In some embodiments, VL includes an LCDR1 , LCDR2, and LCDR3 with the sequences set forth in SEQ ID NOs: 161 , 162, and 163 and VH includes an HCDR1 , HCDR2, and HCDR3 with the sequences set forth in SEQ ID NOs: 164, 165, and 166.

[0086] In some embodiments, VL includes a sequence set forth in SEQ ID NO: 167 and VH includes a sequence set forth in SEQ ID NO: 176. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 168 and VH includes a sequence set forth in SEQ ID NO: 177. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 168 and VH includes a sequence set forth in SEQ ID NO: 178. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 168 and VH includes a sequence set forth in SEQ ID NO: 179. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 180. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 170 and VH includes a sequence set forth in SEQ ID NO: 180. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 171 and VH includes a sequence set forth in SEQ ID NO: 180. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 172 and VH includes a sequence set forth in SEQ ID NO: 180. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 173 and VH includes a sequence set forth in SEQ ID NO: 180. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 181 . In some embodiments, VL includes a sequence set forth in SEQ ID NO: 170 and VH includes a sequence set forth in SEQ ID NO: 181 . In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 182. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 183. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 184. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 185. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 186. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 187. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 188. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 189. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 174 and VH includes a sequence set forth in SEQ ID NO: 190. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 191 . In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 192. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 193. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 194. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 195. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 196. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 197. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 198. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 199. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 200. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 201 . In some embodiments, VL includes a sequence set forth in SEQ ID NO: 175 and VH includes a sequence set forth in SEQ ID NO: 180. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 202. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 203. In some embodiments, VL includes a sequence set forth in SEQ ID NO: 169 and VH includes a sequence set forth in SEQ ID NO: 204.

[0087] In some embodiments, Ki and K2 are each, independently, a peptide linker including between 1 and 200 amino acids or a bond.

[0088] In some embodiments, Ki and K2 are each, independently, a peptide linker including between 5 and 25 amino acids.

[0089] In some embodiments, Ki and K2 are each an independently selected peptide linker including the amino acid sequence of any one of (GS)x, (GGS)x, (GGGGS)x, (GGSG)x, (SGGG)x, or (GGGGS)xGGG, wherein x is an integer from 1 to 10.

[0090] In some embodiments, the Fc domain monomer is an IgG 1 Fc domain monomer.

[0091] In some embodiments, the Fc domain monomer includes the amino acid sequence of any one of SEQ ID NOs: 1-120 and 283.

[0092] In some embodiments, the Fc domain monomer includes the amino acid sequence of any one of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, or SEQ ID NO: 18.

[0093] In some embodiments, the Fc domain monomer includes the amino acid sequence of any one of SEQ ID NO: 80, SEQ ID NO: 81 , SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 118, or SEQ ID NO: 283.

[0094] In some embodiments, the polypeptide includes the amino acid sequence of any one of SEQ ID Nos: 205-272 and 284. In some embodiments, the Fc domain monomer includes the amino acid sequence of any one of SEQ ID NO: 271 or SEQ ID NO: 284.

[0095] In an aspect, a dimer featuring: a first polypeptide described by a foregoing aspect and a second polypeptide described by a foregoing aspect, wherein the Fc domain monomer of the first polypeptide and the Fc domain monomer of the second polypeptide dimerize to form an Fc domain.

[0096] In some embodiments, the first polypeptide and the second polypeptide have the same amino acid sequence and the dimer is a homodimer.

[0097] In an aspect, a pharmaceutical composition featuring the polypeptide of a foregoing aspect or the dimer of a foregoing aspect and a pharmaceutically acceptable carrier. The disclosure features an intermediate (I nt), or a pharmaceutically acceptable salt thereof, of Table 1 . These intermediates include one or more inhibitors of CCR5 and a linker and may be used in the synthesis of a conjugate described herein. In some embodiments, the intermediates of Table 1 may be conjugated to, for example, a polypeptide that contains an Fc domain monomer (e.g., by way of a linker) by any suitable methods known to those of skill in the art, including any of the methods described or exemplified herein. In some embodiments, the intermediates of Table 1 may be conjugated to, for example, an albumin protein (e.g., by way of a linker) by any suitable methods known to those of skill in the art, including any of the methods described or exemplified herein. In some embodiments, the conjugate includes E, wherein E is a polypeptide that includes Fc domain monomer, an Fc domain, or albumin protein. In preferred embodiments, one or more nitrogen atoms of one or more surface exposed lysine residues of E or one or more sulfur atoms of one or more surface exposed cysteines in E is covalently conjugated to a linker (e.g., a PEG2-PEG20linker). 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). In preferred embodiments, 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 disclosure. In yet other embodiments, 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 the linker-azido of the Int forms a conjugate of the disclosure. In yet other embodiments, the Int (e.g., an Int of Table 2) is functionalized with a phenyl ester group (e.g., a trifluorophenyl ester group or a tetrafluorophenyl ester group). Conjugation (e.g., by acylation) of E and the linker-phenyl ester (e.g., trifluorophenyl ester or tetrafluorophenyl ester) of the Int forms a conjugate of the invention. Conjugation (e.g., by acylation) of E and the linker-phenyl ester (e.g., trifluorophenyl ester or tetrafluorophenyl ester) of the Int is conducted by methods described herein or known in the art.

[0098] The disclosure further features a composition (e.g., a pre-conjugation intermediate) having the structure of an Int, or a pharmaceutically acceptable salt thereof, of Table 1 .

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106] The disclosure also features a conjugate, or a pharmaceutically acceptable salt thereof, of Table 2. Each conjugate of Table 2 corresponds to a conjugate of formula (D-l), (D-l I), (D-lll), (M-l), (M-l I), or (M-lll). Conjugates of Table 2 include conjugates formed by the covalent reaction of an Int of Table 1 with E. Conjugates of Table 2 further include conjugates formed by the covalent reaction of an Int of Table 1 with a linker which is in turn conjugated to E. In some embodiments, the reactive moiety of the Int (e.g., the alkyne or azido group) reacts with a corresponding reactive group (e.g., an alkyne or azido group) of a linker covalently attached to E, such that an Int of Table 1 is covalently attached to E. In some embodiments, the reactive moiety of the Int (e.g., the phenyl ester group, e.g., tetrafluorophenyl ester or trifluorophenyl ester group) reacts with a corresponding reactive group (e.g., nitrogen or sulfur atom) of an amino acid side chain of E, such that an Int of Table 1 is covalently attached to E.

[0107] In some embodiments in any conjugate of Table 2, n is 1 or 2. When n is 1 , E is polypeptide including an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-120 and 283). When n is 2, each E is polypeptide including an Fc domain monomer (e.g., an Fc domain monomer having the sequence of any one of SEQ ID NOs: 1-120 and 283), and the Fc domain monomers dimerize to form an Fc domain.

[0108] In some embodiments, when n is 1 , E is polypeptide having the sequence of any one of SEQ ID NOs: 205-272 and 284. When n is 2, each E is polypeptide having the sequence of any one of SEQ ID NOs: 205-272 and 284, and the Fc domain monomers of the polypeptides dimerize to form an Fc domain.

[0109] In some embodiments, when n is 1 , E is an albumin protein having the sequence of any one of SEQ ID NOs: 273-276.

[0110] In some embodiments in any conjugate of Table 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). The disclosure also provides a population of any of the conjugates of Table 2 wherein the average value of T is 1 to 20 (e.g., the average value of T is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 5 to 10, 10 to 15, 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.

[0111] The squiggly line in the conjugates of Table 2 indicates that each Int is covalently attached to an amino acid side chain in E (e.g., the nitrogen atom of a surface exposed lysine or the sulfur atom of a surface exposed cysteine in E), or a pharmaceutically acceptable salt thereof.

[0112] The disclosure also provides a conjugate, or a pharmaceutically acceptable salt thereof, of Table 2, wherein the conjugate is produced by conjugation (e.g., via a linker) of an Int of Table 1 to a polypeptide, Fc domain, an Fc domain monomer, or an albumin protein.

[0113] Table 2. Conjugates corresponding to intermediates of Table 1

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122] The disclosure further features a method of making a conjugate by conjugating (e.g., via a linker) an Int of Table 1 to a polypeptide containing an Fc domain monomer or to an albumin protein. In some embodiments, the disclosure provides a conjugate, wherein the conjugate includes a small molecule targeting agent, wherein the targeting agent is described by an Int of Table 1 , which is conjugated to a polypeptide containing an Fc domain monomer (e.g., via a linker) or to an albumin protein (e.g., via a linker).

[0123] In another aspect the disclosure features a conjugate including a first polypeptide described herein and a second polypeptide described herein; wherein the Fc domain monomer of the first polypeptide and the Fc domain monomer of the second polypeptide dimerize to form an Fc domain. In some embodiments, the first polypeptide and the second polypeptide have the same amino acid sequence and the conjugate is a homodimer.

[0124] In some embodiments, n is 1 and T represents the number of Ai-L or A1-L-A2moieties bound to each E. In some embodiments, n is 2 and the two Es dimerize to form an Fc domain and T represents the number of A1-L or A1-L-A2moieties bound to the Fc domain. In some embodiments, T is an integer from 1 to 20 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20).

[0125] In some embodiments, n is 1 and T represents the number of B1-L or B1-L-B2moieties bound to each E. In some embodiments, n is 2 and the two Es dimerize to form an Fc domain and T represents the number of B1-L or B1-L-B2moieties bound to the Fc domain. In some embodiments, T is an integer from 1 to 20 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20).

[0126] In some embodiments, n is 1 and T represents the number of C1-L or C1-L-C2moieties bound to each E. In some embodiments, n is 2 and the two Es dimerize to form an Fc domain and T represents the number of C1-L or C1-L-C2moieties bound to the Fc domain. In some embodiments, T is an integer from 1 to 20 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20).

[0127] The disclosure also provides a population of conjugates described herein 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.

[0128] In another aspect, the disclosure provides a pharmaceutical composition including a conjugate or a population of conjugates, or a pharmaceutically acceptable salt thereof, described herein and a pharmaceutically acceptable excipient.

[0129] In another aspect, the disclosure provides a method of treating cancer in a subject, the method including administering to the subject a conjugate, population of conjugates, or pharmaceutical composition described herein.

[0130] In some embodiments, the cancer is selected from lung cancer, optionally non-small cell lung cancer or small-cell lung cancer; head and neck cancer, optionally squamous cell carcinoma; renal cell carcinoma; breast cancer; ovarian cancer; pancreatic cancer; colorectal cancer; urothelial cancer; bile duct cancer; endometrial cancer; melanoma; prostate cancer; glioma cancer; or esophageal cancer. In some embodiments, the cancer is PD-L1 negative. In some embodiments, the breast cancer has wildtype BRCA1 or wild-type BRCA2. In some embodiments, the breast cancer has a loss-of-function mutation in BRCA1 or BRCA2. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the triple negative breast cancer is PD-L1 negative. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer overexpresses or is known to overexpress CCR5, PD-1 , or PD-L-1 relative to a non-cancerous cell of the same tissue type.

[0131] In some embodiments, the method further includes administering to the subject a PARP inhibitor or an antibody drug conjugate. In some embodiments, the PARP inhibitor is olaparib or talazoparib. In some embodiments, the antibody drug conjugate is the antibody drug conjugate is Sacituzumab govitecan, Trastuzumab deruxtecan, Datopotamab deruxtecan, Enfortumab vedotin, Tisotumab vedotin, Ladiratumab vedotin, M9140, or ASN004.

[0132] In an aspect, the invention features a method of treating a PD-L1 negative cancer in a subject, the method comprising administering to the subject a conjugate of the disclosure, population of conjugates of the disclosure, or pharmaceutical composition of the disclosure and an antibody drug conjugate. In some embodiments, the PD-L1 negative cancer is triple negative breast cancer. In some embodiments, the PD-L1 negative, triple negative breast cancer has wild-type BRAC1 or wild-type BRCA2. In some embodiments, the antibody drug conjugate is the antibody drug conjugate is Sacituzumab govitecan, Trastuzumab deruxtecan, Datopotamab deruxtecan, Enfortumab vedotin, Tisotumab vedotin, Ladiratumab vedotin, M9140, or ASN004.

[0133] In an aspect, the invention features a method of treating breast cancer in a subject, the method comprising administering to the subject a conjugate of the disclosure, population of conjugates of the disclosure, or pharmaceutical composition of the disclosure and a PARP inhibitor. In some embodiments, the breast cancer is triple negative breast cancer, the breast cancer has a loss-of-function mutation in BRCA1 or BRAC2. In some embodiments, the PARP inhibitor is olaparib or talazoparib.

[0134] In another aspect, the disclosure provides a method of treating or preventing a viral infection in a subject, the method including administering to the subject a conjugate, population of conjugates, or a pharmaceutical composition of the invention.

[0135] In some embodiments, the viral infection is HIV-1 .

[0136] In another aspect, the disclosure provides a method of treating or preventing an inflammatory disorder in a subject, the method including administering to the subject a conjugate, population of conjugates, or a pharmaceutical composition of the invention.

[0137] In some embodiments, the inflammatory disorder is graft-versus-host disease or rheumatoid arthritis.

[0138] In some embodiments of any of the methods of treatment described herein, the conjugate, population of conjugates, or pharmaceutical composition is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically , intraocularally, orally, locally, by inhalation, by injection, or by infusion.

[0139] Definitions

[0140] To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a,” “an,” and “the” are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.

[0141] As used herein, the term “Fc domain monomer” refers to a polypeptide chain that includes at least a hinge domain and second and third antibody constant domains (CH2 and CH3) or functional fragments thereof (e.g., fragments that that capable of (i) dimerizing with another Fc domain monomer to form an Fc domain, and (ii) binding to an Fc receptor. The Fc domain monomer can be any immunoglobulin antibody isotype, including IgG, IgE, IgM, IgA, or IgD (e.g., IgG). Additionally, the Fc domain monomer can be an IgG subtype (e.g., lgG1 , lgG2a, lgG2b, lgG3, or lgG4) (e.g., lgG1). In some embodiments, an Fc domain monomer does not include any portion of an immunoglobulin that is capable of acting as an antigen-recognition region, e.g., a variable domain or a complementarity determining region (CDR). Fc domain monomers in the compositions as described herein can contain one or more changes from a wild-type Fc domain monomer sequence (e.g., 1-10, 1-8, 1-6, 1-4 amino acid substitutions, additions, or deletions) that alter the interaction between an Fc domain and an Fc receptor. Examples of suitable changes are known in the art. In certain embodiments, a human Fc domain monomer (e.g., an IgG heavy chain, such as lgG1) includes a region that extends from any of Asn208, Glu216, Asp221 , Lys222, or Cys226 to the carboxyl-terminus of the heavy chain at Lys447. C-terminal Lys447 of the Fc region may or may not be present, without affecting the structure or stability of the Fc region. C-terminal Lys 447 may be proteolytically cleaved upon expression of the polypeptide. In some embodiments of any of the Fc domain monomers described herein, C-terminal Lys 447 is optionally present or absent. The N-terminal N (e.g., Asn 201) of the Fc region may or may not be present, without affecting the structure of stability of the Fc region. N-terminal Asn may be deamidated upon expression of the polypeptide. In some embodiments of any of the Fc domain monomers described herein, N-terminal Asn is optionally present or absent. Unless otherwise specified herein, numbering of amino acid residues in the IgG or Fc domain monomer is according to the EU numbering system for antibodies, also called the Kabat EU index, as described, for example, in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0142] As used herein, the term “Fc domain” refers to a dimer of two Fc domain monomers that is capable of binding an Fc receptor. In the wild-type Fc domain, the two Fc domain monomers dimerize by the interaction between the two CH3 antibody constant domains, in some embodiments, one or more disulfide bonds form between the hinge domains of the two dimerizing Fc domain monomers.

[0143] The terms “Fab” or “fragment antigen-binding,” as used interchangeably herein, refer to a region on an antibody that binds to an antigen. Fab is a term of art and its meaning is known to those of skill in the art. A Fab region is composed of one constant and one variable domain of each of the heavy and light chain. Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region may be comprised of three domains, CH1 , CH2, or CH3. Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into regions of hypervariability, termed “complementarity determining regions” (CDRs), interspersed with regions that are more conserved, termed “framework regions” (FRs). In antibodies, the heavy chain (e.g., the VH and CH region) is linked to the Fc domain monomer by way of a hinge. The Fc domain monomers described herein may include between 10 or 20 residues (e.g., 11 , 12, 13, 14, 15, 16, 17, 18, or 19 residues) of the Fab domain and hinge region. In certain embodiments, the N-terminus of the Fc domain monomer is any one of amino acid residues 198-205 (corresponding to a residue of the Fab domain). In some embodiments, the N- terminus of the Fc domain monomer is amino acid residue 201 (e.g., Asn 201). In certain embodiments, the N-terminus of the Fc domain monomer is amino acid residue 202 (e.g., Vai 202).

[0144] As used herein, the terms “single-chain variable fragment” and “ScFv” refer to a polypeptide that includes variable regions of the heavy (VH) and light chains (VL) of immunoglobulins. The VH and VL regions are connected by a peptide linker.

[0145] The term “covalently attached” refers to two parts of a conjugate that are linked to each other by a covalent bond formed between two atoms in the two parts of the conjugate.

[0146] As used-herein, a “surface exposed amino acid” or “solvent-exposed amino acid,” such as a surface exposed cysteine or a surface exposed lysine refers to an amino acid that is accessible to the solvent surrounding the protein. A surface exposed amino acid may be a naturally occurring or an engineered variant (e.g., a substitution or insertion) of the protein. In some embodiments, a surface exposed amino acid is an amino acid that when substituted does not substantially change the three- dimensional structure of the protein.

[0147] The term “linker” as used herein, refer to a covalent linkage or connection between two or more components in a conjugate (e.g., between two CCR5 inhibitors in a conjugate described herein, between a CCR5 inhibitor and a polypeptide in a conjugate described herein, and between a dimer of two CCR5. inhibitors and a polypeptide in a conjugate described herein). In some embodiments, a conjugate described herein may contain a linker that has a bivalent structure (e.g., a bivalent linker). A bivalent linker has two arms, in which each arm is covalently linked to a component of the conjugate (e.g., a first arm conjugated to a CCR5 inhibitor and a second arm conjugated to a polypeptide). In some embodiments, a conjugate described herein may contain a linker that has a trivalent structure (e.g., a trivalent linker). A trivalent linker has three arms, in which each arm is covalently linked to a component of the conjugate (e.g., a first arm conjugated to a CCR5 inhibitor, a second arm conjugated to a second CCR5 inhibitor, and a third arm conjugated to a polypeptide). Linkers of the disclosure may be linear or branched.

[0148] In some embodiments, molecules that may be used as linkers include at least two functional groups, which may be the same or different, e.g., two carboxylic acid groups, two amine groups, two sulfonic acid groups, a carboxylic acid group and a maleimide group, a carboxylic acid group and an alkyne group, a carboxylic acid group and an amine group, a carboxylic acid group and a sulfonic acid group, an amine group and a maleimide group, an amine group and an alkyne group, or an amine group and a sulfonic acid group. The first functional group may form a covalent linkage with a first component in the conjugate and the second functional group may form a covalent linkage with the second component in the conjugate. In some embodiments of a trivalent linker, two arms of a linker may contain two dicarboxylic acids, in which the first carboxylic acid may form a covalent linkage with the first CCR5 inhibitor in the conjugate and the second carboxylic acid may form a covalent linkage with the second CCR5 inhibitor in the conjugate, and the third arm of the linker may form a covalent linkage with a polypeptide that contains an Fc domain monomer. Examples of dicarboxylic acids are described further herein. In some embodiments, a molecule containing one or more maleimide groups may be used as a linker, in which the maleimide group may form a carbon-sulfur linkage with a cysteine in a component (e.g., a polypeptide that contains an Fc domain) in the conjugate. In some embodiments, a molecule containing one or more alkyne groups may be used as a linker, in which the alkyne group may form a 1 ,2,3-triazole linkage with an azide in a component (e.g., a polypeptide that contains an Fc domain) in the conjugate. In some embodiments, a molecule containing one or more azide groups may be used as a linker, in which the azide group may form a 1 ,2,3-triazole linkage with an alkyne in a component (e.g., a polypeptide that contains an Fc domain) in the conjugate. In some embodiments, a molecule containing one or more bis-sulfone groups may be used as a linker, in which the bis-sulfone group may form a linkage with an amine group a component (e.g., a polypeptide that contains an Fc domain) in the conjugate. In some embodiments, a molecule containing one or more sulfonic acid groups may be used as a linker, in which the sulfonic acid group may form a sulfonamide linkage with a component in the conjugate. In some embodiments, a molecule containing one or more isocyanate groups may be used as a linker, in which the isocyanate group may form a urea linkage with a component in the conjugate. In some embodiments, a molecule containing one or more haloalkyl groups may be used as a linker, in which the haloalkyl group may form a covalent linkage, e.g., C-N and C-0 linkages, with a component in the conjugate. In some embodiments, a molecule containing one or more phenyl ester groups (e.g., trifluorophenyl ester groups or tetrafluorophenyl ester groups) may be used as a linker, in which the phenyl ester group (e.g., trifluorophenyl ester group or tetrafluorophenyl ester group) may form an amide with an amine in a component (e.g., a fusion protein) in the conjugate.

[0149] In some embodiments, a linker provides space, rigidity, or flexibility between the two or more components. In some embodiments, a linker may be a bond, e.g., a covalent bond. The term “bond” refers to a chemical bond, e.g., an amide bond, a disulfide bond, a C-O bond, a C-N bond, a N-N bond, a C-S bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation. In some embodiments, a linker includes no more than 250 atoms. In some embodiments, a linker includes no more than 250 non-hydrogen atoms. In some embodiments, the backbone of a linker includes no more than 250 atoms. The “backbone” of a linker refers to the atoms in the linker that together form the shortest path from one part of a conjugate to another part of the conjugate (e.g., the shortest path linking a first CCR5 inhibitor and a second CCR5 inhibitor). The atoms in the backbone of the linker are directly involved in linking one part of a conjugate to another part of the conjugate (e.g., linking a first CCR5 inhibitor and a second CCR5 inhibitor). For example, hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the conjugate to another part of the conjugate.

[0150] In some embodiments, a linker may include a synthetic group derived from, e.g., a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer). In some embodiments, a linker may include one or more amino acid residues, such as D- or L-amino acid residues. In some embodiments, a linker may be a residue of an amino acid sequence (e.g., a 1-25 amino acid, 1-10 amino acid, 1-9 amino acid, 1-8 amino acid, 1-7 amino acid, 1-6 amino acid, 1-5 amino acid, 1-4 amino acid, 1-3 amino acid, 1-2 amino acid, or 1 amino acid sequence). In some embodiments, a linker may include one or more, e.g., 1 -100, 1-50, 1- 25, 1-10, 1-5, or 1-3, optionally substituted alkylene, optionally substituted heteroalkylene (e.g., a PEG unit), optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, optionally substituted heteroarylene (e.g., pyridine), O, S, NR' (R' is H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino. For example, a linker may include one or more optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene (e.g., a PEG unit), optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C2-C20heterocycloalkylene, optionally substituted C5-C15 arylene (e.g., C6 arylene), optionally substituted C2-C15 heteroarylene (e.g., imidazole, pyridine), O, S, NR' (R' is H, optionally substituted C1- C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C2-C20heterocycloalkyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino.

[0151] The terms “alkyl,” “alkenyl,” and “alky ny I,” as used herein, include straight-chain and branched- chain monovalent substituents, as well as combinations of these, containing only C and H when unsubstituted. When the alkyl group includes at least one carbon-carbon double bond or carbon-carbon triple bond, the alkyl group can be referred to as an “alkenyl” or “alkynyl” group respectively. The monovalency of an alkyl, alkenyl, or alkynyl group does not include the optional substituents on the alkyl, alkenyl, or alkynyl group. For example, if an alkyl, alkenyl, or alkynyl group is attached to a compound, monovalency of the alkyl, alkenyl, or alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl, alkenyl, or alkynyl group. In some embodiments, the alkyl or heteroalkyl group may contain, e.g., 1-20. 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1- 6, 1-4, or 1-2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, the alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-propenyl, and 3-butynyl. A heterocycloalkyl group refers to a cycloalkyl group that has one or more heteroatoms independently selected from, e.g., N, O, and S. Exemplary heterocycloalkyl groups include pyrrolidine, thiolane, tetrahydrofuran, piperidine, and tetra hydro pyran.

[0152] The term “cycloalkyl,” as used herein, represents a monovalent unsaturated non-aromatic cyclic alkyl group. A cycloalkyl may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C11 , C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkyl” also includes a cyclic compound having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1 Jheptyl and adamantane. The term “cycloalkyl” also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spiro cyclic compounds.

[0153] The term “aryl,” as used herein, refers to any monocyclic or fused ring bicyclic or tricyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthrene. In some embodiments, a ring system contains 5-15 ring member atoms or 5-10 ring member atoms. An aryl group may have, e.g., five to fifteen carbons (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C11 , C5-C12, C5-C13, C5-C14, or C5-C15 aryl). The term “heteroaryl” also refers to such monocyclic or fused bicyclic ring systems containing one or more, e.g., 1- 4, 1-3, 1 , 2, 3, or 4, heteroatoms selected from O, S and N. A heteroaryl group may have, e.g., two to fifteen carbons (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9. C2-C10, C2-C11 , C2-C12, C2-C13, C2-C14, or C2-C15 heteroaryl). The inclusion of a heteroatom permits inclusion of 5-membered rings to be considered aromatic as well as 6-membered rings. Thus, typical heteroaryl systems include, e.g., pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, and imidazolyl. Because tautomers are possible, a group such as phthalimido is also considered heteroaryl. In some embodiments, the aryl or heteroaryl group is a 5- or 6-membered aromatic rings system optionally containing 1-2 nitrogen atoms. In some embodiments, the aryl or heteroaryl group is an optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, or imidazopyridinyl. In some embodiments, the aryl group is phenyl. In some embodiments, an aryl group may be optionally substituted with a substituent such an aryl substituent, e.g., biphenyl.

[0154] The terms “alkylene” as used herein, refer to divalent groups having a specified size. In some embodiments, an alkylene may contain, e.g., 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1- C2). Alkylene includes straight-chain and branched-chain forms, as well as combinations of these. The divalency of an alkylene group does not include the optional substituents on the alkylene group. For example, two CCR5 inhibitors may be attached to each other by way of a linker that includes alkylene or combinations thereof. Each of the alkylene groups in the linker is considered divalent with respect to the two attachments on either end of alkylene group. The divalent nature of an alkylene group (e.g., an alkylene group in a linker) refers to both of the ends of the group and does not include optional substituents that may be present in an alkylene group. Because they are divalent, they can link together multiple (e.g., two) parts of a conjugate, e.g., a first CCR5 inhibitor and a second CCR5 inhibitor. Alkylene groups can be substituted by the groups typically suitable as substituents for alkyl groups as set forth herein. For example, C=O is a C1 alkylene that is substituted by an oxo (=0). Heteroalkylene groups refer to alkylene groups including one or more, e.g., 1-4, 1-3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S. For example, a polyethylene glycol (PEG) polymer or a PEG unit -(CH2)2-O- in a PEG polymer is considered a heteroalkylene containing one or more oxygen atoms. The term “cycloalkylene,” as used herein, refers to a divalent cyclic group linking together two parts of a compound. For example, one carbon within the cycloalkylene group may be linked to one part of the compound, while another carbon within the cycloalkylene group may be linked to another part of the compound. A cycloalkylene group may include unsaturated non-aromatic cyclic groups. A cycloalkylene may have, e.g., three to twenty carbons in the cyclic portion of the cycloalkylene (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C11 , C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkylene). A cycloalkylene group can be substituted by the groups typically suitable as substituents for alkyl groups as set forth herein. Heterocycloalkylene refers to a cycloalkylene group including one or more, e.g., 1-4, 1-3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S. Examples of cycloalkylenes include, but are not limited to, cyclopropylene and cyclobutylene. A tetra hydrofuran may be considered as a heterocycloalkylene.

[0155] The term “arylene,” as used herein, refers to a multivalent (e.g., divalent or trivalent) aryl group linking together multiple (e.g., two or three) parts of a compound. For example, one carbon within the arylene group may be linked to one part of the compound, while another carbon within the arylene group may be linked to another part of the compound. An arylene may have, e.g., five to fifteen carbons in the aryl portion of the arylene (e.g., a C5-C6, C5-C7, C5-C8, C5-C9. C5-C10, C5-C11 , C5-C12, C5-C13, C5- C14, or C5-C15 arylene). An arylene group can be substituted by the groups typically suitable as substituents for alkyl groups as set forth herein. Heteroarylene refers to an aromatic group including one or more, e.g., 1-4, 1-3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S. A heteroarylene group may have, e.g., two to fifteen carbons (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9. C2-C10, C2- C11 , C2-C12, C2-C13, C2-C14, or C2-C15 heteroarylene).

[0156] The term “optionally substituted,” as used herein, refers to having 0, 1 , or more substituents, such as 0-25, 0-20, 0-10 or O-5 substituents. Alkyl, heteroalkyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and oxo may be substituted with alkyl, halogen, aryl, heteroaryl, heteroalkyl, halogen, oxo, alkoxy, carbonyl, oximo, NR2, and CF3, wherein each R is, independently, H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl. In some embodiments, a substituent is further substituted as described herein. For example, a Ci alkyl group, i.e., methyl, may be substituted with oxo to form a formyl group.

[0157] An optionally substituted group or moiety refers to a group or moiety (e.g., any one of the groups or moieties described above) in which one of the atoms (e.g., a hydrogen atom) is optionally replaced with another substituent.

[0158] The term “hetero,” when used to describe a chemical group or moiety, refers to having at least one heteroatom that is not a carbon or a hydrogen, e.g., N, O, and S. Any one of the groups or moieties described above may be referred to as hetero if it contains at least one heteroatom. For example, a heterocycloalkyl group refers to a cycloalkyl group that has one or more heteroatoms independently selected from, e.g., N, O, and S. For example, a heteroaryl group refers to an aromatic group that has one or more heteroatoms independently selected from, e.g., N, O, and S. One or more heteroatoms may also be included in a substituent that replaced a hydrogen atom in a group or moiety as described herein. For example, in an optionally substituted heteroaryl group, if one of the hydrogen atoms in the heteroaryl group is replaced with a substituent (e.g., methyl), the substituent may also contain one or more heteroatoms (e.g., methanol). The term “halo” or “halogen,” as used herein, refers to any halogen atom, e.g., F, Cl, Br, or I. Any one of the groups or moieties described herein may be referred to as a halo moiety if it contains at least one halogen atom, such as haloalkyl.

[0159] The term “oxo,” as used herein, refers to a substituent having the structure =0, where there is a double bond between an atom and an oxygen atom.

[0160] The term “carbonyl,” as used herein, refers to a group having the structure:

[0161] The term “thiocarbonyl,” as used herein, refers to a group having the structure:

[0162] The term “phosphate,” as used herein, represents the group having the structure:

[0163] The term “phosphoryl,” as used herein, represents the group having the structure: or The term “sulfonyl,” as used herein, represents the group having the structure:

[0164] The term “imino,” as used herein, represents the group including C=N (e.g., including the structure: ). For example, an imino group may have any one of the following structures: ,. or, where each of Ri1and Ri2is H or any one of the substituents described herein

[0165] (e.g., C1-C20alkyl and each of i1 and i2 is, independently, 0, 1 , 2, or 3.

[0166] The term “oxime” or “oximo,” as used herein, represents the group including C=N-0 (e.g., including the structure

[0167] The term “-C(O)OCH3” as used herein, refers to the following structure:

[0168] The term “amino acid,” as used herein, means naturally occurring amino acids and non-naturally occurring amino acids. The term “naturally occurring amino acids,” as used herein, means amino acids including Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Vai.

[0169] The term “non-naturally occurring amino acid,” as used herein, means an alpha amino acid that is not naturally produced or found in a mammal. Examples of non-naturally occurring amino acids include D- amino acids; an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine; a pegylated amino acid; the omega amino acids of the formula NH2(CH2)nCOOH where n is 2-6, neutral nonpolar amino acids, such as sarcosine, t-butyl alanine, t-butyl glycine, N-methyl isoleucine, and norleucine; oxymethionine; phenylglycine; citrulline; methionine sulfoxide; cysteic acid; ornithine; diaminobutyric acid; 3-aminoalanine; 3-hydroxy-D-proline; 2,4-diaminobutyric acid; 2-aminopentanoic acid; 2-aminooctanoic acid, 2-carboxy piperazine; piperazine-2-carboxylic acid, 2-amino-4-phenylbutanoic acid; 3-(2-naphthyl)alanine, and hydroxyproline. Other amino acids are a-aminobutyric acid, a-amino-a- methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, aminonorbornyl-carboxylate, L- cyclohexylalanine, cyclopentylalanine, L-N-methylleucine, L-N-methylmethionine, L-N-methylnorvaline, L- N-methylphenylalanine, L-N-methylproline, L-N-methylserine, L-N-methyltry ptophan, D-ornithine, L-N- methylethylglycine, L-norleucine, a-methyl-aminoisobutyrate, a-methylcyclohexylalanine, D-a- methylalanine, D-a-methylarginine, D-a-methylasparagine, D-a-methylaspartate, D-a-methylcysteine, D- a-methylglutamine, D-a-methylhistidine, D-a-methylisoleucine, D-a-methylleucine, D-a-methyllysine, D-a- methylmethionine, D-a-methylornithine, D-a-methylphenylalanine, D-a-methylproline, D-a-methylserine, D-N-methylserine, D-a-methylthreonine, D-a-methyltry ptophan, D-a-methyltyrosine, D-a-methylvaline, D- N-methylalanine, D-N-methylarginine, D-N-methylasparagine, D-N-methylaspartate, D-N-methylcysteine, D-N-methylglutamine, D-N-methylglutamate, D-N-methylhistidine, D-N-methylisoleucine, D-N- methylleucine, D-N-methyllysine, N-methylcyclohexylalanine, D-N-methylornithine, N-methylglycine, N- methylaminoisobutyrate, N-(1-methylpropyl)glycine, N-(2-methylpropyl)glycine, D-N-methyltryptophan, D- N-methyltyrosine, D-N-methylvaline, y-aminobutyric acid, L-t-butylglycine, L-ethylglycine, L- homophenylalanine, L-a-methylarginine, L-a-methylaspartate, L-a-methylcysteine, L-a-methylglutamine, L-a-methylhistidine, L-a-methylisoleucine, L-a-methylleucine, L-a-methylmethionine, L-a-methylnorvaline, L-a-methylphenylalanine, L-a-methylserine, L-a-methyltry ptophan, L-a-methylvaline, N-(N-(2,2- diphenylethyl) carbamylmethylglycine, 1-carboxy-1-(2,2-diphenyl-ethylamino) cyclopropane, 4- hydroxyproline, ornithine, 2-aminobenzoyl (anthraniloyl), D-cyclohexylalanine, 4-phenyl-phenylalanine, L- citrulline, a-cyclohexylglycine, L-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4- carboxylic acid, L-homotyrosine, L-2-furylalanine, L-histidine (3-methyl), N-(3-guanidinopropyl)glycine, O- methyl-L-tyrosine, O-glycan-serine, meta-tyrosine, nor-tyrosine, L-N,N',N"-trimethyllysine, homolysine, norlysine, N-glycan asparagine, 7-hydroxy-1 ,2,3,4-tetrahydro-4-fluorophenylalanine, 4- methylphenylalanine, bis-(2-picolyl)amine, pentafluorophenylalanine, indoline-2-carboxylic acid, 2- aminobenzoic acid, 3-amino-2-naphthoic acid, asymmetric dimethylarginine, L-tetrahydroisoquinoline-1- carboxylic acid, D-tetrahydroisoquinoline-1 -carboxylic acid, 1 -amino-cyclohexane acetic acid, D / L- ally Iglycine, 4-aminobenzoic acid, 1-amino-cyclobutane carboxylic acid, 2 or 3 or 4-aminocyclohexane carboxylic acid, 1-amino-1 -cyclopentane carboxylic acid, 1-aminoindane-1 -carboxylic acid, 4-amino- pyrrolidine-2-carboxylic acid, 2-aminotetraline-2-carboxylic acid, azetidine-3-carboxylic acid, 4-benzyl- pyrolidine-2-carboxy lie acid, tert-buty Iglyci ne, b-(benzothiazolyl-2-yl)-alanine, b-cyclopropyl alanine, 5,5- dimethyl-1 ,3-thiazolidine-4-carboxylic acid, (2R,4S)4-hydroxypiperidine-2-carboxylic acid, (2S,4S) and (2S,4R)-4-(2-naphthylmethoxy)-pyrolidine-2-carboxylic acid, (2S,4S) and (2S,4R)4-phenoxy-pyrrolidine-2- carboxylic acid, (2R,5S)and(2S,5R)-5-phenyl-pyrrolidine-2-carboxylic acid, (2S,4S)-4-amino-1-benzoyl- pyrrolidine-2-carboxylic acid, t-butylalanine, (2S,5R)-5-phenyl-pyrrolidine-2-carboxylic acid, 1- aminomethyl-cyclohexane-acetic acid, 3,5-bis-(2-amino)ethoxy-benzoic acid, 3,5-diamino-benzoic acid, 2- methylamino-benzoic acid, N-methylanthranylic acid, L-N-methylalanine, L-N-methylarginine, L-N- methylasparagine, L-N-methylaspartic acid, L-N-methylcysteine, L-N-methylglutamine, L-N- methylglutamic acid, L-N-methylhistidine, L-N-methylisoleucine, L-N-methyllysine, L-N-methylnorleucine, L-N-methylornithine, L-N-methylthreonine, L-N-methyltyrosine, L-N-methylvaline, L-N-methyl-t- butylglycine, L-norvaline, a-methyl-y-aminobutyrate, 4,4'-biphenylalanine, a-methylcylcopentylalanine, a- methyl-a-napthylalanine, a-methylpenicillamine, N-(4-aminobutyl)glycine, N-(2-aminoethyl)glycine, N-(3- aminopropyl)glycine, N-amino-a-methylbutyrate, a-napthylalanine, N-benzylglycine, N-(2- carbamylethyl)glycine, N-(carbamylmethyl)glycine, N-(2-carboxyethyl)glycine, N-(carboxymethyl)glycine, N-cyclobutylglycine, N-cyclodecylglycine, N-cycloheptylglycine, N-cyclohexylglycine, N-cyclodecylglycine, N-cylcododecylglycine, N-cyclooctylglycine, N-cyclopropylglycine, N-cycloundecylglycine, N-(2,2- diphenylethyl)glycine, N-(3,3-diphenylpropyl)glycine, N-(3-guanidinopropyl)glycine, N-(1- hydroxyethyl)glycine, N-(hydroxyethyl))glycine, N-(imidazolylethyl))glycine, N-(3-indolylyethyl)glycine, N- methyl-y-aminobutyrate, D-N-methylmethionine, N-methylcyclopentylalanine, D-N-methylphenylalanine, D-N-methylproline, D-N-methylthreonine, N-(1-methylethyl)glycine, N-methyl-napthylalanine, N- methylpenicillamine, N-(p-hydroxyphenyl)glycine, N-(thiomethyl)glycine, penicillamine, L-a-methylalanine, L-a-methylasparagine, L-a-methyl-t-butylglycine, L-methylethylglycine, L-a-methylglutamate, L-a- methylhomophenylalanine, N-(2-methylthioethyl)glycine, L-a-methyllysine, L-a-methylnorleucine, L-a- methylornithine, L-a-methylproline, L-a-methylthreonine, L-a-methyltyrosine, L-N-methyl- homophenylalanine, N-(N-(3,3-diphenylpropyl) carbamylmethylglycine, L-pyroglutamic acid, D- pyroglutamic acid, O-methyl-L-serine, O-methyl-L-homoserine, 5-hydroxylysine, a-carboxyglutamate, phenylglycine, L-pipecolic acid (homoproline), L-homoleucine, L-lysine (dimethyl), L-2-naphthylalanine, L- dimethyldopa or L-dimethoxy-phenylalanine, L-3-pyridylalanine, L-histidine (benzoyloxymethyl), N- cycloheptylglycine, L-diphenylalanine, O-methyl-L-homotyrosine, L-p-homolysine, O-glycan-threoine, Ortho-tyrosine, L-N,N'-dimethyllysine, L-homoarginine, neotryptophan, 3-benzothienylalanine, isoquinoline-3-carboxylic acid, diaminopropionic acid, homocysteine, 3,4-dimethoxyphenylalanine, 4- chlorophenylalanine, L-1 ,2,3,4-tetrahydronorharman-3-carboxylic acid, adamantylalanine, symmetrical dimethylarginine, 3-carboxythiomorpholine, D-1 ,2,3, 4-tetrahydronorharman-3-carboxylic acid, 3- aminobenzoic acid, 3-amino-1-carboxymethyl-pyridin-2-one, 1-amino-1 -cyclohexane carboxylic acid, 2- aminocyclopentane carboxylic acid, 1-amino-1 -cyclopropane carboxylic acid, 2-aminoindane-2-carboxylic acid, 4-amino-tetrahydrothiopyran-4-carboxylic acid, azetidine-2-carboxylic acid, b-(benzothiazol-2-yl)- alanine, neopentylglycine, 2-carboxymethyl piperidine, b-cyclobutyl alanine, allylglycine, diaminopropionic acid, homo-cyclohexyl alanine, (2S,4R)- 4-hydroxypiperidine-2-carboxylic acid, octahydroindole-2- carboxylic acid, (2S,4R) and (2S,4R)-4-(2-naphthyl), pyrrolidine-2-carboxylic acid, nipecotic acid, (2S,4R)and (2S,4S)-4-(4-phenylbenzyl) pyrrolidine-2-carboxylic acid, (3S)-1-pyrrolidine-3-carboxylic acid, (2S,4S)-4-tritylmercapto-pyrrolidine-2-carboxylic acid, (2S,4S)-4-mercaptoproline, t-buty Ig lycine, N,N- bis(3-aminopropyl)glycine, 1-amino-cyclohexane-1 -carboxylic acid, N-mercaptoethylglycine, and selenocysteine. In some embodiments, amino acid residues may be charged or polar. Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid, or non-naturally occurring analogs thereof. Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan, or non-naturally occurring analogs thereof. It is specifically contemplated that in some embodiments, a terminal amino group in the amino acid may be an amido group or a carbamate group.

[0170] As used herein, the term “percent (%) identity” refers to the percentage of amino acid residues of a candidate sequence that are identical to the amino acid residues of a reference sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity (i.e., gaps can be introduced in one or both of the candidate and reference sequences for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). Alignment for purposes of determining percent identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. In some embodiments, the percent amino acid sequence identity of a given candidate sequence to, with, or against a given reference sequence (which can alternatively be phrased as a given candidate sequence that has or includes a certain percent amino acid sequence identity to, with, or against a given reference sequence) is calculated as follows:

[0171] 100 x (fraction of A / B) where A is the number of amino acid residues scored as identical in the alignment of the candidate sequence and the reference sequence, and where B is the total number of amino acid residues in the reference sequence. In some embodiments where the length of the candidate sequence does not equal to the length of the reference sequence, the percent amino acid sequence identity of the candidate sequence to the reference sequence would not equal to the percent amino acid sequence identity of the reference sequence to the candidate sequence.

[0172] Two polynucleotide or polypeptide sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence as described above. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A “comparison window” as used herein, refers to a segment of at least about 15 contiguous positions, about 20 contiguous positions, about 25 contiguous positions, or more (e.g., about 30 to about 75 contiguous positions, or about 40 to about 50 contiguous positions), in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

[0173] The term “treating” or “to treat,” as used herein, refers to a therapeutic treatment of a disease (e.g., cancer) in a subject. In some embodiments, a therapeutic treatment may slow the progression of the disease, improve the subject’s outcome, or eliminate tumors. In some embodiments, a therapeutic treatment of the disease in a subject may alleviate or ameliorate of one or more symptoms or conditions associated with the disease, diminish the extent of the symptoms, stabilize (i.e., not worsening) the state of the disease, prevent the spread of the disease, or delay or slow the progress of the disease, as compare the state or the condition of the disease in the absence of the therapeutic treatment.

[0174] The term “average value of T,” as used herein, refers to the mean number of monomers or dimers of CCR5 inhibitors conjugated to a polypeptide monomer or dimer within a population of conjugates. In some embodiments, within a population of conjugates, the average number of monomers of CCR5 inhibitor or dimers of CCR5 inhibitors conjugated to a polypeptide monomer may be from 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.

[0175] The term “subject,” as used herein, can be a human or non-human primate.

[0176] The term “therapeutically effective amount,” as used herein, refers to an amount, e.g., pharmaceutical dose, effective in inducing a desired effect in a subject or in treating a subject having a condition or disorder described herein. It is also to be understood herein that a “therapeutically effective amount” may be interpreted as an amount giving a desired therapeutic or preventative effect, taken in one or more doses or in any dosage or route, or taken alone or in combination with other therapeutic agents. For example, in the context of administering a conjugate described herein that is used for the treatment of a disease described herein, an effective amount of a conjugate is, for example, an amount sufficient to prevent, slow down, or reverse the progression of the disease as compared to the response obtained without administration of the conjugate.

[0177] As used herein, the term “pharmaceutical composition” refers to a medicinal or pharmaceutical formulation that contains at least one active ingredient as well as one or more excipients and diluents to enable the active ingredient suitable for the method of administration. The pharmaceutical composition of the present disclosure includes pharmaceutically acceptable components that are compatible with a conjugate described herein.

[0178] As used herein, the term “pharmaceutically acceptable carrier” refers to an excipient or diluent in a pharmaceutical composition. For example, a pharmaceutically acceptable carrier may be a vehicle capable of suspending or dissolving the active conjugate. The pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient. In the present disclosure, the pharmaceutically acceptable carrier must provide adequate pharmaceutical stability to a conjugate described herein. The nature of the carrier differs with the mode of administration. For example, for oral administration, a solid carrier is preferred; for intravenous administration, an aqueous solution carrier (e.g., WFI, or a buffered solution) is generally used.

[0179] The term “pharmaceutically acceptable salt,” as used herein, represents salts of the conjugates described herein that are, within the scope of sound medical judgment, suitable for use in methods described herein without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Pharmaceutical Salts: Properties, Selection, and Use (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the conjugates described herein or separately by reacting the free base group with a suitable organic acid.

[0180] The term “about,” as used herein, indicates a deviation of ±5%. For example, about 10% refers to from 9.5% to 10.5%.

[0181] The term “triple negative breast cancer,” as used herein, refers to a breast cancer that is estrogen receptor-negative (ER-negative), progesterone receptor-negative (PR-negative), and human epidermal growth factor receptor-2-negative (HER2-negative).

[0182] The term “combined positive score (CPS),” as used herein, refers to the number of PD-L1- staining cells divided by the total number of viable tumor cells, multiplied by 100.

[0183] The term “PD-L1 negative,” as used herein, refers to a subject with cancer having PD-L1 staining defined as negative by any FDA approved PD-L1 complementary diagnostic immunohistochemistry assay. For triple negative breast cancer, a subject is PD-L1 negative if the subject has a CPS of less than 10.

[0184] As used herein, the term “albumin protein” refers to a polypeptide comprising an amino acid sequence corresponding to a naturally-occurring albumin protein (e.g., bovine serum albumin or human serum albumin) or a variant thereof, such as an engineered variant of a naturally-occurring albumin protein. Variants of albumin proteins include polymorphisms, fragments such as domains and subdomains, and fusion proteins (e.g., an albumin protein having a C-terminal or N-terminal fusion, such as a polypeptide linker). Preferably the albumin protein has the amino acid sequence of bovine serum albumin (BSA), human serum albumin (HSA), or a variant or fragment thereof, most preferably a functional variant or fragment thereof. Albumin proteins of the invention include proteins having at least 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to any one of SEQ ID NOs: 273- 276. Albumin proteins of the invention include albumin proteins which have been engineered to include one or more (e.g., two, three, four, or five) solvent-exposed cysteine or lysine residues, which may provide a site for conjugation to an Int of the invention (e.g., conjugation to a CCR5 inhibitor monomer or dimer, including by way of a linker). Most preferably, the albumin protein will contain a single solvent- exposed cysteine or lysine, thus enabling site-specific conjugation of an Int of the invention. Albumin proteins may include only naturally occurring amino acid residues or may include one or more non- naturally occurring amino acid residues. Where included, a non-naturally occurring amino acid residue (e.g., the side chain of a non-naturally occurring amino acid residue) may be used as the point of attachment for an Int of the invention (e.g., a CCR5 inhibitor monomer or dimer, including by way of a linker).

[0185] Any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds.

[0186] As described herein, the term “CCR5 inhibitor” means a molecule or compound that inhibits one or more biological or pathological activities induced by CCR5.

[0187] Other features and advantages of the conjugates described herein will be apparent in the following Detailed Description and the claims. Description of the Drawings

[0188] FIG. 1 is a graph showing inhibition of beta-arrestin as a function of Conjugate 15a concentration in a human CCR5 b-arrestin assay.

[0189] FIG. 2 is a graph showing the tumor volume over time of mice (n=10) treated with Conjugate 15a or vehicle control. Conjugate 15a demonstrated reduced tumor growth compared to vehicle treated animals.

[0190] FIG. 3 is a graph showing the reduction in tumor volume by Conjugate 15a relative to the vehicle control. Conjugate 15a-treated mice demonstrated a statistically significant reduction in tumor growth relative to vehicle treated animals.

[0191] FIG. 4 is a graph showing inhibition of beta-arrestin as a function of Conjugate 15a concentration in a beta-arrestin express based CCR5 inhibition assay.

[0192] FIG. 5 is a bar chart showing the average tumor volume (± SEM) on Day 13 in colon cancer mouse model treated with either vehicle, AB680, a-PD-1 mAb, Oleclumab, Comparator 1 , or Conjugate 47. The data was obtained one week post-treatment in mice.

[0193] FIG. 6 is a graph showing tumor growth in a colon cancer mouse model over time for mice treated with either vehicle, Conjugate 47, or a-PD-1 .

[0194] FIG. 7A is a graph of CCR5 expression activity of Conjugate 15a (gray circles) compared to unconjugated SEQ ID NO: 118 (black circles) in the presence of 100 nM CCL5. FIG. 7B is a graph of CCL5 competition activity (FIG. 7B) of Conjugate 15a (gray circles) compared to unconjugated SEQ ID NO: 118 (black circles) in the presence of 100 nM CCL5.

[0195] FIG. 8A is a graph of CCR5 expression activity of Conjugate 15a (gray circles) compared to unconjugated control (black circles) in the absence (open circle) or presence of 100 nM CCL5 (filled circles). FIG. 8B is a graph of CCL5 competition activity of Conjugate 15a (gray circles) compared to unconjugated control (black circles) in the absence (open circle) or presence of 100 nM CCL5 (filled circles).

[0196] FIG. 9 is a series of graphs displaying the migration inhibition of human CD14+monocytes to CCL5 as a function of test article concentration. Conjugate 40 showed the best activity in this assay across all donors with an EC50value in the single digit nanomolar range across two donors in the presence of 1 nM or 10 nM CCL5.

[0197] FIG. 10 is a graph of migration inhibition of human CD14+monocytes to CCL5 as a function of test article concentration. Conjugate 40 demonstrated an EC50value of 21 nM, whereas Conjugate 15a demonstrated an EC50value of 77 nM.

[0198] FIG. 11 is a box plot of mice tumor volumes on Day 28 after treatment with vehicle or SEQ ID NO: 205.

[0199] FIG. 12A is a survival curve of mice treated with either vehicle or 10 mg / kg SEQ ID NO: 205. FIG. 12B is a survival curve of mice treated with either vehicle or 1 mg / kg SEQ ID NO: 205.

[0200] FIG. 13 is a graph of human CCR5 binding dose response curves of SEQ ID NO: 80, Conjugate 15a, and Leronlimab. FIG. 14 is a graph showing the average tumor volume over 42 days, post-cell injection, in mice treated with either vehicle, Conjugate 47, Conjugate 183, or Conjugate 40.

[0201] FIG. 15 is a graph showing the average tumor volume for mice treated with vehicle, Conjugate 40, Conjugate 47, or Conjugate 183 on Day 42.

[0202] FIGs. 16A-D is a series of graphs showing the tumor volume over time for individual animals treated with: Vehicle (FIG. 16A); Conjugate 40 (FIG. 16B); Conjugate 183 (FIG. 16C); or Conjugate 40 (FIG. 16D).

[0203] Detailed Description

[0204] This disclosure relates to conjugates including a polypeptide that inhibits PD-1 or an albumin protein that is covalently linked to a moiety that inhibits CCR5. This disclosure also provides pharmaceutical compositions including such conjugates and uses of such conjugates in the treatment of disorders associated with dysregulation or overexpression of CCR5 or PD-1 (e.g., cancer). The featured conjugates exhibit desirable tissue distribution (e.g., lung distribution).

[0205] I. Conjugates

[0206] Provided herein are synthetic conjugates that include a polypeptide conjugated to one or more CCR5 inhibitors (e.g., a CCR5 inhibitor of formula (A-l), formula (A-l I), formula (B-l), formula (B-l I), formula (C)), or one or more dimers of two CCR5 inhibitors. The dimers of two CCR5 inhibitors include a CCR5 inhibitor (e.g., a first CCR5 inhibitor of formula (A-l), formula (A-l I), formula (B-l), formula (B-l I), formula (C), and a second CCR5 inhibitor (e.g., a second CCR5 inhibitor of formula (A-l), formula (A-l I), formula (B-l), formula (B-ll), or formula (C). In the context of dimers, e.g., of formula (D-l), (D-ll), or (D-lll) the first and second CCR5 inhibitors are linked to each other by way of a linker.

[0207] Conjugates of the disclosure include CCR5 inhibitor monomers and dimers conjugated to a polypeptide that contains an Fc domain, Fc monomer, Fc-binding peptide, or an albumin protein. The Fc domain in the conjugates described herein binds to the FcyRs (e.g., FcRn, FcyRI, FcyRlla, FcyRllc, FcyRllla, and FcyRI II b) on immune cells. The binding of the Fc domain in the conjugates described herein to the FcyRs on immune cells activates phagocytosis and effector functions, such as antibodydependent cell-mediated cytotoxicity (ADCC).

[0208] Conjugates provided herein are described by any one of formulas (D-l), (D-ll), (D-lll), (M-l), (M-ll), or (M-l II). In some embodiments, the conjugates described herein include one or more monomers of CCR5 inhibitors conjugated to a polypeptide that contains an Fc domain monomer, Fc domain, or an albumin protein. In some embodiments, the conjugates described herein include one or more dimers of CCR5 inhibitors conjugated to a polypeptide that contains an Fc domain monomer, Fc domain, or an albumin protein. In some embodiments, when n is 2, E is a polypeptide that includes a polypeptide that contains an Fc domain monomer that dimerizes to form an Fc domain.

[0209] Conjugates described herein may be synthesized using available chemical synthesis techniques in the art. In cases where a functional group is not available for conjugation, a molecule may be derivatized using conventional chemical synthesis techniques that are well known in the art. In some embodiments, the conjugates described herein contain one or more chiral centers. The conjugates include each of the isolated stereoisomeric forms as well as mixtures of stereoisomers in varying degrees of chiral purity, including racemic mixtures. It also encompasses the various diastereomers, enantiomers, and tautomers that can be formed.

[0210] CCR5 inhibitors

[0211] CCR5 inhibitors can prevent ligand or pathogen binding by achieving partial or complete occupation of one or more sites in CCR5 that the ligand or pathogen requires for interaction (orthosteric inhibitors). Alternatively, CCR5 inhibitors can prevent ligand or pathogen binding by binding to other sites on CCR5 and inducing CCR5 to adopt a conformation or structures that are not recognized by the ligand or pathogen (allosteric inhibitor). CCR5 inhibitors may inhibit the entire repertoire or only a subset of the CCR5 intracellular signaling pathway. CCR5 inhibitors can also act by inducing long-term intracellular sequestration of CCR5, thereby making it inaccessible by extracellular ligands or pathogens.

[0212] CCR5 inhibitors may also act by specifically inhibiting or eliminating expression of the CCR5 gene. A CCR5 inhibitor can also act by binding to one or more ligands or pathogens such that the one or more ligands or pathogens cannot bind to CCR5. Further, inhibitors have the ability to bind CCR5 at its diverse cell surface structures, or induce only low-level proinflammatory signaling, or only a subset of the repertoire of CCR5 intracellular signaling pathways or induce cellular internalization of CCR5 (receptor sequestration, downregulation or downmodulation).

[0213] Conjugates of monomers of CCR5 inhibitors linked to a polypeptide that contains an Fc domain

[0214] In some embodiments, the conjugates described herein include a polypeptide that contains an Fc domain monomer or Fc domain covalently linked to one or more monomers of CCR5 inhibitors, e.g., a conjugate described by formula (M-l). Conjugates of a polypeptide that contains an Fc domain monomer or Fc domain and one or more monomers of CCR5 inhibitors may be formed by linking the Fc domain monomer or Fc domain to each of the monomers of CCR5 inhibitors through a linker, such as any of the linkers described herein.

[0215] In the conjugates having a polypeptide that contains an Fc domain monomer or Fc domain covalently linked to one or more monomers of CCR5 inhibitors described herein, the squiggly line connected to E indicates that one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) monomers of CCR5 inhibitors may be attached to a polypeptide that contains an Fc domain monomer or Fc domain. In some embodiments, when n is 1 , one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) monomers of CCR5 inhibitors may be attached to a polypeptide that contains an Fc domain monomer. In some embodiments, when n is 2, one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) monomers of CCR5 inhibitors may be attached to a polypeptide that contains an Fc domain. The squiggly line in the conjugates described herein is not to be construed as a single bond between one or more monomers of CCR5 inhibitors and an atom in the Fc domain monomer or Fc domain. In some embodiments, when T is 1 , one monomer of CCR5 inhibitor may be attached to an atom in the polypeptide of an Fc domain monomer or Fc domain. In some embodiments, when T is 2, two monomers of CCR5 inhibitors may be attached to an atom in the polypeptide of an Fc domain monomer or Fc domain.

[0216] In some embodiments, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20), each Ai-L may be independently selected (e.g., independently selected from any of the Ai-L structures described herein). In some embodiments, E may be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different Ai-L moieties. In some embodiments, E is conjugated to a first Ai-L moiety, and a second Ai-L, moiety. In some embodiments, Ai of each of the first Ai-L moiety and the second Ai-L moiety is independently selected from any one of formulas (A-l), (A-ll), (A-la), (A-lb), (A-lc), (A-ld), (A-le), (A-lf), (A-lg), (A-lh), (A-lla), and (A-llb).

[0217] In some embodiments, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20), each Bi-L may be independently selected (e.g., independently selected from any of the Bi-L structures described herein). In some embodiments, E may be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different Bi-L moieties. In some embodiments, E is conjugated to a first Bi-L moiety, and a second Bi-L, moiety. In some embodiments, Bi of each of the first Bi-L moiety and the second Bi-L moiety is independently selected from any one of formula (B-l), (B-ll), (B-la), (B-lb), (B-lc), (B-ld), and (B- lla).

[0218] In some embodiments, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20), each Ci-L may be independently selected (e.g., independently selected from any of the Ci-L structures described herein). In some embodiments, E may be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different Ci-L moieties. In some embodiments, E is conjugated to a first Ci-L moiety, and a second Ci-L, moiety. In some embodiments, Ci of each of the first Ci-L moiety and the second Ci- L moiety is independently selected from any one of formula (C), (C-la), (C-lb), (C-lc), and (C-ld).

[0219] In some embodiments, the first Ai-L moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E), and the second Ai-L moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E). In some embodiments, the first Ai-L moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E), and the second Ai-L moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E).

[0220] In some embodiments, the first Bi-L moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E), and the second Bi-L moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E). In some embodiments, the first Bi-L moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E), and the second Bi-L moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E).

[0221] In some embodiments, the first Ci-L moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E), and the second Ci-L moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E). In some embodiments, the first Ci-L moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E), and the second Ci-L moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E).

[0222] As described further herein, a linker in a conjugate having a polypeptide that contains an Fc domain monomer or Fc domain covalently linked to one or more monomers of the CCR5 inhibitors described herein (e.g., L) may be a divalent structure having two arms. One arm in a divalent linker may be attached to the monomer of the CCR5 inhibitor and the other arm may be attached to the polypeptide of an Fc domain monomer or Fc domain.

[0223] In conjugates having a polypeptide that contains an Fc domain covalently linked to one or more monomers of CCR5 inhibitors, as represented by the formulae above, when n is 2, two Fc domain monomers (each Fc domain monomer is represented by E) dimerize to form an Fc domain.

[0224] Conjugates of dimers of CCR5 inhibitors linked to a polypeptide that contains an Fc domain

[0225] The conjugates described herein include a polypeptide that contains an Fc domain monomer or Fc domain covalently linked to one or more dimers of CCR5 inhibitors, e.g., a conjugate described by formula (D-l), (D-ll), or (D-lll). The dimers of two CCR5 inhibitors include a first CCR5 inhibitor (e.g., a first CCR5 inhibitor of formula (A-l), (A-ll), (A-la), (A-lb), (A-lc), (A-ld), (A-le), (A-ll), (A-lg), (A-lh), (A-lla), or (A- llb)) and a second CCR5 inhibitor (e.g., a second CCR5 inhibitor of formula (A-l), (A-ll), (A-la), (A-lb), (A- Ic), (A-ld), (A-le), (A-lf), (A-lg), (A-lh), (A-lla), or (A-l I b)). The first and second CCR5 inhibitors are linked to each other by way of a linker, such as a linker described herein. In some embodiments of the dimers of CCR5 inhibitors, the first and second CCR5 inhibitors are the same. In some embodiments, the first and second CCR5 inhibitors are different.

[0226] The conjugates described herein include a polypeptide that contains an Fc domain monomer or Fc domain covalently linked to one or more dimers of CCR5 inhibitors, e.g., a conjugate described by formula (D-l), (D-ll), or (D-lll). The dimers of two CCR5 inhibitors include a first CCR5 inhibitor (e.g., a first CCR5 inhibitor of formula (B-l), (B-ll), (B-la), (B-lb)), (B-lc), (B-ld), or (B-lla), and a second CCR5 inhibitor (e.g., a second CCR5 inhibitor of formula (B-l), (B-ll), (B-la), (B-lb), (B-lc), (B-ld), or (B-lla)). The first and second CCR5 inhibitors are linked to each other by way of a linker, such as a linker described herein. In some embodiments of the dimers of CCR5 inhibitors, the first and second CCR5 inhibitors are the same. In some embodiments, the first and second CCR5 inhibitors are different.

[0227] The conjugates described herein include a polypeptide that contains an Fc domain monomer or Fc domain covalently linked to one or more dimers of CCR5 inhibitors, e.g., a conjugate described by formula (D-l), (D-ll), or (D-lll). The dimers of two CCR5 inhibitors include a first CCR5 inhibitor (e.g., a first CCR5 inhibitor of formula (C), (C-la), (C-lb), (C-lc), or (C-ld)) and a second CCR5 inhibitor (e.g., a second CCR5 inhibitor of formula (C), (C-la), (C-lb), (C-lc), or (C-ld)). The first and second CCR5 inhibitors are linked to each other by way of a linker, such as a linker described herein. In some embodiments of the dimers of CCR5 inhibitors, the first and second CCR5 inhibitors are the same. In some embodiments, the first and second CCR5 inhibitors are different.

[0228] In some embodiments, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,

[0229] 15, 16, 17, 18, 19, or 20), each A1-L-A2may be independently selected (e.g., independently selected from any of the A1-L-A2structures described herein). In some embodiments, E may be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different A1-L-A2moieties. In some embodiments, E is conjugated to a first A1-L-A2moiety, and a second A1-L-A2, moiety. In some embodiments, each of A1 and A2 of the first A1-L-A2moiety and of the second A1-L-A2moiety are independently selected from any one of formulas (A), (A-l), (A-II(A- la), (A-lb), (A-lc), (A-ld), (A-le), (A-lf), (A-lg), (A-lh), (A-lla), or (A-llb).

[0230] In some embodiments, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20), each B1-L-B2may be independently selected (e.g., independently selected from any of the A1-L-A2structures described herein). In some embodiments, E may be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different B1-L-B2moieties. In some embodiments, E is conjugated to a first B1-L-B2moiety, and a second B1-L-B2, moiety. In some embodiments, each of Bi and B2 of the first B1-L-B2moiety and of the second B1-L-B2moiety are independently selected from any one of formulas (B), (B-l), (B-ll), (B-lll), or (B-IV).

[0231] In some embodiments, when T is greater than 1 (e.g., T is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20), each A1-L-A2may be independently selected (e.g., independently selected from any of the C1-L-C2structures described herein). In some embodiments, E may be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different C1-L-C2moieties. In some embodiments, E is conjugated to a first C1-L-C2moiety, and a second C1-L-C2, moiety. In some embodiments, each of Ci and C2 of the first C1-L-C2moiety and of the second C1-L-C2moiety are independently selected from any one of formulas (C), (C-l), (C-ll), (C-lll), or (C-IV).

[0232] In some embodiments, the first A1-L-A2moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E), and the second A1-L-A2moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E). In some embodiments, the first A1-L-A2moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E), and the second A1-L-A2moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E).

[0233] In some embodiments, the first B1-L-B2moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E), and the second B1-L-B2moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E). In some embodiments, the first B1-L-B2moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E), and the second B1-L-B2moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E).

[0234] In some embodiments, the first C1-L-C2moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E), and the second C1-L-C2moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E). In some embodiments, the first C1-L-C2moiety is conjugated specifically to cysteine residues of E (e.g., the sulfur atoms of surface exposed cysteine residues of E), and the second C1-L-C2 moiety is conjugated specifically to lysine residues of E (e.g., the nitrogen atoms of surface exposed lysine residues of E).

[0235] In the conjugates described herein, the squiggly line connected to E indicates that one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) dimers of CCR5 inhibitors may be attached to a polypeptide that contains an Fc domain monomer or Fc domain. In some embodiments, when n is 1 , one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) dimers of CCR5 inhibitors may be attached to a polypeptide that contains an Fc domain monomer. In some embodiments, when n is 2, one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) dimers of CCR5 inhibitors may be attached to a polypeptide that contains an Fc domain. The squiggly line in the conjugates described herein is not to be construed as a single bond between one or more dimers of CCR5 inhibitors and an atom in the Fc domain monomer or Fc domain. In some embodiments, when T is 1 , one dimer of CCR5 inhibitors may be attached to an atom in the polypeptide of an Fc domain monomer or Fc domain. In some embodiments, when T is 2, two dimers of CCR5 inhibitors may be attached to an atom in the polypeptide of an Fc domain monomer or Fc domain.

[0236] As described further herein, a linker in a conjugate described herein may be a branched structure. As described further herein, a linker in a conjugate described herein may be a multivalent structure, e.g., a divalent or trivalent structure having two or three arms, respectively. In some embodiments when the linker has three arms, two of the arms may be attached to the first and second CCR5 inhibitors and the third arm may be attached to the polypeptide of an Fc domain monomer or Fc domain.

[0237] In conjugates having a polypeptide that contains an Fc domain covalently linked to one or more dimers of CCR5 inhibitors, as represented by the formulae above, when n is 2, two Fc domain monomers (each Fc domain monomer is represented by E) dimerize to form an Fc domain.

[0238] II. Fc domain monomers and Fc domains

[0239] The disclosure features compositions (e.g., polypeptides and conjugates) which include one or more Fc domain monomers. When two compositions including an Fc domain monomer dimerize, the result is an Fc domain. An Fc domain monomer includes a hinge domain, a CH2 antibody constant domain, and a CH3 antibody constant domain. The Fc domain monomer can be of immunoglobulin antibody isotype IgG, IgE, IgM, IgA, or IgD. The Fc domain monomer can also be of any immunoglobulin antibody isotype (e.g., IgG 1 , lgG2a, lgG2b, lgG3, or lgG4). The Fc domain monomer can be of any immunoglobulin antibody allotype (e.g., IGHG1*01 (i.e., G1 m(za)), IGHG1*07 (i.e., G1 m(zax)), IGHG1*04 (i.e., G1 m(zav)), IGHG1*03 (G1m(f)), IGHG1*08 (i.e., G1 m(fa)), IGHG2*01 , IGHG2*06, IGHG2*02, IGHG3*01 , IGHG3*05, IGHG3*10, IGHG3*04, IGHG3*09, IGHG3*11 , IGHG3*12, IGHG3*06, IGHG3*07, IGHG3*08, IGHG3*13, IGHG3*03, IGHG3*14, IGHG3*15, IGHG3*16, IGHG3*17, IGHG3*18, IGHG3*19, IGHG2*04, IGHG4*01 , IGHG4*03, or IGHG4*02) (as described in, for example, Vidarsson et al. IgG subclasses and allotypes: from structure to effector function. Frontiers in Immunology. 5(520): 1 -17 (2014)). The Fc domain monomer can also be of any species, e.g., human, murine, or mouse. A dimer of Fc domain monomers is an Fc domain that can bind to an Fc receptor, which is a receptor located on the surface of leukocytes.

[0240] In some embodiments, an Fc domain monomer described herein may contain one or more amino acid substitutions, additions, or deletion relative to an Fc domain monomer having a sequence of any one of SEQ ID NOs: 1 -120 and 283. In some embodiments, an Asn (e.g., N297) in an Fc domain monomer in the conjugates as described herein may be replaced by Ala (e.g., N297A), Gly (e.g., N297G), or Gin (e.g., N297Q) in order to prevent N-linked glycosylation. In some embodiments, the amino acid corresponding to N297 is substituted with Ala, Gly, or Gin.

[0241] In some embodiments, an Fc domain monomer in a conjugate or fusion protein described herein includes an additional moiety for purification (e.g., a hexa-histidine peptide), or a signal sequence (e.g., IL2 signal sequence) attached to the N- or C-terminus of the Fc domain monomer. In some embodiments, an additional moiety for purification (e.g., a hexa-histidine peptide), or a signal sequence (e.g., IL2 signal sequence) attached to the N- or C-terminus of the Fc domain monomer is cleaved after expression of the polypeptide. In some embodiments, an Fc domain monomer in the compositions does not contain any type of antibody variable region, e.g., VH, VL, a complementarity determining region (CDR), or a hypervariable region (HVR).

[0242] In some embodiments, an Fc domain monomer in a polypeptide or conjugate described herein may have a sequence that is at least 95% identical (e.g., 97%, 99%, or 99.5% identical) to the sequence of any one of SEQ ID NOs: 1-120 and 283, shown below. In some embodiments, an Fc domain monomer in the polypeptides or conjugates as described herein may include a sequence of any one of SEQ ID NOs: 1-120 and 283, shown below.

[0243] SEQ ID NO: 1 : mature human Fc lgG1 , Z1is Cys or Ser, and wherein X1is Met or Tyr, X2is Ser or Thr, X3is Thr or Glu, X4is Asp or Glu, and X5is Leu or Met, X6is Met or Leu, and X7is Asn or Ser NVNHKPSNTKVDKKVEPKSZ1DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLX1IX2RX3PEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPGK

[0244] SEQ ID NO: 2: mature human Fc lgG1 , Cys to Ser substitution (#), and wherein X1is Met or Tyr, X2is Ser or Thr, X3is Thr or Glu, X4is Asp or Glu, and X5is Leu or Met, X6is Met or Leu, and X7is Asn or Ser NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLXIIX2RX3PEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPGK

[0245] SEQ ID NO: 3: mature human IgG 1 Fc, Cys to Ser substitution (#), X4is Asp or Glu, and X5is Leu or Met NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF

[0246] LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0247] SEQ ID NO: 4: mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(f) (bold italics)

[0248] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0249] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

[0250] KAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0251] YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0252] SEQ ID NO: 5: mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(fa) (bold italics)

[0253] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0254] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

[0255] KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0256] YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0257] SEQ ID NO: 6: mature human lgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutations

[0258] (Bold / Underlined), allotype G1 m(fa) (bold italics)

[0259] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0260] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

[0261] KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0262] YSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

[0263] SEQ ID NO: 7: mature human IgG 1 Fc, Cys to Ser substitution (#), M428L, N434S mutations

[0264] (Bold / Underlined), allotype G1 m(f) (bold italics)

[0265] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0266] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

[0267] KAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0268] YSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

[0269] SEQ ID NO: 8: mature human IgG 1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0270] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVWDVSH

[0271] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

[0272] KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0273] YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 9: mature human IgG 1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1 m(f) (bold italics) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0274] SEQ ID NO: 10: mature human Fc IgG 1 , Z1is Cys or Ser, and wherein X1is Met or Tyr, X2is Ser or Thr, X3is Thr or Glu, X4is Asp or Glu, and X5is Leu or Met, X6is Met or Leu, and X7is Asn or Ser NVNHKPSNTKVDKKVEPKSZ1DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLX1IX2RX3PEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPG

[0275] SEQ ID NO: 11 : mature human Fc IgG 1 , Cys to Ser substitution (#), and wherein X1is Met or Tyr, X2is Ser or Thr, X3is Thr or Glu, X4is Asp or Glu, and X5is Leu or Met, X6is Met or Leu, and X7is Asn or Ser NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLXIIX2RX3PEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPG

[0276] SEQ ID NO: 12: mature human IgG 1 Fc, Cys to Ser substitution (#), X4is Asp or Glu, and X5is Leu or Met NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0277] SEQ ID NO: 13: mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(f) (bold italics) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0278] SEQ ID NO: 14: mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(fa) (bold italics) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 15: mature human lgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutations (Bold / Underlined), allotype G1 m(fa) (bold italics)

[0279] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0280] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

[0281] KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0282] YSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0283] SEQ ID NO: 16: mature human lgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutations (Bold / Underlined), allotype G1 m(f) (bold italics)

[0284] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0285] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

[0286] KAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0287] YSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0288] SEQ ID NO: 17: mature human lgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0289] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVWDVSH

[0290] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

[0291] KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0292] YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0293] SEQ ID NO: 18: mature human lgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0294] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVWDVSH

[0295] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

[0296] KAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0297] YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0298] SEQ ID NO: 19: mature human Fc IgG 1 , Z1is Cys or Ser, and wherein X1is Met or Tyr, X2is Ser or Thr, X3is Thr or Glu, X4is Asp or Glu, and X5is Leu or Met, X6is Met or Leu, and X7is Asn or Ser

[0299] VNHKPSNTKVDKKVEPKSZ1DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLX1IX2RX3PEVTCVVVDVSHE

[0300] DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK

[0301] AKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0302] YSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPGK SEQ ID NO: 20: mature human Fc IgG 1 , Cys to Ser substitution (#), and wherein X1is Met or Tyr, X2is Ser or Thr, X3is Thr or Glu, X4is Asp or Glu, and X5is Leu or Met, X6is Met or Leu, and X7is Asn or Ser VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLXIIX2RX3PEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPGK

[0303] SEQ ID NO: 21 : mature human IgG 1 Fc, Cys to Ser substitution (#), X4is Asp or Glu, and X5is Leu or Met VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0304] SEQ ID NO: 22: mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(f) (bold italics) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0305] SEQ ID NO: 23: mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(fa) (bold italics) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0306] SEQ ID NO: 24: mature human lgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutations (Bold / Underlined), allotype G1 m(fa) (bold italics) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

[0307] SEQ ID NO: 25: mature human lgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutations (Bold / Underlined), allotype G1 m(f) (bold italics) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

[0308] SEQ ID NO: 26: mature human lgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1 m(fa) (bold italics) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0309] SEQ ID NO: 27: mature human lgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1 m(f) (bold italics) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0310] SEQ ID NO: 28: mature human Fc IgG 1 , Z1is Cys or Ser, and wherein X1is Met or Tyr, X2is Ser or Thr, X3is Thr or Glu, X4is Asp or Glu, and X5is Leu or Met, X6is Met or Leu, and X7is Asn or Ser VNHKPSNTKVDKKVEPKSZ1DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLX1IX2RX3PEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPG

[0311] SEQ ID NO: 29: mature human Fc IgG 1 , Cys to Ser substitution (#), and wherein X1is Met or Tyr, X2is Ser or Thr, X3is Thr or Glu, X4is Asp or Glu, and X5is Leu or Met, X6is Met or Leu, and X7is Asn or Ser VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLXIIX2RX3PEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPG

[0312] SEQ ID NO: 30: mature human IgG 1 Fc, Cys to Ser substitution (#), X4is Asp or Glu, and X5is Leu or Met VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 31 : mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(f) (bold italics)

[0313] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0314] SEQ ID NO: 32: mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(fa) (bold italics)

[0315] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0316] SEQ ID NO: 33: mature human lgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutations (Bold / Underlined), allotype G1 m(fa) (bold italics)

[0317] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0318] SEQ ID NO: 34: mature human lgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutations (Bold / Underlined), allotype G1 m(f) (bold italics)

[0319] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0320] SEQ ID NO: 35: mature human lgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0321] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0322] SEQ ID NO: 36: mature human lgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0323] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 37: mature human Fc IgG 1 , Ji is Asn or absent, J2 is Lys or absent, Z1 is Cys or Ser, and wherein X1is Met or Tyr, X2is Ser or Thr, X3is Thr or Glu, X4is Asn or Ala, X5is Leu or Asp, Xa is Gin or His, X7is Asp or Glu, and Xa is Leu or Met, X9is Met or Leu, and X10 is Asn or Ser

[0324] J1VNHKPSNTKVDKKVEPKSZ1DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLX1IX2RX3PEVTCVWDVSH

[0325] EDPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTVX5HX6DVVLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVX9HEALHX10HYTQKSLSLSPGJ2

[0326] SEQ ID NO: 38: mature human Fc IgG 1 , Cys to Ser substitution (#), Ji is Asn or absent, J2 is Lys or absent, and wherein X4is Asn or Ala, X5is Leu or Asp, X6is Gin or His, X7is Asp or Glu, and Xa is Leu or Met, and X10 is Asn or Ser

[0327] JiVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTVX5HX6DWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHX10HYTQKSLSLSPGJ2

[0328] SEQ ID NO: 39: mature human Fc lgG1 , Cys to Ser substitution (#), DHS triple mutation (bold and underlined), Ji is Asn or absent, J2 is Lys or absent, wherein X4is Asn or Ala, X7is Asp or Glu, and Xa is Leu or Met

[0329] JiVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH

[0330] EDPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGJ2

[0331] SEQ ID NO: 40: mature human Fc lgG1 , Cys to Ser substitution (#), DHS triple mutation (bold and underlined), wherein X4is Asn or Ala, X7is Asp or Glu, and Xa is Leu or Met

[0332] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0333] EDPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0334] SEQ ID NO: 41 : mature human Fc IgG 1 , Cys to Ser substitution (#), DHS triple mutation (bold and underlined), wherein X7is Asp or Glu and Xa is Leu or Met

[0335] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK SEQ ID NO: 42: mature human Fc lgG1 , Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0336] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0337] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0338] SEQ ID NO: 43: mature human Fc lgG1 , Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0339] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0340] SEQ ID NO: 44: mature human Fc lgG1 , Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0341] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0342] SEQ ID NO: 45: mature human Fc lgG1 , Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0343] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0344] SEQ ID NO: 46: mature human Fc lgG1 , Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0345] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0346] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0347] SEQ ID NO: 47: mature human Fc lgG1 , Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0348] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0349] EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0350] SEQ ID NO: 48: mature human Fc lgG1 , Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0351] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0352] SEQ ID NO: 49: mature human Fc lgG1 , Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0353] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0354] SEQ ID NO: 50: mature human Fc IgG 1 , Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), wherein X7is Asp or Glu and X8is Leu or Met

[0355] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0356] SEQ ID NO: 51 : mature human Fc IgG 1 , Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0357] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0358] SEQ ID NO: 52: mature human Fc IgG 1 , Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0359] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK SEQ ID NO: 53: mature human Fc IgG 1 , Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0360] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0361] SEQ ID NO: 54: mature human Fc IgG 1 , Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0362] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0363] SEQ ID NO: 55: mature human Fc IgG 1 , Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0364] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0365] SEQ ID NO: 56: mature human Fc IgG 1 , Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0366] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0367] EDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0368] SEQ ID NO: 57: mature human Fc IgG 1 , Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0369] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0370] SEQ ID NO: 58: mature human Fc IgG 1 , Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0371] VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE

[0372] DPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0373] SEQ ID NO: 59: mature human Fc IgG 1 , Ji is Asn or absent, J2 is Lys or absent, and wherein X4is Asn or Ala, X5is Leu or Asp, Xa is Gin or His, X7is Asp or Glu, and Xa is Leu or Met, and X10 is Asn or Ser

[0374] J1VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE

[0375] DPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRWSVLTVX5HX6DWLNGKEYKCKVSNKALPAPIEKTIS

[0376] KAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF

[0377] LYSKLTVDKSRWQQGNVFSCSVMHEALHX10HYTQKSLSLSPGJ2

[0378] SEQ ID NO: 60: mature human Fc IgG 1 , DHS triple mutation (bold and underlined), Ji is Asn or absent,

[0379] J2 is Lys or absent, and wherein X4is Asn or Ala, X7is Asp or Glu, and Xa is Leu or Met

[0380] J1VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE

[0381] DPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISK

[0382] AKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0383] YSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGJ2

[0384] SEQ ID NO: 61 : mature human Fc IgG 1 , DHS triple mutation (bold and underlined), wherein X4is Asn or

[0385] Ala, and X7is Asp or Glu, and Xa is Leu or Met

[0386] NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED

[0387] PEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKA

[0388] KGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

[0389] SKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0390] SEQ ID NO: 62: mature human Fc IgG 1 , DHS triple mutation (bold and underlined), wherein X7is Asp or Glu and Xa is Leu or Met

[0391] NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED

[0392] PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKA

[0393] KGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

[0394] SKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0395] SEQ ID NO: 63: mature human Fc lgG1 , DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0396] NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED

[0397] PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKA

[0398] KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS

[0399] KLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK SEQ ID NO: 64: mature human Fc lgG1 , DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0400] NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED

[0401] PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKA

[0402] KGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS

[0403] KLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0404] SEQ ID NO: 65: mature human Fc lgG1 , DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0405] VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

[0406] EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKAK

[0407] GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0408] SEQ ID NO: 66: mature human Fc lgG1 , DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0409] VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

[0410] EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKAK

[0411] GQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK

[0412] LTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0413] SEQ ID NO: 67: mature human Fc lgG1 , DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0414] NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED

[0415] PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKA

[0416] KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS

[0417] KLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0418] SEQ ID NO: 68: mature human Fc lgG1 , DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0419] NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED

[0420] PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKA

[0421] KGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS

[0422] KLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0423] SEQ ID NO: 69: mature human Fc lgG1 , DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0424] VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

[0425] EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0426] SEQ ID NO: 70: mature human Fc IgG 1 , DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0427] VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0428] SEQ ID NO: 71 : mature human Fc IgG 1 , Asn to Ala substitution (*), DHS triple mutation (bold and underlined), wherein X? is Asp or Glu and Xa is Leu or Met NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

[0429] YSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0430] SEQ ID NO: 72: mature human Fc IgG 1 , Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics) NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISK

[0431] AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0432] SEQ ID NO: 73: mature human Fc IgG 1 , Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics) NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISK

[0433] AKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0434] SEQ ID NO: 74: mature human Fc IgG 1 , Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0435] VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

[0436] EVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK SEQ ID NO: 75: mature human Fc IgG 1 , Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0437] VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

[0438] EVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0439] SEQ ID NO: 76: mature human Fc IgG 1 , Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0440] NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED

[0441] PEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0442] SEQ ID NO: 77: mature human Fc IgG 1 , Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0443] NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED

[0444] PEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGK

[0445] SEQ ID NO: 78: mature human Fc IgG 1 , Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(fa) (bold italics)

[0446] VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

[0447] EVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0448] SEQ ID NO: 79: mature human Fc IgG 1 , Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1 m(f) (bold italics)

[0449] VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

[0450] EVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0451] SEQ ID NO: 80: mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(f) (bold italics), Asn to Ala substitution (*)

[0452] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH

[0453] EDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0454] SEQ ID NO: 81 : mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(fa) (bold italics), Asn to Ala substitution (*) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0455] SEQ ID NO: 82: mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(f) (bold italics), YTE triple mutation (bold and underlined), Asn to Ala substitution (*) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0456] SEQ ID NO: 83: mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(fa) (bold italics), YTE triple mutation (bold and underlined), Asn to Ala substitution (*) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0457] In some embodiments, the variant Fc domain includes an amino acid substitution at position 246 (e.g., K246X where X is any amino acid that is not Lys, such as K246S, K246G, K246A, K246T, K246N, K246Q, K246R, K246H, K246E, or K246DC220S). In some embodiments, the variant Fc domain monomer includes at least the following mutations K246X, M252Y, S254T, and T256E, where X is not Lys. In some embodiments, the variant Fc domain monomer includes at least the following mutations K246X, V309D, Q311 H, and N434S, where X is not Lys. In some embodiments, the variant Fc domain monomer includes at least the following mutations K246X, M428L, and N434S, where X is not Lys. In some embodiments, the variant Fc domain further includes a mutation of position 220, e.g., a C220S mutation. Amino acid substitutions are relative to a wild-type Fc monomer amino acid sequence, e.g., wild-type human IgG 1 or lgG2.

[0458] In some embodiments, a variant Fc domain monomer includes a sequence that is at least 95% identical (e.g., 97%, 99%, or 99.5% identical) to the sequence of any one of SEQ ID Nos: 84-120 and 283 shown below. In some embodiments, a variant Fc domain monomer includes the sequence of any one of SEQ ID Nos: 84-120 and 283 shown below. In some embodiments, a variant Fc domain monomer includes at least the following mutations K246X, M252Y, S254T, and T256E, where X is not Lys. In some embodiments, a variant Fc domain monomer includes at least the following mutations K246X, V309D, Q311 H, and N434S, where X is not Lys. In some embodiments, a variant Fc domain monomer includes at least the following mutations K246X, M428L, and N434S, where X is not Lys. In some embodiments, the substitution at K246X is selected from Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp. In some embodiments, the substitution at K246X is Ser.

[0459] SEQ ID NO: 84: mature human IgG 1 Fc; X1(position 201) is Asn or absent; X2(position 220) is Cys or Ser; X3(position 246) is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X4(position 252) is Met or Tyr; X5(position 254) is Ser or Thr; X6(position 256) is Thr or Glu; X7(position 297) is Asn or Ala; X8(position 309) is Leu or Asp; X9(position 311) is Gin or His; X10(position 356) is Asp or Glu; and X11(position 358) is Leu or Met; X12 (position 428) is Met or Leu; X13 (position 434) is Asn or Ser; X14(position 447) is Lys or absent; N-terminal Fab residues are underlined; hinge residues are italicized X1VNHKPSNTKVDKKVEPKSX2DKTHTCPPC PAP E LLG G PS VF LFP PX3P KDTLX4I X5RX6P E VTCVVVD VS HEDPEVKFNWYVDGVEVHNAKTKPREEQYX7STYRVVSVLTVX8HX9DVVLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRX10EX11TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVX12HEALH X13HYTQKSLSLSPGX14

[0460] SEQ ID NO: 85: mature human IgG 1 Fc; Cys to Ser substitution (#); X1is Asn or absent; X2is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X3is Asn or Ala; X4is Asp or Glu; and X5is Leu or Met; X6is Lys or absent; N-terminal Fab residues are underlined; hinge residues are italicized X1VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPX2PKDTLMISRTPEVTCVWDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYX3STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGX6

[0461] SEQ ID NO: 86: mature human lgG1 Fc; Cys to Ser substitution (#); X1is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X2is Asn or Ala; X3is Asp or Glu; and X4is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized

[0462] NVNHKPSNTKVDKKVEPKSS(D#) KTHTCPPC P AP E LLG G PS VF LFP PX1P KDTLM I S RTPE VTC WVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYX2STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX3EX4TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0463] SEQ ID NO: 87: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); X1is Asp or Glu; and X2is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized

[0464] NVNHKPSNTKVDKKVEPKSS(#)D / <T / - / TCPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV

[0465] SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRX1EX2TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

[0466] FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0467] SEQ ID NO: 88: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized

[0468] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0469] SEQ ID NO: 89: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); allotype G1 m(f) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized

[0470] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0471] SEQ ID NO: 90: mature human IgG 1 Fc; Cys to Ser substitution (#); Asn to Ala substitution (A); X1is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X2is Asp or Glu; and X3is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized

[0472] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PX1P KDTLM I S RTPE VTC WVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYA(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRX2EX3TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0473] SEQ ID NO: 91 : mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); Asn to Ala substitution (A); X1is Asp or Glu; and X2is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized

[0474] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRX1EX2TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0475] SEQ ID NO: 92: mature human lgG1 Fc; Cys to Ser substitution (#); YTE triple mutation (bold and underlined); X1is Asn or absent; X2is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X3is Asn or Ala; X4is Asp or Glu; and X5is Leu or Met; X6is Lys or absent; N-terminal Fab residues are underlined; hinge residues are italicized X1VNHKPSNTKVDKKVEPKSS(#)DKTHT CPPCPAPELLGGPSVFLFPPX2PKDTLYITREPEVTCWVDVS

[0476] HEDPEVKFNWYVDGVEVHNAKTKPREEQYX3STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF

[0477] FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGX6

[0478] SEQ ID NO: 93: mature human lgG1 Fc; Cys to Ser substitution (#); YTE triple mutation (bold and underlined); X1is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X2is Asn or Ala; X3is Asp or Glu; and X4is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized

[0479] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PX1P KDTLYI TRE P E VTCVWDVS H

[0480] EDPEVKFNWYVDGVEVHNAKTKPREEQYX2STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRX3EX4TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0481] SEQ ID NO: 94: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); YTE triple mutation (bold and underlined); X1is Asp or Glu; and X2is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized

[0482] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PS(*) P KDTL YITRE P EVTC WVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX1EX2TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0483] SEQ ID NO: 95: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); YTE triple mutation (bold and underlined); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized

[0484] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PS(*) P KDTL YITRE P EVTC WVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0485] SEQ ID NO: 96: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); YTE triple mutation (bold and underlined); allotype G1 m(f) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized

[0486] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PS(*) P KDTL YITRE P EVTC WVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 97: mature human IgG 1 Fc; Cys to Ser substitution (#); Asn to Ala substitution (A); YTE triple mutation (bold and underlined); X1is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X2is Asp or Glu; and X3is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized

[0487] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PX1P KDTLYI TRE P E VTCVWDVS H EDPEVKFNWYVDGVEVHNAKTKPREEQYA(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX2EX3TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0488] SEQ ID NO: 98: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); Asn to Ala substitution (A); YTE triple mutation (bold and underlined); X1is Asp or Glu; and X2is Leu or Met; N- terminal Fab residues are underlined; hinge residues are italicized

[0489] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PS(*) P KDTL YITRE P EVTC WVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYA(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRX1EX2TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0490] SEQ ID NO: 99: mature human lgG1 Fc; Cys to Ser substitution (#); DHS triple mutation (bold and underlined); X1is Asn or absent; X2is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X3is Asn or Ala; X4is Asp or Glu; and X5is Leu or Met; X6is Lys or absent; N-terminal Fab residues are underlined; hinge residues are italicized

[0491] XIVNHKPSNTKVDKKVEPKSS(#)DK7H7~CPPCPAPELLGGPSVFLFPPX2PKDTLMISRTPEVTCVWDVS

[0492] HEDPEVKFNWYVDGVEVHNAKTKPREEQYX3STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPGX6

[0493] SEQ ID NO: 100: mature human IgG 1 Fc; Cys to Ser substitution (#); DHS triple mutation (bold and underlined); X1is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X2is Asn or Ala; X3is Asp or Glu; and X4is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized

[0494] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PX1P KDTLM I S RTPE VTC WVDVS

[0495] HEDPEVKFNWYVDGVEVHNAKTKPREEQYX2STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX3EX4TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0496] SEQ ID NO: 101 : mature human lgG1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); DHS triple mutation (bold and underlined); X1is Asp or Glu; and X2is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized

[0497] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRX1EX2TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0498] SEQ ID NO: 102: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); DHS triple mutation (bold and underlined); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized

[0499] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0500] SEQ ID NO: 103: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); DHS triple mutation (bold and underlined); allotype G1 m(f) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized

[0501] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVDHHDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0502] SEQ ID NO: 104: mature human IgG 1 Fc; Cys to Ser substitution (#); Asn to Ala substitution (A); DHS triple mutation (bold and underlined); X1is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X2is Asp or Glu; and X3is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized

[0503] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PX1P KDTLM I S RTPE VTC WVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYA(A)STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRX2EX3TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[0504] SEQ ID NO: 105: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); Asn to Ala substitution (A); DHS triple mutation (bold and underlined); X1is Asp or Glu; and X2is Leu or Met; N- terminal Fab residues are underlined; hinge residues are italicized

[0505] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(A)STYRVVSVLTVDHHDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSR X1EX2TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG SEQ ID NO: 106: mature human IgG 1 Fc; Cys to Ser substitution (#); LS double mutation (bold and underlined); X1is Asn or absent; X2is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X3is Asn or Ala; X4is Asp or Glu; and X5is Leu or Met; X6is Lys or absent; N-terminal Fab residues are underlined; hinge residues are italicized X1VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPX?PKDTLMISRTPEVTCWVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYX3STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGX6

[0506] SEQ ID NO: 107: mature human IgG 1 Fc; Cys to Ser substitution (#); LS double mutation (bold and underlined); X1is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X2is Asn or Ala; X3is Asp or Glu; and X4is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PX1P KDTLM I S RTPE VTC WVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYX2STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI

[0507] SKAKGQPREPQVYTLPPSRX3EX4TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0508] SEQ ID NO: 108: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); LS double mutation (bold and underlined); X1is Asp or Glu; and X2is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)D / <77- / 7~CPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV

[0509] SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRX1EX2TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0510] SEQ ID NO: 109: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); LS double mutation (bold and underlined); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)D / <77- / 7~CPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV

[0511] SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0512] SEQ ID NO: 110: mature human lgG1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); LS double mutation (bold and underlined); allotype G1 m(f) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)D / <77- / 7~CPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV

[0513] SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0514] SEQ ID NO: 111 : mature human IgG 1 Fc; Cys to Ser substitution (#); Asn to Ala substitution (A); LS double mutation (bold and underlined); X1is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X2is Asp or Glu; and X3is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PX1P KDTLM I S RTPE VTC WVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYA(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRX2EX3TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0515] SEQ ID NO: 112: mature human IgG 1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); Asn to Ala substitution (A); LS double mutation (bold and underlined); X1is Asp or Glu; and X2is Leu or Met; N- terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRX1EX2TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0516] SEQ ID NO: 113: mature human lgG1 Fc; Cys to Ser substitution (#); Asn to Gin substitution (A); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPP CPAP E LLG G PS VF LF PP KPKDTLM I S RTP E VTCVVVD VSH EDPEVKFNWYVDGVEVHNAKTKPREEQYQ(A)STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0517] SEQ ID NO: 114: mature human IgG 1 Fc; Cys to Ser substitution (#); Asn to Gin substitution (A); allotype G1 m(f) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYQ(A)STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0518] SEQ ID NO: 115: mature human IgG 1 Fc; Cys to Ser substitution (#);Lys to Ser substitution(*); LS double mutation (bold and underlined); Asn to Gin substitution (A); allotype G1 m(f) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYQ(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0519] SEQ ID NO: 116: mature human IgG 1 Fc; Cys to Ser substitution (#);LS double mutation (bold and underlined); Asn to Gin substitution (A); X1is Ser, Gly, Ala, Thr, Asn, Gin, Arg, His, Glu, or Asp; X2is Asp or Glu; and X3is Leu or Met; N-terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPC P AP E LLG G PS VF LFP PX1P KDTLM I S RTPE VTC WVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYQ(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRX2EX3TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0520] SEQ ID NO: 117: mature human lgG1 Fc; Cys to Ser substitution (#); Lys to Ser substitution(*); Asn to Gin substitution (A); LS double mutation (bold and underlined); X1is Asp or Glu; and X2is Leu or Met; N- terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)D / <77- / 7~CPPCPAPELLGGPSVFLFPPS(*)PKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYQ(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRX1EX2TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[0521] SEQ ID NO: 118: mature human lgG1 Fc; Cys to Ser substitution (#); Asn to Gin substitution (A); allotype G1 m(f) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYQ(A)STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0522] SEQ ID NO: 119: mature human lgG1 Fc; Cys to Ser substitution (#); Asn to Gin substitution (A); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized; GGGS insertion (bold, no italics)

[0523] NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPP CPAP E LLG GG GSG PS VF LF PP KP KDTLM I S RTP E VTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQ(A)STYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0524] SEQ ID NO: 120: mature human IgG 1 Fc; Cys to Ser substitution (#); allotype G1 m(fa) (bold italics); N- terminal Fab residues are underlined; hinge residues are italicized; GGGS insertion (bold, no italics) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPP CPAP E LLG GG GSG PS VF LF PP KP KDTLM I S RTP E VTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD

[0525] GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0526] SEQ ID NO: 283: mature human lgG1 Fc; Cys to Ser substitution (#); allotype G1 m(fa) (bold italics); N- terminal Fab residues are underlined; hinge residues are italicized; GGGS insertion (bold, no italics) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPP CPAP E LLG GG GSG PS VF LF PP KP KDTLM I S RTP E VTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0527] As defined herein, an Fc domain includes two Fc domain monomers that are dimerized by the interaction between the CH3 antibody constant domains, as well as one or more disulfide bonds that form between the hinge domains of the two dimerizing Fc domain monomers. An Fc domain forms the minimum structure that binds to an Fc receptor, e.g., Fc-gamma receptors (i.e. , Fey receptors (FcγR)), Fc-alpha receptors (i.e., Fea receptors (FcaR)), Fc-epsilon receptors (i.e., Fcε receptors ( FcεR)), or the neonatal Fc receptor (FcRn). In some embodiments, an Fc domain of the present disclosure binds to an Fey receptor (e.g., FcRn, FcyRI (CD64), FcyRlla (CD32), FcyRllb (CD32), FcyRllla (CD16a), FcyRlllb (CD16b)), or FcyRIV or the neonatal Fc receptor (FcRn).

[0528] In some embodiments, the Fc domain monomer or Fc domain of the disclosure is an aglycosylated Fc domain monomer or Fc domain (e.g., an Fc domain monomer or an Fc domain that maintains engagement to an Fc receptor (e.g., FcRn). For example, the Fc domain is an aglycosylated lgG1 variants that maintains engagement to an Fc receptor (e.g., an lgG1 having an amino acid substitution at N297 or T299 of the glycosylation motif). Exemplary aglycosylated Fc domains and methods for making aglycosylated Fc domains are known in the art, for example, as described in Sazinsky S.L. et al., Aglycosylated immunoglobulin G1 variants productively engage activating Fc receptors, PNAS, 2008, 105(51):20167-20172, which is incorporated herein in its entirety.

[0529] In some embodiments, the Fc domain or Fc domain monomer of the disclosure is engineered to enhance binding to the neonatal Fc receptor (FcRn). For example, the Fc domain may include the triple mutation corresponding to M252Y / S254T / T256E (YTE) (e.g., an IgG 1 , such as a human or humanized lgG1 having a YTE mutation). The Fc domain may include the single mutant corresponding to N434H (e.g., an lgG1 , such as a human or humanized IgG 1 having an N434H mutation). The Fc domain may include the single mutant corresponding to C220S (e.g., and lgG1 , such as a human or humanized lgG1 having a C220S mutation). The Fc domain may include a quadruple mutant corresponding to C220S / L309D / Q311 H / N434S (CDHS) (e.g., an lgG1 , such as a human or humanized lgG1 having a DHS mutation). The Fc domain may include a triple mutant corresponding to L309D / Q311 H / N434S (DHS) (e.g., an lgG1 , such as a human or humanized IgG 1 having a DHS mutation). The Fc domain may include a combination of one or more of the above-described mutations that enhance binding to the FcRn. Enhanced binding to the FcRn may increase the half-life Fc domain-containing conjugate. For example, incorporation of one or more amino acid mutations that increase binding to the FcRn (e.g., a YTE mutation, an LS mutation, or an N434H mutation) may increase the half-life of the conjugate by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%. 100%, 200%, 300%, 400%, 500% or more relative to a conjugate having the corresponding Fc domain without the mutation that enhances FcRn binding. Exemplary Fc domains with enhanced binding to the FcRN and methods for making Fc domains having enhanced binding to the FcRN are known in the art, for example, as described in Maeda, A. et al., Identification of human IgG 1 variant with enhanced FcRn binding and without increased binding to rheumatoid factor autoantibody, MABS, 2017, 9(5):844-853, which is incorporated herein in its entirety. As used herein, an amino acid “corresponding to” a particular amino acid residue (e.g., of a particular SEQ ID NO.) should be understood to include any amino acid residue that one of skill in the art would understand to align to the particular residue (e.g., of the particular sequence). For example, any one of SEQ ID NOs: 1-120 and 283 may be mutated to include a YTE mutation, an LS mutation, or an N434H mutation by mutating the “corresponding residues” of the amino acid sequence.

[0530] In some embodiments, the Fc domain or Fc domain monomer of the disclosure has the sequence of any one of SEQ ID NOs: 1-120 and 283 may further include additional amino acids at the N-terminus (Xaa)x or additional amino acids at the C-terminus (Xaa)z, wherein Xaa is any amino acid and x and z are a whole number greater than or equal to zero, generally less than 100, preferably less than 10 and more preferably 0, 1 , 2, 3, 4, or 5. For example, the additional amino acids may be a single amino acid on the C-terminus corresponding to Lys330 of IgG 1 .

[0531] In some embodiments, the Fc domain monomer includes less than about 300 amino acid residues (e.g., less than about 300, less than about 295, less than about 290, less than about 285, less than about 280, less than about 275, less than about 270, less than about 265, less than about 260, less than about 255, less than about 250, less than about 245, less than about 240, less than about 235, less than about 230, less than about 225, or less than about 220 amino acid residues). In some embodiments, the Fc domain monomer is less than about 40 kDa (e.g., less than about 35kDa, less than about 30kDa, less than about 25kDa).

[0532] In some embodiments, the Fc domain monomer includes at least 200 amino acid residues (e.g., at least 210, at least 220, at least 230, at least 240, at least 250, at least 260, at least 270, at least 280, at least 290, or at least 300 amino residues). In some embodiments, the Fc domain monomer is at least 20 kDa (e.g., at least 25 kDa, at least 30 kDa, or at least 35 kDa).

[0533] In some embodiments, the Fc domain monomer includes 200 to 400 amino acid residues (e.g., 200 to 250, 250 to 300, 300 to 350, 350 to 400, 200 to 300, 250 to 350, or 300 to 400 amino acid residues). In some embodiments, the Fc domain monomer is 20 to 40 kDa (e.g., 20 to 25 kDa, 25 to 30 kDa, 35 to 40 kDa, 20 to 30 kDa, 25 to 35 kDa, or 30 to 40 KDa).

[0534] In some embodiments, the Fc domain monomer includes an amino acid sequence at least 90% identical (e.g., at least 95%, at least 98%) to the sequence of any one of SEQ ID NOs: 1-120 and 283, or a region thereof. In some embodiments, the Fc domain monomer includes the amino acid sequence of any one of SEQ ID NOs: 1-120 and 283, or a region thereof.

[0535] In some embodiments, the Fc domain monomer includes a region of any one of SEQ ID NOs: 1-

[0536] 120 and 283, wherein the region includes positions 220, 252, 254, and 256. In some embodiments, the region includes at least 40 amino acid residues, at least 50 amino acid residues, at least 60 amino acid residues, at least 70 amino acids residues, at least 80 amino acids residues, at least 90 amino acid residues, at least 100 amino acid residues, at least 110 amino acid residues, at least 120 amino residues, at least 130 amino acid residues, at least 140 amino acid residues, at least 150 amino acid residues, at least 160 amino acid residues, at least 170 amino acid residues, at least 180 amino acid residues, at least 190 amino acid residues, or at least 200 amino acid residues.

[0537] Activation of Immune Cells

[0538] Fc-gamma receptors (FcyRs) bind the Fc portion of immunoglobulin G (IgG) and play important roles in immune activation and regulation. For example, the IgG Fc domains in immune complexes (les) engage FcyRs with high avidity, thus triggering signaling cascades that regulate immune cell activation. The human FcyR family contains several activating receptors (FcyRI, FcyRlla, FcyRllc, FcyRllla, and FcyRlllb) and one inhibitory receptor (FcyRllb). FcyR signaling is mediated by intracellular domains that contain immune tyrosine activating motifs (ITAMs) for activating FcyRs and immune tyrosine inhibitory motifs (ITIM) for inhibitory receptor FcyRllb. In some embodiments, FcyR binding by Fc domains results in ITAM phosphorylation by Src family kinases; this activates Syk family kinases and induces downstream signaling networks, which include PI3K and Ras pathways.

[0539] In the polypeptides or conjugates described herein, the Fc domain portion of the polypeptide or conjugate bind to FcyRs (e.g., FcRn, FcyRI, FcyRlla, FcyRllc, FcyRllla, and FcyRlllb) on immune cells and activate phagocytosis and effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC). Examples of immune cells that may be activated by the conjugates described herein include, but are not limited to, macrophages, neutrophils, eosinophils, basophils, lymphocytes, follicular dendritic cells, natural killer cells, and mast cells.

[0540] Tissue distribution

[0541] After a therapeutic enters the systemic circulation, it is distributed to the body’s tissues. Distribution is generally uneven because of differences in blood perfusion, tissue binding, regional pH, and permeability of cell membranes. The entry rate of a drug into a tissue depends on the rate of blood flow to the tissue, tissue mass, and partition characteristics between blood and tissue. Distribution equilibrium (when the entry and exit rates are the same) between blood and tissue is reached more rapidly in richly vascularized areas unless diffusion across cell membranes is the rate-limiting step. The size, shape, charge, target binding, FcRn and target binding mechanisms, route of administration, and formulation affect tissue distribution.

[0542] In some instances, the conjugates or polypeptides described herein may be optimized to distribute to lung tissue. In some instances, the conjugates or polypeptides have a concentration ratio of distribution in epithelial lining fluid of at least 30% the concentration of the conjugate or polypeptide in plasma within 2 hours after administration. In certain embodiments, ratio of the concentration is at least 45% within 2 hours after administration. In some embodiments, the ratio of concentration is at least 55% within 2 hours after administration. In particular, the ratio of concentration is at least 60% within 2 hours after administration.

[0543] III. Complementarity-determining regions of the disclosure

[0544] The disclosure features compositions (e.g., polypeptides and conjugates) which include complementarity-determining regions (CDRs) sequences from anti-PD-1 monoclonal antibodies. In some embodiments, the Fc domain may include three heavy chain variable regions and three light chain variable regions and binds to PD-1 (Table 3). In some embodiments, the polypeptide of each E includes three LCDRs and three HCDRs selected from SEQ ID NOs: 121-166.

[0545] In some embodiments, the polypeptide includes LCDR1* (SEQ ID NO: 121), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDR1* (SEQ ID NO: 126), HCDR2* (SEQ ID NO: 129), and HCDR3 (SEQ ID NO: 137).

[0546] In some embodiments, the polypeptide includes LCDRIa (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRIa (SEQ ID NO: 127), HCDR2a (SEQ ID NO: 130), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRIa (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRIa (SEQ ID NO: 127), HCDR2b (SEQ ID NO: 131), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI a (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRIa (SEQ ID NO: 127), HCDR2c (SEQ ID NO: 132), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI a (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRIa (SEQ ID NO: 127), HCDR2d (SEQ ID NO: 133), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRIa (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRI a (SEQ ID NO: 127), HCDR2e (SEQ ID NO: 134), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRIa (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRIa (SEQ ID NO: 127), HCDR2f (SEQ ID NO: 135), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI a (SEQ ID NO: 122), LCDR2 (SEQ ID NO:

[0547] 124), LCDR3 (SEQ ID NO: 125), HCDRI a (SEQ ID NO: 127), HCDR2g (SEQ ID NO: 136), and HCDR3 (SEQ ID NO: 137).

[0548] In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRIa (SEQ ID NO: 127), HCDR2a (SEQ ID NO: 130), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRIa (SEQ ID NO: 127), HCDR2b (SEQ ID NO: 131), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125) HCDRI a (SEQ ID NO: 127), HCDR2c (SEQ ID NO: 132), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRIa (SEQ ID NO: 127), HCDR2d (SEQ ID NO: 133), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO:

[0549] 125), HCDRI a (SEQ ID NO: 127), HCDR2e (SEQ ID NO: 134), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRIa (SEQ ID NO: 127), HCDR2f (SEQ ID NO: 135), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO:

[0550] 124), LCDR3 (SEQ ID NO: 125), HCDRI a (SEQ ID NO: 127), HCDR2g (SEQ ID NO: 136), and HCDR3 (SEQ ID NO: 137).

[0551] In some embodiments, the polypeptide includes LCDRIa (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRI b (SEQ ID NO: 128), HCDR2a (SEQ ID NO: 130), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRIa (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRI b (SEQ ID NO: 128), HCDR2b (SEQ ID NO: 131), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI a (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRI b (SEQ ID NO: 128), HCDR2c (SEQ ID NO: 132), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI a (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRI b (SEQ ID NO: 128), HCDR2d (SEQ ID NO: 133), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRIa (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO:

[0552] 125), HCDRI b (SEQ ID NO: 128), HCDR2e (SEQ ID NO: 134), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRIa (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRI b (SEQ ID NO: 128), HCDR2f (SEQ ID NO: 135), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI a (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO: 125), HCDRI b (SEQ ID NO: 128), HCDR2g (SEQ ID NO: 136), and HCDR3 (SEQ ID NO: 137).

[0553] In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO:125), HCDRI b (SEQ ID NO: 128), HCDR2a (SEQ ID NO: 130), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO:125), HCDRI b (SEQ ID NO: 128), HCDR2b (SEQ ID NO: 131), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO:125), HCDRI b (SEQ ID NO: 128), HCDR2c (SEQ ID NO: 132), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO:125), HCDRI b (SEQ ID NO: 128), HCDR2d (SEQ ID NO: 133), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO:125), HCDRI b (SEQ ID NO: 128), HCDR2e (SEQ ID NO: 134), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO:125), HCDRI b (SEQ ID NO: 128), HCDR2f (SEQ ID NO: 135), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDRI b (SEQ ID NO: 123), LCDR2 (SEQ ID NO: 124), LCDR3 (SEQ ID NO:125), HCDRI b (SEQ ID NO: 128), HCDR2g (SEQ ID NO: 136), and HCDR3 (SEQ ID NO: 137). In some embodiments, the polypeptide includes LCDR1 (SEQ ID NO: 138), LCDR2 (SEQ ID NO: 139), LCDR3 (SEQ ID NO: 140), HCDR1 (SEQ ID NO: 141), HCDR2 (SEQ ID NO: 142), and HCDR3 (SEQ ID NO: 143).

[0554] In some embodiments, the polypeptide includes LCDR1 (SEQ ID NO: 122), LCDR2 (SEQ ID NO: 144), LCDR3 (SEQ ID NO: 145), HCDR1 (SEQ ID NO: 146), HCDR2 (SEQ ID NO: 147), and HCDR3

[0555] (SEQ ID NO: 148).

[0556] In some embodiments, the polypeptide includes LCDR1 (SEQ ID NO: 149), LCDR2 (SEQ ID NO: 150), LCDR3 (SEQ ID NO: 151), HCDR1 (SEQ ID NO: 152), HCDR2 (SEQ ID NO: 153), and HCDR3 (SEQ ID NO: 154). In some embodiments, the polypeptide includes LCDR1 (SEQ ID NO: 155), LCDR2 (SEQ ID NO:

[0557] 156), LCDR3 (SEQ ID NO:157), HCDR1 (SEQ ID NO:158), HCDR2 (SEQ ID NO: 159), and HCDR3 (SEQ ID NO: 160).

[0558] In some embodiments, the polypeptide includes LCDR1 (SEQ ID NO: 161), LCDR2 (SEQ ID NO: 162), LCDR3 (SEQ ID NO: 163), HCDR1 (SEQ ID NO: 164), HCDR2 (SEQ ID NO: 165), and HCDR3 (SEQ ID NO: 166).

[0559] Table 3. CDR sequences of the polypeptides of the present disclosure

[0560] Nivolumab is a humanized, lgG4 monoclonal antibody that binds to human PD-1 , and its CDRs and variants thereof are incorporated herein by reference (see US Patent No. 7,943,743).

[0561] Pembrolizumab is a humanized, lgG4 monoclonal antibody that binds to human PD-1 , and its CDRs and variants thereof are incorporated herein by reference (see US Patent No. 8,354,509). Cemiplimab is a humanized, lgG4 monoclonal antibody that binds to human PD-1 , and its CDRs and variants thereof are incorporated herein by reference (see US 9,987,500).

[0562] Dostarlimab is a humanized, lgG4 monoclonal antibody that binds to human PD-1 , and its CDRs and variants thereof are incorporated herein by reference (see US Patent No. 9,815,897). Retifanlimab is a humanized, lgG4 monoclonal antibody that binds to human PD-1 , and its CDRs and variants thereof are incorporated herein by reference (see US Patent No. 11 ,623,959).

[0563] Tislelizumab is a humanized, lgG4 monoclonal antibody that binds to human PD-1 , and its CDRs and variants thereof are incorporated herein by reference (see US Patent No. 9,217,034). IV. VL, VH, and ScFv sequences of the disclosure

[0564] In some embodiments, VL is an anti-PD-1 light chain variable region and VH is an anti-PD-1 heavy chain variable region. In some embodiments, the polypeptide of each E includes one VL and one VH. In some embodiments, the polypeptide of each E includes a VL selected from SEQ ID NOs: 167-175 (Table 4).

[0565] Table 4. VL sequences of the polypeptides of the present disclosure, CDRs are bolded. In some embodiments, the polypeptide of each E includes a VH selected from SEQ ID NOs: 176- 4 (Table 5).

[0566] Table 5. VH sequences of the polypeptides of the present disclosure, CDRs are bolded.

[0567] In some embodiments, the polypeptide of each E is selected from SEQ ID NOs: 205-272 and 284. The C-terminal Lys of the Fc region may or may not be present, without affecting the structure or stability of the Fc region. The C-terminal Lys may be proteolytically cleaved upon expression of the polypeptide. In some embodiments of any of the polypeptide sequences described herein, the C-terminal Lys is optionally present or absent.

[0568] SEQ ID NO: 205: CDRs bolded, Fc underlined

[0569] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSKRYYADSVKGRFTISRDNSKNT LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

[0570] CSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 206: CDRs (bolded), Lys to Arg substitution (A), Fc underlined

[0571] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0572] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0573] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSR(A)RYYADSVKGRFTISRDNSK NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK

[0574] VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV

[0575] FSCSVMHEALHNHYTQKSLSLSPG

[0576] SEQ ID NO: 207: CDRs bolded, Lys to Gin substitution (A), Fc underlined

[0577] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSQ(A)RYYADSVKGRFTISRDNSK

[0578] NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

[0579] SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG

[0580] SEQ ID NO: 208: CDRs bolded, Asn to Asp substitution (A), Fc underlined

[0581] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0582] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0583] VVQPGRSLRLDCKASGITFSD(A)SGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSK NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE

[0584] VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG

[0585] SEQ ID NO: 209: CDRs bolded, Vai to Ala substitution (A), Lys to Arg substitution (#), Fc underlined EIA(A)LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG TDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESG

[0586] GGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSR(#)RYYADSVKGRFTISRDN SKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVD KKVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG

[0587] VEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 210: CDRs bolded, Vai to Ala substitution (A), Lys to Arg substitution (#), Fc underlined EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQA(A)QLVESG GGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSR(#)RYYADSVKGRFTISRDN SKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVD KKVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG

[0588] SEQ ID NO: 211 : CDRs bolded, Lys to Arg substitution (A), Leu to Thr substitution (#), Fc underlined EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSR(A)RYYADSVKGRFTISRDNSK NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTT(#)VTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDK KVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPG

[0589] SEQ ID NO: 212: CDRs bolded, Lys to Ser substitution (A), Fc underlined

[0590] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSS(A)RYYADSVKGRFTISRDNSK NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG

[0591] SEQ ID NO: 213: CDRs bolded, Vai to Ala substitution (A), Fc underlined

[0592] EIA(A)LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG TDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESG GGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSK NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG

[0593] SEQ ID NO: 214: CDRs bolded, Leu to Thr substitution (A), Fc underlined

[0594] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0595] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0596] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0597] LFLQMNSLRAEDTAVYYCATNDDYWGQGTT(A)VTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKV

[0598] EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV

[0599] HNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS

[0600] RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPG

[0601] SEQ ID NO: 215: CDRs bolded, Vai to Glu substitution (A), Fc underlined

[0602] EIE(A)LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG

[0603] TDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESG

[0604] GGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSK

[0605] NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK

[0606] VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE

[0607] VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

[0608] SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG

[0609] SEQ ID NO: 216: CDRs bolded, Vai to Ser substitution (A), Fc underlined

[0610] EIS(A)LTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG

[0611] TDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESG

[0612] GGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSK

[0613] NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK

[0614] VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE

[0615] VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

[0616] SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG

[0617] SEQ ID NO: 217: CDRs bolded, Tyr to Ser substitution (A), Fc underlined

[0618] EIVLTQSPATLSLSPGERATLSCRASQSVSSS(A)LAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG

[0619] TDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESG

[0620] GGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSK

[0621] NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK

[0622] VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

[0623] SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV

[0624] FSCSVMHEALHNHYTQKSLSLSPG

[0625] SEQ ID NO: 218: CDRs bolded, Gly to Glu substitution (A), Fc underlined

[0626] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0627] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGE

[0628] (A)WQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSK

[0629] NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK

[0630] VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE

[0631] VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

[0632] SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG

[0633] SEQ ID NO: 219: CDRs bolded, Leu to Ser substitution (A), Fc underlined

[0634] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0635] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0636] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0637] LFLQMNSLRAEDTAVYYCATNDDYWGQGTS(A)VTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKV

[0638] EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV

[0639] HNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS

[0640] RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF

[0641] SCSVMHEALHNHYTQKSLSLSPG

[0642] SEQ ID NO: 220: CDRs bolded, Lys to Arg substitution (A), Fc underlined, Glycosylated Fc from Gin to

[0643] Asn substitution (#)

[0644] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0645] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0646] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSR(A)RYYADSVKGRFTISRDNSK

[0647] NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK

[0648] VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE

[0649] VHNAKTKPREEQYN(#)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL

[0650] PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG

[0651] SEQ ID NO: 221 : CDRs bolded, Fc underlined, Glycosylated Fc from Gin to Asn substitution (#)

[0652] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0653] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0654] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNT LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0655] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0656] NAKTKPREEQYN(#)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

[0657] SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG

[0658] SEQ ID NO: 222: CDRs bolded, Lys to Arg substitution (A), Fc underlined, GGGS insertion in Fc bolded and italicized

[0659] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0660] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0661] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSR(A)RYYADSVKGRFTISRDNSK

[0662] NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK

[0663] VEPKSSDKTHTCPPCPAPELLGGGGSGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

[0664] DGVEVHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV

[0665] YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0666] SEQ ID NO: 223: CDRs bolded, Fc underlined, GGGS insertion in Fc bolded and italicized, Glycosylated

[0667] Fc from Gin to Asn substitution (A)

[0668] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0669] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0670] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0671] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0672] PKSSDKTHTCPPCPAPELLGGGGSGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG

[0673] VEVHNAKTKPREEQYN(A)STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

[0674] TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ

[0675] QGNVFSCSVMHEALHNHYTQKSLSLSPG

[0676] SEQ ID NO: 224: CDRs bolded, Lys to Arg substitution (A), Fc underlined, GGGS insertion in Fc bolded and italicized, Glycosylated Fc from Gin to Asn substitution (#)

[0677] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0678] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0679] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSR(A)RYYADSVKGRFTISRDNSK

[0680] NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK

[0681] VEPKSSDKTHTCPPCPAPELLGGGGSGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

[0682] DGVEVHNAKTKPREEQYN(#)STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP

[0683] QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR

[0684] WQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 225: CDRs bolded, Lys to Asn substitution (A), Fc underlined

[0685] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0686] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0687] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSN(A)RYYADSVKGRFTISRDNSK NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

[0688] SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG

[0689] SEQ ID NO: 226: CDRs bolded, Fc underlined

[0690] DIVMTQSPDSLAVSLGERATINCKSSESVSNDVAWYQQKPGQPPKLLINYAFHRFTGVPDRFSGSGYGT

[0691] DFTLTISSLQAEDVAVYYCHQAYSSPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGP GLVKPSETLSLTCTVSGFSLTSYGVHWIRQPPGKGLEWIGVIYADGSTNYNPSLKSRVTISKDTSKNQVS LKLSSVTAADTAVYYCARAYGNYWYIDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSG GGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

[0692] NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0693] SEQ ID NO: 227: CDRs bolded, (GGGGS)x linker in brackets, mature human IgG 1 Fc; Cys to Ser substitution (#); Asn to Gin substitution (A); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized

[0694] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0695] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK[GGGGSGGGGSGGGGSGGGGS]QVQLVESGG GWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKN TLFLQMNSLRAEDTARYYCATNDDYWGQGTKVEVSSIGGGGSGGGGSGGGGS1NVNHKPSNTKVDKK VEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGV

[0696] EVHNAKTKPREEQYQ(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPG

[0697] SEQ ID NO: 228: CDRs bolded, (GGGGS)x linker in brackets, mature human IgG 1 Fc; Cys to Ser substitution (#); Asn to Gin substitution (A); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized

[0698] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0699] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK[GGGGSGGGGSGGGGSGGGGS]QVQLVESGG GWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSHRYYADSVKGRFTISRDNSKN TLFLQMNSLRAEDTARYYCATNDDYWGQGTKVEVSSIGGGGSGGGGSGGGGS1NVNHKPSNTKVDKK yEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYQ(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPG

[0700] SEQ ID NO: 229: CDRs bolded, (GGGGS)x linker in brackets, mature human IgG 1 Fc; Cys to Ser substitution (#); Asn to Gin substitution (A); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized

[0701] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK[GGGGSGGGGSGGGGSGGGGS]QVQLVESGG GWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSERYYADSVKGRFTISRDNSKN TLFLQMNSLRAEDTARYYCATNDDYWGQGTKVEVSSIGGGGSGGGGSGGGGS1NVNHKPSNTKVDKK yEPKSS(#)DK7HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGV

[0702] EVHNAKTKPREEQYQ(A)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPG

[0703] SEQ ID NO: 230: CDRs bolded, (GGGGS)x linker in brackets, mature human IgG 1 Fc, Cys to Ser substitution (#), allotype G1 m(f) (bold italics)

[0704] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK[GGGGSGGGGSGGGGSGGGGS]QVQLVESGG GWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKN TLFLQMNSLRAEDTARYYCATNDDYWGQGTKVEVSS[GGGGSGGGGSGGGGS]NVNHKPSNTKVDKK VEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG

[0705] SEQ ID NO: 231 : CDRs bolded, (GGGGS)x linker in brackets, mature human lgG1 Fc, Cys to Ser substitution (#), allotype G1 m(f) (bold italics)

[0706] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK[GGGGSGGGGSGGGGSGGGGS]QVQLVESGG GWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSHRYYADSVKGRFTISRDNSKN TLFLQMNSLRAEDTARYYCATNDDYWGQGTKVEVSS[GGGGSGGGGSGGGGS]NVNHKPSNTKVDKK VEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 232: CDRs bolded, (GGGGS)x in brackets, mature human lgG1 Fc, Cys to Ser substitution

[0707] (#), allotype G1 m(f) (bold italics)

[0708] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0709] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK[GGGGSGGGGSGGGGSGGGGS]QVQLVESGG

[0710] GWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSERYYADSVKGRFTISRDNSKN

[0711] TLFLQMNSLRAEDTARYYCATNDDYWGQGTKVEVSS[GGGGSGGGGSGGGGS]NVNHKPSNTKVDKK

[0712] VEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV

[0713] EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP

[0714] PSREE / WTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG

[0715] NVFSCSVMHEALHNHYTQKSLSLSPG

[0716] SEQ ID NO: 233: CDRs bolded, (GGGGS)x linker in brackets, mature human IgG 1 Fc; Cys to Ser substitution (#); Asn to Gin substitution (A); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized; GGGS insertion (bolded and underlined)

[0717] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0718] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK[GGGGSGGGGSGGGGSGGGGS]QVQLVESGG

[0719] GWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKN

[0720] TLFLQMNSLRAEDTARYYCATNDDYWGQGTKVEVSSIGGGGSGGGGSGGGGS1NVNHKPSNTKVDKK

[0721] VEPKSS(#)DKTHTCPPCPAPELLGGGGSGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNW

[0722] YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR

[0723] WQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0724] SEQ ID NO: 234: CDRs bolded, (GGGGS)x linker in brackets, mature human IgG 1 Fc; Cys to Ser substitution (#); Asn to Gin substitution (A); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized; GGGS insertion (bolded and underlined)

[0725] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0726] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK[GGGGSGGGGSGGGGSGGGGS]QVQLVESGG

[0727] GWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSHRYYADSVKGRFTISRDNSKN

[0728] TLFLQMNSLRAEDTARYYCATNDDYWGQGTKVEVSSIGGGGSGGGGSGGGGS1NVNHKPSNTKVDKK

[0729] VEPKSS(#)DKTHTCPPCPAPELLGGGGSGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNW

[0730] YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR

[0731] WQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0732] SEQ ID NO: 235: CDRs bolded, (GGGGS)x in brackets, mature human lgG1 Fc; Cys to Ser substitution (#); Asn to Gin substitution (A); allotype G1 m(fa) (bold italics); N-terminal Fab residues are underlined; hinge residues are italicized; GGGS insertion (bolded and underlined)

[0733] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK[GGGGSGGGGSGGGGSGGGGS]QVQLVESGG

[0734] GWQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSERYYADSVKGRFTISRDNSKN

[0735] TLFLQMNSLRAEDTARYYCATNDDYWGQGTKVEVSSfGGGGSGGGGSGGGGSINVNHKPSNTKVDKK

[0736] VEPKSS(#)DKTHTCPPCPAPELLGGGGSGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNW

[0737] YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP

[0738] QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR

[0739] WQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0740] SEQ ID NO: 236: CDRs (bolded), Lys to Glu substitution (A), Fc underlined

[0741] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0742] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0743] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSE(A)RYYADSVKGRFTISRDNSK

[0744] NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK

[0745] VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE

[0746] VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

[0747] SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV

[0748] FSCSVMHEALHNHYTQKSLSLSPG

[0749] SEQ ID NO: 237: CDRs (bolded), Lys to His substitution (A), Fc underlined

[0750] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0751] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0752] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSH(A)RYYADSVKGRFTISRDNSK

[0753] NTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKK

[0754] VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVE

[0755] VHNAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

[0756] SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV

[0757] FSCSVMHEALHNHYTQKSLSLSPG

[0758] SEQ ID NO: 238: CDRs (bolded), Fc underlined

[0759] EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGS

[0760] GSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLV

[0761] QSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTT

[0762] DSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSGGGGSGGGGSGGGGSNVN

[0763] HKPSNTKVDKKVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEV

[0764] KFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ

[0765] PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

[0766] DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 239: CDRs (bolded), Fc underlined

[0767] EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGS

[0768] GSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLV

[0769] QSGG(A)G(*)VKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRV

[0770] TLTTDSSTTTAYMELKSLQADDTAVYYCARRDYRFDMGFDYWGQGTLVTVSSGGGGSGGGGSGGGGS

[0771] NVNHKPSNTKVDKKVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED

[0772] PEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

[0773] KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS

[0774] KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0775] SEQ ID NO: 240: CDRs (bolded), Fc underlined

[0776] EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYRESGVPARFSGS

[0777] GSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLV

[0778] QSGGGVKKPGASVKVDCKASGYTFTNYYMYVWRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTT

[0779] DSSTTTAYMELKSLQADDTAVYYCARRDYRFDMGFDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVN

[0780] HKPSNTKVDKKVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEV

[0781] KFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ

[0782] PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV

[0783] DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0784] SEQ ID NO: 241 : CDRs (bolded), Fc underlined

[0785] EIKLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGS

[0786] GSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLV

[0787] QSGKERKKPGASVKVSCKASGYTFTNYYMYVWRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTT

[0788] DSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTRVTVSSGGGGSGGGGSGGGGSNVN

[0789] HKPSNTKVDKKVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEV

[0790] KFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ

[0791] PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0792] SEQ ID NO: 242: CDRs (bolded), Fc underlined

[0793] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0794] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0795] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSRRYYADSVKGRFTISRDNSKNT

[0796] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0797] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0798] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0799] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 243: CDRs (bolded), Fc underlined

[0800] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0801] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0802] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0803] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0804] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0805] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0806] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0807] SEQ ID NO: 244: CDRs (bolded) , Fc underlined

[0808] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0809] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0810] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSRRYYADSVKGRFTISRDNSKNT

[0811] LFLQMNSLRAEDTAVYYCATNDDYWGQGTSVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0812] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0813] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0814] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0815] SEQ ID NO: 245: CDRs (bolded), Fc underlined

[0816] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0817] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0818] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0819] LFLQMNSLRAEDTAVYYCATNDDYWGQGTSVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0820] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0821] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0822] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0823] SEQ ID NO: 246: CDRs (bolded), Fc underlined

[0824] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0825] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0826] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0827] LFLQMNSLRAEDTARYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0828] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0829] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

[0830] CSVMHEALHNHYTQKSLSLSPG

[0831] SEQ ID NO: 247: CDRs (bolded), Fc underlined

[0832] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0833] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0834] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0835] LFLQMNSLRAEDTAKYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0836] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0837] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0838] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0839] SEQ ID NO: 248: CDRs (bolded), Fc underlined

[0840] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0841] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0842] KVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0843] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0844] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0845] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0846] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0847] SEQ ID NO: 249: CDRs (bolded), Fc underlined

[0848] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0849] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0850] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0851] LFLQMNSLRAEDTAVYYCATNDDYWGQGTHVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0852] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0853] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0854] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0855] SEQ ID NO: 250: CDRs (bolded), Fc underlined

[0856] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0857] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0858] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0859] LFLQMNSLRAEDTAVYYCATNDDYWGQGTDVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0860] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0861] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

[0862] CSVMHEALHNHYTQKSLSLSPG

[0863] SEQ ID NO: 251 : CDRs (bolded), Fc underlined

[0864] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0865] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0866] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0867] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVEVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0868] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0869] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0870] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0871] SEQ ID NO: 252: CDRs (bolded), Fc underlined

[0872] DIVMTQSPDSLAVSLGERATINCKSSESVSNDVAWYQQKPGQPPKLLINYAFHRFTGVPDRFSGSGYGT

[0873] DFTLTISSLQAEDVAVYYCHQAYSSPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGP

[0874] GLVKPSETLSLTCTVSGFSLTSYGVHWIRQPPGKGLEWIGVIYADGSTNYNPSLKSRVTISKDTSKNQVS

[0875] LKLSSVTAADTAVYYCARAYGNYWYIDVWGQGTTVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDK

[0876] KVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGV

[0877] EVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP

[0878] PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPG

[0879] SEQ ID NO: 253: CDRs (bolded), Fc underlined

[0880] DIVMTQSPDSLAVSLGERATINCKSSESVSNDVAWYQQKPGQPPKLLINYAFHRFTGVPDRFSGSGYGT

[0881] DFTLTISSLQAEDVAVYYCHQAYSSPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGP

[0882] GLVKPSETLSLTCTVSGFSLTSYGVHWIRQPPGKGLEWIGVIYADGSTNYNPSLKSRVTISKDTSKNQVS

[0883] LKLSSVTAADTAVYYCARAYGNYWYIDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSD THTCP

[0884] PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY

[0885] NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT

[0886] CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG

[0887] SEQ ID NO: 254: CDRs (bolded), Fc underlined

[0888] QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKN

[0889] RVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSGGGGSGGGGSGGG

[0890] GSGGGGSEIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGV

[0891] PARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKGGGGSGGGGSGGGGSNVNH KPSNTKVDKKVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

[0892] FNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP

[0893] REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD

[0894] KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0895] SEQ ID NO: 255: CDRs (bolded), Fc underlined

[0896] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0897] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEGGGGSGGGGSGGGGSGVQLVESGGGVVQPGR

[0898] SLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKNTLFLQMN

[0899] SLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVEPKSSDKT

[0900] HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR

[0901] EEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ

[0902] VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

[0903] ALHNHYTQKSLSLSPG

[0904] SEQ ID NO: 256: CDRs (bolded), Fc underlined

[0905] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0906] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0907] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0908] LFLQMNSLRAEDTAVYYCATNDDYWGQGTKVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0909] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0910] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0911] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

[0912] CSVMHEALHNHYTQKSLSLSPG

[0913] SEQ ID NO: 257: CDRs (bolded), Fc underlined

[0914] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0915] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0916] SVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSKRYYADSVKGRFTISRDNSKNT

[0917] LFLQMNSLRAEDTAVYYCATNDDYWGQGTKVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0918] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0919] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0920] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

[0921] CSVMHEALHNHYTQKSLSLSPG

[0922] SEQ ID NO: 258: CDRs (bolded), Fc underlined

[0923] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0924] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0925] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKNT LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0926] PKSSDKTHTCPPCPAPELLGGGGSGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG

[0927] NVFSCSVMHEALHNHYTQKSLSLSPG

[0928] SEQ ID NO: 259: CDRs (bolded), Fc underlined

[0929] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0930] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0931] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSQRYYADSVKGRFTISRDNSKNT

[0932] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0933] PKSSDKTHTCPPCPAPELLGGGGSGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDG

[0934] VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG

[0935] SEQ ID NO: 260: CDRs (bolded), Fc underlined

[0936] EIELTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0937] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0938] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKNT

[0939] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0940] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0941] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0942] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0943] SEQ ID NO: 261 : CDRs (bolded), Fc underlined

[0944] EIELTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0945] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0946] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKNT

[0947] LFLQMNSLRAEDTAVYYCATNDDYWGQGTKVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0948] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0949] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0950] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0951] SEQ ID NO: 262: CDRs (bolded), Fc underlined

[0952] EIELTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0953] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSQRYYADSVKGRFTISRDNSKNT

[0954] LFLQMNSLRAEDTAKYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0955] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0956] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0957] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0958] SEQ ID NO: 263: CDRs (bolded), Fc underlined

[0959] EIELTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0960] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0961] KVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSQRYYADSVKGRFTISRDNSKNT

[0962] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0963] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0964] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0965] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0966] SEQ ID NO: 264: CDRs (bolded), Fc underlined

[0967] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0968] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEGGGGSGGGGSGGGGSGVQLVESGGGVVQPGR

[0969] SLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKNTLFLQMN

[0970] SLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVEPKSSDKT

[0971] HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR

[0972] EEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ

[0973] VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG

[0974] SEQ ID NO: 265: CDRs (bolded), Fc underlined

[0975] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0976] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0977] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKNT

[0978] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSNVNHKPSNTKVDKKVEPKSSDKTHTCPP

[0979] CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQ

[0980] STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC

[0981] LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH

[0982] YTQKSLSLSPG SEQ ID NO: 266: CDRs (bolded), Fc underlined

[0983] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0984] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0985] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSQRYYADSVKGRFTISRDNSKNT

[0986] LFLQMNSLRAEDTAVYYCATNDDYWGQGKLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0987] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[0988] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[0989] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[0990] SEQ ID NO: 267: CDRs (bolded), Fc underlined

[0991] EIVLTQSPATLSLSPGERATLSCRASQSVSSRLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[0992] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[0993] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSQRYYADSVKGRFTISRDNSKNT

[0994] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[0995] PKSSDKTHTCPPCPAPELLGGGGSGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDG

[0996] VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG

[0997] SEQ ID NO: 268: CDRs (bolded), Fc underlined

[0998] DIELTQSPDTLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGT

[0999] DFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGG

[1000] GWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKN

[1001] TLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[1002] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[1003] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[1004] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[1005] SEQ ID NO: 269: CDRs (bolded), Fc underlined

[1006] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[1007] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGGG

[1008] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKNT

[1009] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[1010] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[1011] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[1012] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 270: CDRs (bolded), Fc underlined

[1013] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[1014] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[1015] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSTRYYADSVKGRFTISRDNSKNT

[1016] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[1017] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[1018] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[1019] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[1020] SEQ ID NO: 271 : CDRs (bolded), Fc underlined

[1021] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[1022] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[1023] VVQPGRSLRLDCKASGITFSNSGMHVWRQAPGKGLEVWAVIWYDGSQRYYADSVKGRFTISRDNSKNT

[1024] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[1025] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[1026] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

[1027] DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPG

[1028] SEQ ID NO: 272: CDRs (bolded), Fc underlined

[1029] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[1030] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEPGGGGSGGGGSGPGVQLVESGGGVVQPGRSLR

[1031] LDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKNTLFLQMNSLR

[1032] AEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVEPKSSDKTHT

[1033] CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE

[1034] QYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVS

[1035] LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG

[1036] SEQ ID NO: 284: CDRs (bolded), Fc underlined

[1037] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD

[1038] FTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGG

[1039] VVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSQRYYADSVKGRFTISRDNSKNT

[1040] LFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSGGGGSGGGGSGGGGSNVNHKPSNTKVDKKVE

[1041] PKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

[1042] NAKTKPREEQYQSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

[1043] CSVMHEALHNHYTQKSLSLSPGK

[1044] V. Albumin proteins and albumin protein-binding peptides

[1045] Albumin proteins

[1046] An albumin protein of the invention may be a naturally-occurring albumin or a variant thereof, such as an engineered variant of a naturally-occurring albumin protein. Variants include polymorphisms, fragments such as domains and sub-domains, and fusion proteins. An albumin protein may include the sequence of an albumin protein obtained from any source. Preferably the source is mammalian, such as human or bovine. Most preferably, the albumin protein is bovine serum albumin (BSA), human serum albumin (HSA), or a variant thereof. Human serum albumins include any albumin protein having an amino acid sequence naturally occurring in humans, and variants thereof. An albumin protein coding sequence is obtainable by methods known to those of skill in the art for isolating and sequencing cDNA corresponding to human genes. An albumin protein of the invention may include the amino acid sequence of human serum albumin (HSA), provided in SEQ ID NO: 273 or SEQ ID NO: 274, the amino acid sequence of mouse serum albumin (MSA), provided in SEQ ID NO: 275, the amino acid sequence of bovine serum albumin (BSA), provided in SEQ ID NO: 276, or a variant or fragment thereof, preferably a functional variant or fragment thereof. A fragment or variant may or may not be functional, or may retain the function of albumin to some degree. For example, a fragment or variant may retain the ability to bind to an albumin receptor, such as HSA or MSA, by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 105% of the ability of the parent albumin (e.g., the parent albumin from which the fragment or variant is derived). Relative binding ability may be determined by methods known in the art, such as by surface plasmon resonance.

[1047] The albumin protein may be a naturally-occurring polymorphic variant of an albumin protein, such as human serum albumin. Generally, variants or fragments of human serum albumin will have at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or 70%, and preferably 80%, 90%, 95%, 100%, or 105% or more of human serum albumin or mouse serum albumin’s ligand binding activity.

[1048] The albumin protein may include the amino acid sequence of bovine serum albumin. Bovine serum albumin proteins include any albumin having an amino acid sequence naturally occurring in cows, for example, as described by Swissprot accession number P02769, and variants thereof as defined herein. Bovine serum albumin proteins also include fragments of full-length bovine serum albumin or variants thereof, as defined herein.

[1049] The albumin protein may comprise the sequence of an albumin derived from one of serum albumin from cow (e.g., Swissprot accession number P02769), dog (e.g., Swissprot accession number P49822-1), pig (e.g., Swissprot accession number P08835-1), goat (e.g., Sigma product no. A2514 or A4164), cat (e.g., Swissprot accession number P49064-1), chicken (e.g., Swissprot accession number P19121-1), ovalbumin (e.g., chicken ovalbumin) (e.g., Swissprot accession number P01012-1), turkey ovalbumin (e.g., Swissprot accession number 073860-1), donkey (e.g., Swissprot accession number Q5XLE4-1), guinea pig (e.g., Swissprot accession number Q6WDN9-1), hamster (e.g., as described in DeMarco et al. International Journal for Parasitology 37(11): 1201 -1208 (2007)), horse (e.g., Swissprot accession number P35747-1), rhesus monkey (e.g., Swissprot accession number Q28522-1), mouse (e.g., Swissprot accession number P07724-1), pigeon (e.g., as defined by Khan et al. Int. J. Biol. Macromol. 30(3-4), 171-8 (2002)), rabbit (e.g., Swissprot accession number P49065-1), rat (e.g., Swissprot accession number P02770-1), or sheep (e.g., Swissprot accession number P14639-1), and includes variants and fragments thereof as defined herein.

[1050] Many naturally-occurring mutant forms of albumin are known to those skilled in the art. Naturally- occurring mutant forms of albumin are described in, for example, Peters, et al. All About Albumin: Biochemistry, Genetics and Medical Applications, Academic Press, Inc., San Diego, Calif., p.170-181 (1996).

[1051] Albumin proteins of the invention include variants of naturally-occurring albumin proteins. A variant albumin refers to an albumin protein having at least one amino acid mutation, such as an amino acid mutation generated by an insertion, deletion, or substitution, either conservative or non-conservative, provided that such changes result in an albumin protein for which at least one basic property has not been significantly altered (e.g., has not been altered by more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%). Exemplary properties which may define the activity of an albumin protein include binding activity (e.g., including binding specificity or affinity to bilirubin, or a fatty acid such as a long-chain fatty acid), osmolarity, or behavior in a certain pH-range.

[1052] Typically an albumin protein variant will have at least 40%, at least 50%, at least 60%, and preferably at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity with a naturally-occurring albumin protein, such as the albumin protein of any one of SEQ ID NOs: 273-276.

[1053] Methods for the production and purification of recombinant human albumins are well-established (Sleep et al. Biotechnology, 8(1):42-6 (1990)), and include the production of recombinant human albumin for pharmaceutical applications (Bosse et al. J Clin Pharmacol 45(1):57-67 (2005)). The three- dimensional structure of HSA has been elucidated by X-ray crystallography (Carter et al. Science. 244(4909): 1195-8(1998)); Sugio et al. Protein Eng. 12(6):439-46 (1999)). The HSA polypeptide chain has 35 cysteine residues, which form 17 disulfide bonds, and one unpaired (e.g., free) cysteine at position 34 of the mature protein. Cys-34 of HSA has been used for conjugation of molecules to albumin (Leger et al. Bioorg Med Chem Lett 14(17):4395-8 (2004); Thibaudeau et al. Bioconjug Chem 16(4):1000-8 (2005)), and provides a site for site-specific conjugation.

[1054] SEQ ID NO: 273 Human serum albumin (HSA), variant 1 DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLF GDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYL YEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGER AFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECC EKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRL AKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVS TPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCF

[1055] SALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCC KADDKETCFAEEGKKLVAASQAALGL

[1056] SEQ ID NO: 274 Human serum albumin (HSA), variant 2

[1057] RGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCD

[1058] KSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNE

[1059] ETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCAS

[1060] LQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSIS

[1061] SKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYS

[1062] VVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTK

[1063] KVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLV

[1064] NRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAA FVEKCCKADDKETCFAEEGKKLVAASQAALGL

[1065] SEQ ID NO: 275 Mouse serum albumin (MSA)

[1066] RGVFRREAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCD

[1067] KSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTT

[1068] FMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSS

[1069] MQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATI

[1070] SSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDY

[1071] SVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYT

[1072] QKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLV

[1073] ERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQ FLDTCCKAADKDTCFSTEGPNLVTRCKDALA

[1074] SEQ ID NO: 276 Bovine serum albumin (BSA)

[1075] MKWVTFISLLLLFSSAYSRGVFRRDTHKSEIAHRFKDLGEEHFKGLVLIAFSQYLQQCPFDEHVKLVNELT

[1076] EFAKTCVADESHAGCEKSLHTLFGDELCKVASLRETYGDMADCCEKQEPERNECFLSHKDDSPDLPKLK

[1077] PDPNTLCDEFKADEKKFWGKYLYEIARRHPYFYAPELLYYANKYNGVFQECCQAEDKGACLLPKIETMRE

[1078] KVLASSARQRLRCASIQKFGERALKAWSVARLSQKFPKAEFVEVTKLVTDLTKVHKECCHGDLLECADD

[1079] RADLAKYICDNQDTISSKLKECCDKPLLEKSHCIAEVEKDAIPENLPPLTADFAEDKDVCKNYQEAKDAFL

[1080] GSFLYEYSRRHPEYAVSVLLRLAKEYEATLEECCAKDDPHACYSTVFDKLKHLVDEPQNLIKQNCDQFEK

[1081] LGEYGFQNALIVRYTRKVPQVSTPTLVEVSRSLGKVGTRCCTKPESERMPCTEDYLSLILNRLCVLHEKTP

[1082] VSEKVTKCCTESLVNRRPCFSALTPDETYVPKAFDEKLFTFHADICTLPDTEKQIKKQTALVELLKHKPKAT EEQLKTVMENFVAFVDKCCAADDKEACFAVEGPKLWSTQTALA Conjugation of albumin proteins

[1083] An albumin protein of the invention may be conjugated to (e.g., by way of a covalent bond) to any Int of the invention (e.g., by way of the linker portion of a CCR5 inhibitor monomer or dimer). The albumin protein may be conjugated to any Int of the invention by any method well-known to those of skill in the art for producing small-molecule-protein conjugates. This may include covalent conjugation to a solvent- exposed amino acid, such as a solvent exposed cysteine or lysine. For example, human serum albumin may be conjugated to an Int of the invention by covalent linkage to the sulfur atom corresponding to Cys34 of SEQ ID NO: 273 or Cys40 of SEQ ID NO: 274.

[1084] An albumin protein of the invention may be conjugated to any Int of the invention by way of an amino acid located within 10 amino acid residues of the C-terminal or N-terminal end of the albumin protein. An albumin protein may include a C-terminal or N-terminal polypeptide fusion of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 or more amino acid. The C-terminal or N-terminal polypeptide fusion may include one or more solvent-exposed cysteine or lysine residues, which may be used for covalent conjugation of an Int of the invention (e.g., conjugation to a CCR5 inhibitor monomer or dimer, including by way of a linker).

[1085] Albumin proteins of the invention include any albumin protein which has been engineered to include one or more solvent-exposed cysteine or lysine residues, which may provide a site for conjugation to an Int of the invention (e.g., conjugation to a CCR5 inhibitor monomer or dimer, including by way of a linker). Most preferably, the albumin protein will contain a single solvent-exposed cysteine or lysine, thus enabling site-specific conjugation of an Int of the invention.

[1086] Exemplary methods for the production of engineered variants of albumin proteins that include one or more conjugation-competent cysteine residues are provided in U.S. Patent Application No. 2017 / 0081389, which is incorporated herein by reference in its entirety. Briefly, preferred albumin protein variants are those comprising a single, solvent-exposed, unpaired (e.g., free) cysteine residue, thus enabling site-specific conjugation of a linker to the cysteine residue.

[1087] Albumin proteins which have been engineered to enable chemical conjugation to a solvent- exposed, unpaired cysteine residue include the following albumin protein variants:

[1088] (a) an albumin protein having a substitution of a non-cysteine amino acid residue with a cysteine at an amino acid residue corresponding to any of L585, D1 , A2, D562, A364, A504, E505, T79, E86, D129, D549, A581 , D121 , E82, S270, Q397, and A578 of SEQ ID NO: 273;

[1089] (b) an albumin protein having an insertion of a cysteine at a position adjacent the N- or C-terminal side of an amino acid residue corresponding to any of L585, D1 , A2, D562, A364, A504, E505, T79, E86, D129, D549, A581 , D121 , E82, S270, Q397, and A578 of SEQ ID NO: 273;

[1090] (c) an albumin protein engineered to have an unpaired cysteine having a free thiol group at a residue corresponding to any of C369, C361 , C91 , C177, C567, C316, C75, C169, C124, or C558 of SEQ ID NO: 275, and which may or may not be generated by deletion or substitution of a residue corresponding to C360, C316, C75, C168, C558, C361 , C91 , C124, C169, or C567 of SEQ ID NO: 273; and / or

[1091] (d) addition of a cysteine to the N- or C-terminus of an albumin protein. In some embodiments of the invention, the net result of the substitution, deletion, addition, or insertion events of (a), (b), (c) and / or (d) is that the number of conjugation competent cysteine residues of the polypeptide sequence is increased relative to the parent albumin sequence. In some embodiments of the invention, the net result of the substitution, deletion, addition, or insertion events of (a), (b), (c) and / or (d) is that the number of conjugation competent-cysteine residues of the polypeptide sequence is one, thus enabling site-specific conjugation.

[1092] Preferred albumin protein variants also include albumin proteins having a single solvent-exposed lysine residue, thus enabling site-specific conjugation of a linker to the lysine residue. Such variants may be generated by engineering an albumin protein, including any of the methods previously described (e.g., insertion, deletion, substitution, or C-terminal or N-terminal fusion).

[1093] VI. Linkers

[1094] A linker refers to a linkage or connection between two or more components in a conjugate described herein (e.g., between two CCR5 inhibitors in a conjugate described herein, between a CCR5 inhibitor and E (e.g., a polypeptide that contains an Fc domain or albumin protein) in a conjugate described herein, and between a dimer of two CCR5 inhibitors and a polypeptide that contains an Fc domain in a conjugate described herein).

[1095] Linkers in conjugates having an E covalently linked to monomers of CCR5 inhibitors

[1096] In a conjugate containing an E (e.g., a polypeptide that contains an Fc domain monomer, an Fc domain, or an albumin protein) covalently linked to one or more monomers of CCR5 inhibitors as described herein, a linker in the conjugate may be a divalent structure having two arms. One arm in a divalent linker may be attached to the monomer of CCR5 inhibitor and the other arm may be attached to the E (e.g., a polypeptide of an Fc domain monomer, an Fc domain, or an albumin protein). In some embodiments, the one or more monomers of CCR5 inhibitors in the conjugates described herein may each be, independently, connected to an atom in the E (e.g., an atom in the polypeptide of an Fc domain monomer, an Fc domain, or albumin protein).

[1097] In some embodiments, the linker includes a first linker Y and a second linker L. In some embodiments, Y is absent. In some embodiments, the linker (e.g., Y or L) is described by formula: J1-(Q1)g-(T1)h-(Q2)i-(T2)j-(Q3)k-(T3)|-(Q4)m-(T4)n-(Q5)o-J2wherein J1is a bond attached to Ai; J2is a bond attached to E or is a functional group capable of reacting with a functional group conjugated to E (e.g., maleimide and cysteine, amine and activated carboxylic acid (e.g., carboxylic acid activated by tetrafluorophenyl or trifluorophenol), thiol and maleimide, activated sulfonic acid and amine, isocyanate and amine, azide and alkyne, and alkene and tetrazine); each of Q1, Q2, Q3, Q4, and Q5is, independently, optionally substituted C1-C40 alkylene, optionally substituted C1-C40 heteroalkylene, optionally substituted C1-C40 alkoxylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C2-C20heterocycloalkylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene; each of T1, T2, T3, T4is, independently, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, imino, or oximo; R' is H, optionally substituted C1-C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C2-C20heterocycloalkyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl; and each of g, h, i, j, k, I, m, n, and 0 is, independently, 0, 1 , or 2. In some embodiments, each of g, h, i, j, k, I, m, n, and 0 is, independently, 0 or 1 .

[1098] In some embodiments, optionally substituted includes substitution with a polyethylene glycol (PEG). A PEG has a repeating unit structure (-CH2CH2O-)n, wherein n is an integer from 2 to 100. A polyethylene glycol may be selected from any one of PEG2 to PEG100 (e.g., PEG2, PEG3, PEG4, PEG5, PEG5-PEG10, PEG10-PEG20, PEG20-PEG30, PEG30-PEG40, PEG50-PEG60, PEG60-PEG70, PEG70-PEG80, PEG80-PEG90, PEG90-PEG100).

[1099] In some embodiments, J2may have two points of attachment to the Fc domain monomer or Fc domain (e.g., two J2).

[1100] Peptide linkers

[1101] In the present disclosure, a linker between a peptide and an Fc domain monomer (e.g., in a polypeptide), between a VL and VH, between a VH and VL, or between two peptides (e.g. Ki or K2) can be polypeptide including 1-200 amino acids (e.g., 1-200, 1 -180, 1-160, 1-140, 1-120, 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 4-200, 5-200, 6-200, 7-200, 8-200, 9-200, 10-200, 15-200, 20-200, 25-200, 30-200, 35-200, 40-200, 45-200, 50-200, 60-200, 70-200, 80-200, 90-200, 100-200, 120-200, 140-200, 160-200, or 180-200 amino acids). In some embodiments, a linker is an polypeptide containing at least 12 amino acids, such as 12-200 amino acids (e.g., 12-200, 12-180, 12-160, 12-140, 12-120, 12-100, 12-90, 12-80, 12-70, 12-60, 12-50, 12-40, 12-30, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, or 12-13 amino acids) (e.g., 14-200, 16-200, 18-200, 20- 200, 30-200, 40-200, 50-200, 60-200, 70-200, 80-200, 90-200, 100-200, 120-200, 140-200, 160-200, 180-200, or 190-200 amino acids). In some embodiments, a linker is polypeptide containing 12-30 amino acids (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids).

[1102] Suitable peptide linkers are known in the art, and include, for example, peptide linkers containing flexible amino acid residues such as glycine and serine. In certain embodiments, a linker can contain motifs, e.g., multiple or repeating motifs, of GS, GGS, GGGGS (SEQ ID NO: 277), GGSG (SEQ ID NO: 278), or SGGG (SEQ ID NO: 279). In preferred embodiments, a peptide linker (e.g., Ki or K2) is a peptide linker including the amino acid sequence of any one of (GS)x, (GGS)x, (GGGGS)x, (GGSG)x, (SGGG)x, wherein x is an integer from 1 to 50 (e.g., 1 -40, 1-30, 1-20, 1-10, or 1 -5). In some embodiments, the peptide linker is GGGGSGGGGS (SEQ ID NO: 280), GGGGSGGGGSGGGGS (SEQ ID NO: 281); or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 282).

[1103] In some embodiments, a peptide linker contains only glycine residues, e.g., at least 4 glycine residues (e.g., 4-200, 4-180, 4-160, 4-140, 4-40, 4-100, 4-90, 4-80, 4-70, 4-60, 4-50, 4-40, 4-30, 4-20, 4- 19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11 , 4-10, 4-9, 4-8, 4-7, 4-6 or 4-5 glycine residues) (e.g., 4- 200, 6-200, 8-200, 10-200, 12-200, 14-200, 16-200, 18-200, 20-200, 30-200, 40-200, 50-200, 60-200, 70- 200, 80-200, 90-200, 100-200, 120-200, 140-200, 160-200, 180-200, or 190-200 glycine residues). In certain embodiments, a linker has 4-30 glycine residues (e.g., 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 glycine residues). In some embodiments, a linker containing only glycine residues may not be glycosylated (e.g., O-linked glycosylation, also referred to as O-glycosylation) or may have a decreased level of glycosylation (e.g., a decreased level of O- glycosylation) (e.g., a decreased level of O-glycosylation with glycans such as xylose, mannose, sialic acids, fucose (Fuc), or galactose (Gal) (e.g., xylose) as compared to, e.g., a linker containing one or more serine residues.

[1104] In some embodiments, a linker containing only glycine residues may not be O-glycosylated (e.g., O-xylosylation) or may have a decreased level of O-glycosylation (e.g., a decreased level of O- xylosylation) as compared to, e.g., a linker containing one or more serine residues.

[1105] Linkers

[1106] In some embodiments, linker provides space, rigidity, or flexibility between the CCR5 inhibitors and E (e.g., the polypeptide of an Fc domain monomer, an Fc domain, or an albumin protein) in the conjugates described herein or between two CCR5 inhibitors in the conjugates described herein. In some embodiments, a linker may be a bond, e.g., a covalent bond, e.g., an amide bond, a disulfide bond, a C-0 bond, a C-N bond, a N-N bond, a C-S bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation. In some embodiments, a linker (e.g., L as shown in formula (D-l), (D-l I), (D-lll), (M- I), (M-ll), or (M-lll)) includes no more than 250 atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1- 110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)). In some embodiments, a linker (L) includes no more than 250 non-hydrogen atoms (e.g., 1-2, 1- 4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 non-hydrogen atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non-hydrogen atom(s)). In some embodiments, the backbone of a linker (L) includes no more than 250 atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1- 250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)). The “backbone” of a linker refers to the atoms in the linker that together form the shortest path from one part of the conjugate to another part of the conjugate. The atoms in the backbone of the linker are directly involved in linking one part of the conjugate to another part of the conjugate. For example, hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the conjugate to another part of the conjugate. Molecules that may be used to make linkers (L) include at least two functional groups, e.g., two carboxylic acid groups. In some embodiments of a trivalent linker, two arms of a linker may contain two dicarboxylic acids, in which the first carboxylic acid may form a covalent linkage with the first CCR5 inhibitor in the conjugate and the second carboxylic acid may form a covalent linkage with the second CCR5 inhibitor in the conjugate, and the third arm of the linker may for a covalent linkage (e.g., a C-0 bond) with E (e.g., a polypeptide that contains an Fc domain monomer, an Fc domain, or an albumin protein) in the conjugate. In some embodiments of a divalent linker, the divalent linker may contain two carboxylic acids, in which the first carboxylic acid may form a covalent linkage with one component (e.g., a CCR5 inhibitor) in the conjugate and the second carboxylic acid may form a covalent linkage (e.g., a C- S bond or a C-N bond) with another component (e.g., a polypeptide that contains an Fc domain monomer, an Fc domain, or an albumin protein) in the conjugate.

[1107] In some embodiments, dicarboxylic acid molecules may be used as linkers (e.g., a dicarboxylic acid linker). For example, in a conjugate containing a peptide of an Fc domain monomer, an Fc domain, or an albumin protein covalently linked to one or more dimers of CCR5 inhibitors, the first carboxylic acid in a dicarboxylic acid molecule may form a covalent linkage with a hydroxyl or amine group of the first CCR5 inhibitor and the second carboxylic acid may form a covalent linkage with a hydroxyl or amine group of the second CCR5 inhibitor.

[1108] In some embodiments, dicarboxylic acid molecules, such as the ones described herein, may be further functionalized to contain one or more additional functional groups. Dicarboxylic acids may be further functionalized, for example, to provide an attachment point to a polypeptide that contains an Fc domain monomer, an Fc domain, or an albumin protein (e.g., by way of a linker, such as a PEG linker).

[1109] In some embodiments, when the CCR5 inhibitor is attached to a polypeptide that contains an Fc domain monomer, an Fc domain, or an albumin protein, the linker may include a moiety including a carboxylic acid moiety and an amino moiety that are spaced by from 1 to 25 atoms.

[1110] In some embodiments, a linker may include a diamino moiety, such as the ones described herein, may be further functionalized to contain one or more additional functional groups. Such diamino linker may be further functionalized, for example, to provide an attachment point to a polypeptide that contains an Fc domain monomer, an Fc domain, or an albumin protein (e.g., by way of a linker, such as a PEG linker).

[1111] In some embodiments, a molecule containing an azide group may be used to form a linker, in which the azide group may undergo cycloaddition with an alkyne to form a 1 ,2,3-triazole linkage. In some embodiments, a molecule containing an alkyne group may be used to form a linker, in which the alkyne group may undergo cycloaddition with an azide to form a 1 ,2,3-triazole linkage. In some embodiments, a molecule containing a maleimide group may be used to form a linker, in which the maleimide group may react with a cysteine to form a C-S linkage. In some embodiments, a molecule containing one or more haloalkyl groups may be used to form a linker, in which the haloalky I group may form a covalent linkage, e.g., C-N and C-0 linkages, with a CCR5 inhibitor.

[1112] In some embodiments, a linker (L) may include a synthetic group derived from, e.g., a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer). In some embodiments, a linker may include one or more amino acid residues. In some embodiments, a linker may be an amino acid sequence (e.g., a 1-25 amino acid, 1-10 amino acid, 1-9 amino acid, 1-8 amino acid, 1-7 amino acid, 1-6 amino acid, 1-5 amino acid, 1-4 amino acid, 1-3 amino acid, 1-2 amino acid, or 1 amino acid sequence). In some embodiments, a linker (L) may include one or more optionally substituted C1-C40 alkylene, optionally substituted C1- C40 heteroalkylene (e.g., a PEG unit), optionally substituted C1-C40 alkoxylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C2-C20heterocycloalkylene, optionally substituted C5-C15 arylene (e.g., C6 arylene), optionally substituted C2- C15 heteroarylene (e.g., imidazole, pyridine), O, S, NR' (R' is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C2-C20heterocycloalkyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino.

[1113] Conjugation chemistries

[1114] CCR5 inhibitor monomers or dimers may be conjugated to E (e.g., a polypeptide that contains an Fc domain monomer or an Fc domain or an albumin protein), e.g., by way of a linker, by any standard conjugation chemistries known to those of skill in the art. The following conjugation chemistries are specifically contemplated, e.g., for conjugation of a PEG linker (e.g., a functionalized PEG linker) to E (e.g., a polypeptide that contains an Fc domain monomer or an Fc domain).

[1115] Covalent conjugation of two or more components in a conjugate using a linker may be accomplished using well-known organic chemical synthesis techniques and methods. Complementary functional groups on two components may react with each other to form a covalent bond. Examples of complementary reactive functional groups include, but are not limited to, e.g., maleimide and cysteine, amine and activated carboxylic acid, thiol and maleimide, activated sulfonic acid and amine, isocyanate and amine, azide and alkyne, and alkene and tetrazine. Site-specific conjugation to a polypeptide may be accomplished using techniques known in the art. Exemplary techniques for site-specific conjugation of a small molecule to a polypeptide that contains an Fc domain are provided in Agarwall. P., et al. Bioconjugate Chem. 26:176-192 (2015).

[1116] Other examples of functional groups capable of reacting with amino groups include, e.g., alkylating and acylating agents. Representative alkylating agents include: (i) an a-haloacetyl group, e.g., XCH2CO- (where X=Br, Cl, or I); (ii) a N-maleimide group, which may react with amino groups either through a Michael type reaction or through acylation by addition to the ring carbonyl group; (iii) an aryl halide, e.g., a nitrohaloaromatic group; (iv) an alkyl halide; (v) an aldehyde or ketone capable of Schiff’s base formation with amino groups; (vi) an epoxide, e.g., an epichlorohydrin and a bisoxirane, which may react with amino, sulfhydryl, or phenolic hydroxyl groups; (vii) a chlorine-containing of s-triazine, which is reactive towards nucleophiles such as amino, sulfhydryl, and hydroxyl groups; (viii) an aziridine, which is reactive towards nucleophiles such as amino groups by ring opening; (ix) a squaric acid diethyl ester; and (x) an a-haloalkyl ether.

[1117] Examples of amino-reactive acylating groups include, e.g., (i) an isocyanate and an isothiocyanate; (ii) a sulfonyl chloride; (iii) an acid halide; (iv) an active ester, e.g., a nitrophenylester or N- hydroxysuccinimidyl ester; (v) an acid anhydride, e.g., a mixed, symmetrical, or N-carboxyanhydride; (vi) an acylazide; and (vii) an imidoester. Aldehydes and ketones may be reacted with amines to form Schiff’s bases, which may be stabilized through reductive amination.

[1118] It will be appreciated that certain functional groups may be converted to other functional groups prior to reaction, for example, to confer additional reactivity or selectivity. Examples of methods useful for this purpose include conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylhomocysteine thiolactone, S- acetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives; conversion of thiols to carboxyls using reagents such as a -haloacetates; conversion of thiols to amines using reagents such as ethylenimine or 2-bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols to thiols using reagents such as tosyl chloride followed by transesterification with thioacetate and hydrolysis to the thiol with sodium acetate.

[1119] In some embodiments, a linker of the disclosure (e.g., L), is conjugated (e.g., by any of the methods described herein) to E (e.g., a polypeptide that contains an Fc domain or an albumin protein). In preferred embodiments of the disclosure, the linker is conjugated by way of: (a) a thiourea linkage (i.e., - NH(C=S)NH-) to a lysine of E; (b) a carbamate linkage (i.e., -NH(C=O)-O) to a lysine of E; (c) an amine linkage by reductive amination (i.e., -NHCH2) between a lysine and E; (d) an amide (i.e., -NH-(C=O)CH2) to a lysine of E; I a cysteine-maleimide conjugate between a maleimide of the linker to a cysteine of E; (f) an amine linkage by reductive amination (i.e., -NHCH2) between the linker and a carbohydrate of E (e.g., a glycosyl group of a polypeptide that contains an Fc domain monomer or an Fc domain); (g) a rebridged cysteine conjugate, wherein the linker is conjugated to two cysteines of E; (h) an oxime linkage between the linker and a carbohydrate of E (e.g., a glycosyl group of a polypeptide that contains an Fc domain monomer or an Fc domain); (i) an oxime linkage between the linker and an amino acid residue of E; (j) an azido linkage between the linker and E; (k) direct acylation of a linker to E; or (I) a thioether linkage between the linker and E.

[1120] In some embodiments, a linker is conjugated to E, wherein the linkage includes the structure -NH(C=NH)X-, wherein X is O, HN, or a bond. In some embodiments, a linker is conjugated to E, wherein the linkage between the remainder of the linker and E includes the structure -NH(C=O)NH-.

[1121] In some embodiments, a linker is conjugated to E, wherein the linkage includes the structure -RgOR9C(=O)NH-, wherein R9 is H, optionally substituted C1-C20alkyl, optionally substituted C3- C20 cycloalkyl, optionally substituted C2-C20heterocycloalkyl; optionally substituted C5-C15aryl, or optionally substituted C2-C15heteroaryl. In some embodiments, the linker is conjugated to E, wherein the linkage between the remainder of the linker and E includes the structure -CH2OCH2C(=O)NH-.

[1122] Exemplary linking strategies (e.g., methods for linking a monomer or a dimer of a CCR5 inhibitor to E, such as, by way of a linker) are further described in the Examples.

[1123] In some embodiments, a linker (e.g., an active ester, e.g., a nitrophenylester or N- hydroxysuccinimidyl ester, or derivatives thereof (e.g., a functionalized PEG linker (e.g., azido-PEG2- PEG40-NHS ester), is conjugated to E, with a T of (e.g., drug-antibody ratio or DAR) of between 0.5 and 10.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1 , 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1 , 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In these instances, the E-(PEG2-PEG40)-azide can react with an Int having a terminal alkyne linker (e.g., L) through click conjugation. During click conjugation, the copper-catalyzed reaction of the azide (e.g., the Fc-(PEG2-PEG40)-azide) with the alkyne (e.g., the Int having a terminal alkyne linker (e.g., L) forming a 5-membered heteroatom ring. In some embodiments, the linker conjugated to E is a terminal alkyne and is conjugated to an Int having a terminal azide. Exemplary preparations of preparations of E- (PEG2-PEG40)-azide are described in the Examples. One of skill in the art would readily understand the final product from a click chemistry conjugation. Exemplary linking strategies are further depicted herein.

[1124] VII. Methods of treatment

[1125] This disclosure provides uses of conjugates and pharmaceutical compositions described herein in the treatment of disorders associated with dysregulation or overexpression of CCR5 or PD-1 (e.g., cancer or viral infections).

[1126] Cancer

[1127] The conjugates and pharmaceutical compositions described herein can be used to treat a cancer in a subject. In some embodiments, the cancer overexpresses or is known to overexpress CCR5 relative to a non-cancerous cell of the same tissue type. In some embodiments, the subject has been determined to have a cancer that overexpresses CCR5 relative to a non-cancerous cell of the same tissue type. In some embodiments, the method further comprises a step of determining whether the cancer overexpresses CCR5 relative to a non-cancerous cell of the same tissue type and administering the conjugate only if the cancer overexpresses CCR5.

[1128] The conjugates and pharmaceutical compositions described herein can be used to treat a cancer in a subject. In some embodiments, the cancer overexpresses or is known to overexpress PD-1 relative to a non-cancerous cell of the same tissue type. In some embodiments, the subject has been determined to have a cancer that overexpresses PD-1 relative to a non-cancerous cell of the same tissue type. In some embodiments, the method further comprises a step of determining whether the cancer overexpresses PD-1 relative to a non-cancerous cell of the same tissue type and administering the conjugate only if the cancer overexpresses PD-1 .

[1129] In some embodiments, the cancer is selected from lung cancer, optionally non-small cell lung cancer or small-cell lung cancer; head and neck cancer, optionally squamous cell carcinoma; renal cell carcinoma; breast cancer; ovarian cancer; pancreatic cancer; colorectal cancer; urothelial cancer; bile duct cancer; endometrial cancer; melanoma; prostate cancer; glioma cancer; or esophageal cancer. In some embodiments, the cancer is PD-L1 negative. In some embodiments, the breast cancer has wildtype BRCA1 or wild-type BRCA2. In some embodiments, the breast cancer has a loss-of-function mutation in BRCA1 or BRCA2. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the triple negative breast cancer is PD-L1 negative. In some embodiments, the cancer is a solid tumor.

[1130] Combination Therapies

[1131] In some embodiments, one or more anticancer agents (e.g., immune checkpoint inhibitors, chemotherapeutic agents, PARP inhibitors, antibody drug conjugates, or a combination thereof) may be administered in combination (e.g., administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions) or administered separately) at different times with a conjugate described herein (e.g., a conjugate of formula (D-l), (D-ll), (D-lll), (M-l), (M-ll), or (M-lll)). In some embodiments, one or more anticancer agents may be administered in combination with a conjugate described herein to treat breast cancer. In some embodiments, the breast cancer is triple negative breast cancer.

[1132] The anticancer agent may be administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions) as the conjugates, or may be administered prior to or following the conjugates (e.g., within a period of 1 day, 2, days, 5, days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 6 months, or 12 months, or more).

[1133] / . Immune checkpoint inhibitors

[1134] In some embodiments, the method further includes administering to the subject an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is an inhibitor of any one of more of the following immune checkpoint targets: CTLA-4, PD-1 , PD-L1 , LAG-3, B7.1 , B7-H3, B7-H4, TIM3, VISTA, CD137, OX-40, CD40, CD27, CCR4, GITR, NKG2D, and KIR. In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody selected from one or more of an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG3 antibody, an anti-B7.1 antibody, an anti-B7H3 antibody, an anti-B7H4 antibody, an anti-TIM3 antibody, an anti-VISTA antibody, an anti-CD137 antibody, an anti- 0X40 antibody, an anti-CD40 antibody, an anti-CD27 antibody, an anti-CCR4 antibody, an anti-GITR antibody, an anti-NKG2D antibody, and an anti-KIR antibody.

[1135] Immune checkpoint inhibitors approved or in development include, but are not limited to, YERVOY® (ipilimumab), OPDIVO® (nivolumab), KEYTRUDA® (pembrolizumab), tremelimumab, galiximab, MDX-1106, BMS-936558, MEDI4736, MPDL3280A, MEDI6469, BMS-986016, BMS-663513, PF-05082566, IPH2101 , KW-0761 , CDX-1127, CP-870, CP-893, GSK2831781 , MSB0010718C, MK3475, CT-011 , AMP-224, MDX-1105, IMP321 , MGA271 , dostarlimab, and cemiplimab, as well as numerous other antibodies or polypeptides directed to immune checkpoint proteins described herein. In some embodiments, the immune checkpoint inhibitor is pembrolizumab, nivolumab, dostarlimab, dostarlimab, or cemiplimab.

[1136] In some embodiments, the method includes administering to said subject (1) a conjugate described herein and (2) an immune checkpoint inhibitor. In some embodiments, the conjugate described herein is administered first, followed by administering of the immune checkpoint inhibitor alone. In some embodiments, the immune checkpoint inhibitor is administered first, followed by administering of the conjugate described herein alone. In some embodiments, the conjugate described herein and the immune checkpoint inhibitor are administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions). In some embodiments, when a conjugate described herein and an immune checkpoint inhibitor are administered together (e.g., substantially simultaneously in the same or separate pharmaceutical compositions, or separately in the same treatment regimen), tumor growth suppression of each of the conjugate and the immune checkpoint inhibitor may be greater (e.g., occur at a lower concentration) than inhibition of tumor growth suppression of each of the conjugate and the immune checkpoint inhibitor when each is used alone in a treatment regimen.

[1137] / / . Chemotherapeutic agents

[1138] In some embodiments, the method includes administering to the subject one or more chemotherapeutic agents, e.g.,:

[1139] (a) a cytotoxic agent;

[1140] (b) an antimetabolite;

[1141] (c) an alkylating agent;

[1142] (d) an anthracycline;

[1143] (e) an antibiotic;

[1144] (f) an anti-mitotic agent;

[1145] (g) a hormone therapy;

[1146] (h) a signal transduction inhibitor;

[1147] (i) a gene expression modulator;

[1148] (j) an apoptosis inducer;

[1149] (k) an angiogenesis inhibitor;

[1150] (l) an immunotherapy agent;

[1151] (m) a DNA damage repair inhibitor;

[1152] (n) a kinase inhibitor;

[1153] (o) an ionizing radiation therapy;

[1154] (p) a radioligand therapy; or a combination thereof.

[1155] The cytotoxic agent may be, e.g., actinomycin-D, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, amphotericin, amsacrine, arsenic trioxide, asparaginase, azacitidine, azathioprine, Bacille Calmette-Guerin (BCG), bendamustine, bexarotene, bevacuzimab, bleomycin, bortezomib, busulphan, capecitabine, carboplatin, carfilzomib, carmustine, cetuximab, cisplatin, chlorambucil, cladribine, clofarabine, colchicine, crisantaspase, cyclophosphamide, cyclosporine, cytarabine, cytochalasin B, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, 1 - dehydrotestosterone, denileukin, dexamethasone, dexrazoxane, dihydroxy anthracin dione, disulfiram, docetaxel, doxorubicin, liposomal doxorubicin, emetine, epirubicin, erlotinib, epigallocatechin gallate, epoetin alfa, estramustine, ethidium bromide, etoposide, everolimus, filgrastim, finasunate, floxuridine, fludarabine, flurouracil (5-FU), fulvestrant, ganciclovir, geldanamycin, gemcitabine, glucocorticoids, gramicidin D, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib, irinotecan, interferons, interferon alfa-2a, interferon alfa-2b, ixabepilone, lactate dehydrogenase A (LDH-A), lenalidomide, letrozole, leucovorin, levamisole, lidocaine, lomustine, mechlorethamine, melphalan, 6- mercaptopurine, mesna, methotrexate, methoxsalen, metoprine, metronidazole, mithramycin, mitomycin- C, mitoxantrone, nandrolone, nelarabine, nilotinib, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, nab- paclitaxel, pemetrexed, pentostatin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, procaine, procarbazine, propranolol, puromycin, quinacrine, radicicol, radioactive isotopes, raltitrexed, rapamycin, rasburicase, salinosporamide A, sargramostim, sunitinib, temozolomide, teniposide, tetracaine, 6-thioguanine, thiotepa, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, zoledronate, or a combination thereof.

[1156] The antimetabolite may be, e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5- fluorouracil decarbazine, cladribine, pemetrexed, gemcitabine, capecitabine, hydroxyurea, mercaptopurine, fludarabine, pralatrexate, clofarabine, cytarabine, decitabine, floxuridine, nelarabine, trimetrexate, thioguanine, pentostatin, or a combination thereof.

[1157] The alkylating agent may be, e.g., mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin, altretamine, cyclophosphamide, ifosfamide, hexamethylmelamine, altretamine, procarbazine, dacarbazine, temozolomide, streptozocin, carboplatin, cisplatin, oxaliplatin, uramustine, bendamustine, trabectedin, semustine, or a combination thereof.

[1158] The anthracycline may be, e.g., daunorubicin, doxorubicin, aclarubicin, aldoxorubicin, amrubicin, annamycin, carubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, or a combination thereof.

[1159] The antibiotic may be, e.g., dactinomycin, bleomycin, mithramycin, anthramycin (AMC), ampicillin, bacampicillin, carbenicillin, cioxacillin, dicloxacillin, flucioxacillin, mezlocillin, nafcillin, oxacillin, piperacillin, pivampicillin, pivmecillinam, ticarcillin, aztreonam, imipenem, doripenem, ertapenem, meropenem, cephalosporins, clarithromycin, dirithromycin, roxithromycin, telithromycin, lincomycin, pristinamycin, quinupristin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, tobramycin, streptomycin, sulfamethizole, sulfamethoxazole, sulfisoxazole, demeclocycline, minocycline, oxytetracycline, tetracycline, penicillin, amoxicillin, cephalexin, erythromycin, clarithromycin, azithromycin, ciprofloxacin, levofloxacin, ofloxacin, doxycycline, clindamycin, metronidazole, tigecycline, chloramphenicol, metronidazole, tinidazole, nitrofurantoin, vancomycin, teicoplanin, telavancin, linezolid, cycloserine, rifamycins, polymyxin B, bacitracin, viomycin, capreomycin, quinolones, daunorubicin, doxorubicin, 4’-deoxydoxorubicin, epirubicin, idarubicin, plicamycin, mitomycin-c, mitoxantrone, or a combination thereof.

[1160] The anti-mitotic agent may be, e.g., vincristine, vinblastine, vinorelbine, docetaxel, estramustine, ixabepilone, paclitaxel, maytansinoid, a dolastatin, a cryptophycin, or a combination thereof. The signal transduction inhibitor may be, e.g., imatinib, trastuzumab, erlotinib, sorafenib, sunitinib, temsirolimus, vemurafenib, lapatinib, bortezomib, cetuximab panitumumab, matuzumab, gefitinib, STI 571 , rapamycin, flavopiridol, imatinib mesylate, vatalanib, semaxinib, motesanib, axitinib, afatinib, bosutinib, crizotinib, cabozantinib, dasatinib, entrectinib, pazopanib, lapatinib, vandetanib, or a combination thereof.

[1161] The gene expression modulator may be, e.g., a siRNA, a shRNA, an antisense oligonucleotide, an HDAC inhibitor, or a combination thereof. An HDAC inhibitor may be, e.g., trichostatin A, trapoxin B, valproic acid, vorinostat, belinostat, LAQ824, panobinostat, entinostat, tacedinaline, mocetionstat, givinostat, resminostat, abexinostat, quisinostat, rocilinostat, practinostat, CHR-3996, butyric acid, phenylbutyric acid, 4SC202, romidepsin, sirtinol, cambinol, EX-527, nicotinamide, or a combination thereof. An antisense oligonucleotide may be, e.g., custirsen, apatorsen, AZD9150, trabadersen, EZN- 2968, LErafAON-ETU, or a combination thereof. An siRNA may be, e.g., ALN-VSP, CALAA-01 , Atu-027, SPC2996, or a combination thereof.

[1162] The hormone therapy may be, e.g., a luteinizing hormone-releasing hormone (LHRH) antagonist. The hormone therapy may be, e.g., firmagon, leuproline, goserelin, buserelin, flutamide, bicalutadmide, ketoconazole, aminoglutethimide, prednisone, hydroxyl-progesterone caproate, medroxy-progesterone acetate, megestrol acetate, diethylstil-bestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, toremifine citrate, megestrol acetate, exemestane, fadrozole, vorozole, letrozole, anastrozole, nilutamide, tripterelin, histerelin, arbiraterone, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, tretinoin, fenretinide, troxacitabine, or a combination thereof.

[1163] The apoptosis inducers may be, e.g., a recombinant human TNF-related apoptosis-inducing ligand (TRAIL), camptothecin, bortezomib, etoposide, tamoxifen, or a combination thereof.

[1164] The angiogenesis inhibitors may be, e.g., sorafenib, sunitinib, pazopanib, everolimus or a combination thereof.

[1165] The immunotherapy agent may be, e.g., a monoclonal antibody, cancer vaccine (e.g., a dendritic cell (DC) vaccine), oncolytic virus, cytokine, adoptive T cell therapy, Bacille Calmette-Guerin (BCG), GM- CSF, thalidomide, lenalidomide, pomalidomide, imiquimod, or a combination thereof. The monoclonal antibody may be, e.g., anti-CTLA4, anti-LAG3, anti-KIR, or a combination thereof. The monoclonal antibody may be, e.g., alemtuzumab, trastuzumab, ibritumomab tiuxetan, brentuximab vedotin, trastuzumab, ado-trastuzumab emtansine, blinatumomab, bevacizumab, cetuximab, pertuzumab, panitumumab, ramucirumab, obinutuzumab, ofatumumab, rituximab, pertuzumab, tositumomab, gemtuzumab ozogamicin, tositumomab, or a combination thereof. The cancer vaccine may be, e.g., Sipuleucel-T, BioVaxID, NeuVax, DCVax, SuVaxM, CIMAvax®, Provenge,®, hsp110 chaperone complex vaccine, CDX-1401 , MIS416, CDX-110, GVAX Pancreas, HyperAcute™ Pancreas, GTOP-99 (MyVax®), or Imprime PGG®. The oncolytic virus may be, e.g., talimogene laherparepvec. The cytokine may be, e.g., IL-2, IFNa, or a combination thereof. The adoptive T cell therapy may be, e.g., tisagenlecleucel, axicabtagene ciloleucel, or a combination thereof. The DNA damage repair inhibitor may be, e.g., a PARP inhibitor, a DNA-PK inhibitor, a cell checkpoint kinase inhibitor, or a combination thereof. The PARP inhibitor may be, e.g., olaparib, rucaparib, veliparib (ABT-888), niraparib (ZL-2306), iniparib (BSI-201), talazoparib (BMN 673), 2X-121 , CEP-9722, KU-0059436 (AZD2281), PF-01367338, AZD5305, AZD9574, seneparib (IMP4297), fluzoparib (SHR-3162), XIN005104, NMS-293 or a combination thereof. The DNA-PK inhibitor may be AZD7648, nedisertib (M3814), M9831 , or BAY-8400. The cell checkpoint kinase inhibitor may be, e.g., RP-6306, MK-1775 or AZD1775, AZD7762, LY2606368, PF-0477736, AZD0156, GDC-0575, ARRY-575, CCT245737, PNT-737 or a combination thereof.

[1166] DNA-dependent Protein Kinase (DNA-PK) inhibitors that may be used in the present invention include compounds that upon contacting DNA-PK, whether in vitro, in cell culture, or in an animal, reduce the activity of DNA-PK, such that the measured DNA-PK IC50is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain DNA-PK inhibitors, the DNA-PK IC50may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the DNA-PK IC50is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM).

[1167] DNA-PK inhibitors include AZD-7648, Peposertib, M9831 , IMP11 , NU5455, BAY-8400, ZL-2201 , adMare Bioinnovations DNA-PK Program, XRD-0394, Avadomide, NERx Ku program, CC-115, KU57788, ZSTK474, LY3023414, BR101801 , XRD-0394 and NK-314.

[1168] Radiotherapy may be used in conjunction with the other methods of this disclosure for the treatment of cancer. Radiotherapy is a treatment method where ionizing radiation is provided to cancerous tissue to induce DNA damage and cell death. Radiotherapy methods of this disclosure include radiation from an external beam (i.e., external beam radiation), sealed source radiotherapy, (i.e., brachytherapy), and injection of radionuclide isotopes (i.e., radionuclide therapy) or radioligand therapy (RLT) in which pharmaceuticals including antibodies or cell surface ligands are linked to radionuclides for administration. External beam radiation can include treatment with photons (X-rays), electrons, protons, carbon ions, boron capture neutrons, etc. Radionuclides used in brachytherapy, radionuclide therapy, and radioligand therapy can include:131l,177Lu,153Sm,90Y,223Ra,225Ac,211At,213Bi,212Pb / 212Bi,161Tb,125l,131Cs,106Ru,103Pd,32P,33P,67Cu,89Sr,165Dy,166Ho,186Re,188Re,60Co, etc.

[1169] In some embodiments, the radiotherapy is part of a chemoradiotherapy (CRT). The chemotherapeutic agent can be etoposide, doxorubicin, topotecan, irinotecan, fluorouracil, gemcitabine, paclitaxel, a platin, an anthracycline, and a combination thereof. The radiotherapy can be a treatment given with electrons, photons, protons, alpha-emitters, beta-emitters, other ions, radio-nucleotides, boron capture neutrons, and combinations thereof. In some embodiments, the radiotherapy is given either with fractionation (e.g., 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1 .10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1 .80, 1 .85, 1 .90, 1 .95, and 2.00 Gy per day for 5 days a week) up to a total dose of 50-70 Gy. In some embodiments, the radiotherapy is given either with fractionation (0.1 to 2 Gy per day for 5 days a week) up to a total dose of 50-70 Gy. Other fractionation schedules could also be envisioned, for example, a lower dose per fraction but given twice daily. Higher daily doses over a shorter period of time can also be given. In one embodiment, stereotactic radiotherapy as well as the gamma knife are used. In the palliative setting, other fractionation schedules are also widely used for example 25 Gy in 5 fractions or 30 Gy in 10 fractions. For radiotherapy, the duration of treatment will be the time frame when radiotherapy is given. These interventions apply to treatment given with electrons, photons and protons, alfa-emitters or other ions, treatment with radio-nucleotides, for example, treatment with131l given to patients with thyroid cancer, as well in patients treated with boron capture neutron therapy.

[1170] Radiotherapy Ligands (RLTs) that may be used in the present invention include agents that upon contacting cancer cells, whether in vitro, in cell culture, or in an animal, inhibit the cancer cell, such that the measured IC50is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain RLTs, the IC50may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the RLT IC50is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). RLTs include Zevalin, Actimab-A, lomab-ACT, lomab-B, Lutetium-177-DOTAGA-PEG-IAC, Tozaride, SS0110, BAY-2701439, 177Lu-rhPSMA-10.1 , CTT-1403, lopofosine, SAR-BBN, SAR-bisPSMA, SARTATE, FAP- 2286, CONV-01-a,177Lu-PSMA-l&T, FPI-2059, FPI-1434, FPI-1966, [177Lu] ludotadipep,161Tb-PSMA-l&T, ITM-31 , ITM-11 , JNJ-69086420, l-131-1095, Azedra, PSMA TTC / BAY-2315497,177Lu-DOTA-EB-TATE, Betalutin, AAA817, AAA603, Lutathera, Pluvicto, PPMX-T002, 186RNL, PNT2003, CAM-H2, AlphaMedix, RYZ101 , Sn-117m-DTPA, TLX592, TLX66, TLX250, TLX591 , TLX101 ,124l-omburtamab, GD2-SADA, and131l-omburtamab.

[1171] In some embodiments, the chemotherapeutic agent is selected from paclitaxel, docetaxel, liposomal doxorubicin, carboplatin, gemcitabine, nab-paclitaxel, doxorubicin, oxaliplatin, cisplatin, carboplatin, or a combination thereof.

[1172] Hi. PARP Inhibitors

[1173] In some embodiments, the method includes administering to the subject a PARP inhibitor. PARP inhibitors include compounds that upon contacting PARP, whether in vitro, in cell culture, in an animal or in a patient, reduce the activity of PARP, such that the measured PARP IC50is 10 μM or less (e.g., 5 pM or less or 1 pM or less). For certain PARP inhibitors, the PARP IC50may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the PARP IC50is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). For example, certain PARP inhibitors may be prepared using techniques and methods disclosed in, e.g., International Application No. PCT / US2022 / 025357, which is incorporated by reference herein. The PARP inhibitor may be, e.g., olaparib, rucaparib, veliparib (ABT-888), niraparib (ZL-2306), iniparib (BSI-201), talazoparib (BMN 673), 2X-121 , CEP-9722, KU-0059436 (AZD2281), PF-01367338, AZD5305, AZD9574, seneparib (IMP4297), fluzoparib (SHR-3162), XIN005104, NMS-293 or a combination thereof.

[1174] Non-limiting examples of PARP inhibitors include those described in PCT applications PCT / CN2022 / 086311 , PCT / CN2022 / 1 15259, PCT / US2022 / 027334, PCT / CN2022 / 088989, and PCT / CN2022 / 087969 and U.S. Patent Nos. 11 ,325,906, 8,716,493, 8,236,802, 8,071 ,623, 8,012,976, 7,732,491 , 7,550,603, 7,531 ,530, 7,151 ,102, and 6,495,541 , each of which is incorporated herein by reference herein. A PARP inhibitor may be isotopically enriched (e.g., enriched for deuterium). In some embodiments, the PARP inhibitor is olaparib or talazoparib. iv. Antibody drug conjugates

[1175] In some embodiments, the method includes administering to the subject an antibody drug conjugate (ADC). ADCs that may be used in the present invention include conjugates that upon contacting cancer cells, whether in vitro, in cell culture, or in an animal, inhibit the cancer cell, such that the measured IC50is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain ADCs, the IC50may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the ADC IC50is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM).

[1176] ADCs include Disitamab vedotin, Belantamab mafodotin, Trastuzumab deruxtecan, Ujvira, Mirvetuximab soravtansine, Gemtuzumab ozogamicin, Enfortumab vedotin, Inotuzumab ozogamicin, Trastuzumab emtansine, Tisotumab vedotin, Sacituzumab govitecan, Ladiratumab vedotin, Polatuzumab vedotin, Loncastuximab Tesirine, Brentuximab vedotin, PF-06804103, MGTA-117, FOR46, MRG001 , SOT102, ZV0203, AOC 1020, PRO1184, BAT8009, BB-1705, JS107, SHR-A1912, CMG901 , Ladiratuzumab vedotin, BAT8006, RC108, BAT8008, Mipasetamab Uzoptirine, NBE-002, Zanidatamab zovodotin, F0002-ADC, SKB315, GQ1001 , ABBV-637, XMT-2056, TORL-1-23, FDA022, DYNE-251 , STI- 6129, Ozuriftamab vedotin, Farletuzumab Ecteribulin, Trastuzumab vedotin, DB-1303, OMTX705, TRS005, Ispectamab debotansine, DXC-005, ESG-401 , ARX788, BAT8010, Tusamitamab ravtansine, ABBV-154, Naratuximab emtansine, PSMA ADC, TAK-164, ADCT-602, ADCT-901 , SHR-A1201 , GB251 , ABL202, SHR-A1921 , 9MW2821 , HS-20093, BIO-106, SKB264, Camidanlumab Tesirine, Datopotamab deruxtecan, Telisotuzumab vedotin, L-DOS47, AVID100, OBI-999, DP303c, AURIXIM, MT-8633, IMGC936, BB-1701 , AOC 1001 , JS108, TAC-001 , SYSA1801 , SHR-A2009, TORL-2-307-ADC, BL- M07D1 , STRO-001 , A166, Mecbotamab vedotin, Trastuzumab duocarmazine, ASN004, ABBV-011 , Mirzotamab clezutoclax, OBT076, HS630, SGN-STNV, FDA018, ABBV-400, AZD8205, IBI-343, SGN- ALPV, TAK-500, JBH492, ALT-P7, Ifinatamab deruxtecan, DXC-004, IMGN151 , XMT-1660, M1231 , LM- 102, ORM-5029, STI-3258, SGN-B7H4V, TPX-4589, IKS03, Zilovertamab Vedotin, ARX517, Pivekimab Sunirine, Lonigutamab Ugodotin, TRPH-222, MRG004a, DS-6000a, REGN5093-M114, Trastuzumab imbotolimod, RC88, HTI-1066, BI-CON-02, SGN-CD228A, AOC 1044, DB-1305, ABBV-319, Patritumab Deruxtecan, RC118, Trastuzumab rezetecan, ARX305, Upifitamab Rilsodotin, NBT828, TAA013, BL- B01 D1 , BL-M02D1 , GQ1007, DS-9606a, NBT508, B003, DX126-262, XB002, FS-1502, Praluzatamab ravtansine, AMT-151 , M9140, Indatuximab ravtansine, Cofetuzumab pelidotin, RG7861 , AGS62P1 , CX- 2029, SGN-B6A, Unspecified TROP2 ADC, Unspecified HER2 ADC, RC98 ADC, DYNE-101 , SHR- A1904, Anetumab ravtansine, Vobramitamab duocarmazine, Luveltamab tazevibulin, Serclutamab talirine, MRG003, SYD1875, BYON3521 , SGN-PDL1 V, JSKN-003, YL201 , HS-20089, DXC-007, SYS6002, and HDP-101 . In some embodiments, the antibody drug conjugate is the antibody drug conjugate is Sacituzumab govitecan, Trastuzumab deruxtecan, Datopotamab deruxtecan, Enfortumab vedotin, Tisotumab vedotin, Ladiratumab vedotin, M9140, or ASN004. Viral infections

[1177] The conjugates and pharmaceutical compositions described herein can be used to treat viral infections in a subject. The conjugates and pharmaceutical compositions described herein can also be used to prevent viral infections in a subject susceptible to viral infection or at increased risk of contracting a viral infection (e.g., a subject that is hospitalized, immunocompromised, who is preparing for surgery, who recently underwent surgery, or who is taking a medication that affects the immune system, such as a chemotherapy of radiation).

[1178] In some embodiments, the viral infection is human immunodeficiency virus type 1 (HIV-1).

[1179] In some embodiments, the method further includes administering to the subject an antiviral agent or an antiviral vaccine. In some embodiments, the method includes administering to said subject (1) a conjugate described herein and (2) an antiviral agent or an antiviral vaccine. In some embodiments, the conjugate described herein is administered first, followed by administering of the antiviral agent or antiviral vaccine alone. In some embodiments, the antiviral agent or antiviral vaccine is administered first, followed by administering of the conjugate described herein alone. In some embodiments, the conjugate described herein and the antiviral agent or antiviral vaccine are administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions). In some embodiments, when a conjugate described herein and an antiviral agent or antiviral vaccine are administered together (e.g., substantially simultaneously in the same or separate pharmaceutical compositions, or separately in the same treatment regimen), inhibition of viral replication of each of the conjugate and the antiviral agent or antiviral vaccine may be greater (e.g., occur at a lower concentration) than inhibition of viral replication of each of the conjugate and the antiviral agent or antiviral vaccine when each is used alone in a treatment regimen.

[1180] VIII. Pharmaceutical compositions

[1181] A conjugate described herein may be formulated in a pharmaceutical composition for use in the methods described herein. In some embodiments, a conjugate described herein may be formulated in a pharmaceutical composition alone. In some embodiments, a conjugate described herein may be formulated in combination with a second therapeutic agent in a pharmaceutical composition. In some embodiments, a conjugate described herein may be administered in combination with a second therapeutic agent as part of a dosing regimen (e.g., administered sequentially or simultaneously). In some embodiments, the pharmaceutical composition includes a conjugate described herein and pharmaceutically acceptable carriers and excipients.

[1182] Acceptable carriers and excipients in the pharmaceutical compositions are nontoxic to recipients at the dosages and concentrations employed. Acceptable carriers and excipients may include buffers such as phosphate, citrate, HEPES, and TAE, antioxidants such as ascorbic acid and methionine, preservatives such as hexamethonium chloride, octadecyldimethylbenzyl ammonium chloride, resorcinol, and benzalkonium chloride, proteins such as human serum albumin, gelatin, dextran, and immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acid residues such as glycine, glutamine, histidine, and lysine, and carbohydrates such as glucose, mannose, sucrose, and sorbitol.

[1183] Examples of other excipients include, but are not limited to, antiadherents, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, sorbents, suspensing or dispersing agents, or sweeteners. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[1184] The conjugates herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the conjugates herein be prepared from inorganic or organic bases. Frequently, the conjugates are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulfuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art.

[1185] Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethyla...

Claims

CLAIMS1 . A conjugate, or a pharmaceutically acceptable salt thereof, described by formula (D-l) or (M-l):wherein each of A1and A2, independently, has the structure of formula (A-l) or (A-ll):R1is H or phenyl optionally substituted with one or two fluorines;R2is H or phenyl optionally substituted with one or two fluorines; wherein when R1is H, then R2is phenyl optionally substituted with one or two fluorines and when R1is phenyl optionally substituted with one or two fluorines, then R2is H;R3is CF3, C3-C5carbocycle, C3-C4 heteroaryl, or C1-C3alkyl optionally substituted with 1 to 2 oxygen atoms;R4is C1-C3alkyl optionally substituted with -CO2H or C3-C5carbocycle optionally substituted with an O-benzyl group or a six-membered heterocycle substituted with one acetyl that forms a spirocycle with the carbocycle;X1is C3-C6heteroalkyl, C3 heteroaryl, C3-C6heterocycle optionally substituted with sulfonyl or C1acyl, or C3-C5carbocycle optionally substituted with 1 to 2 fluorines, trifluoromethyl, 1 to 2 methyls or a six-membered heterocycle substituted with one methyl that forms a spirocycle with the carbocycle, or C1- C3 alkyl optionally substituted with 1 to 2 oxygen atoms;X2is N or X2is C and X2and R4together, with the atoms to which each is attached, join to form a 5- to 7-membered aromatic or non-aromatic carbocycle or heterocycle that is optionally substituted with -C(O)OCH3;Y is a first linker covalently attached to L or absent;L is a second linker; n is 1 or 2; each E is a polypeptide comprising an Fc domain monomer or an albumin protein;T is an integer from 1 to 20; and the squiggly line indicates that L is covalently attached to E.

2. A conjugate, or a pharmaceutically acceptable salt thereof, described by formula (D-l I) or (M-ll):wherein each of B1and B2, independently, has the structure of formula (B-l) or (B-l I):R1is H or phenyl optionally substituted with one or two fluorines;R2is H or phenyl optionally substituted with one or two fluorines; wherein when R1is H, then R2is phenyl optionally substituted with one or two fluorines and when R1is phenyl optionally substituted with one or two fluorines, then R2is H;R3is C1-C3alkyl or CF3;X1is C3-C6heteroalkyl, C3heteroaryl, C3-C6heterocycle optionally substituted with sulfonyl or Ci acyl, or C3-C5carbocycle optionally substituted with 1 to 2 fluorines, trifluoromethyl, 1 to 2 methyls, or a six-membered heterocycle substituted with one methyl that forms a spirocycle with the carbocycle, or C1- C3alkyl optionally substituted with 1 to 2 oxygen atoms;Ring A is a 5- to 7-membered aromatic or non-aromatic carbocycle or heterocycle;Y is a first linker covalently attached to L or absent;L is a second linker; n is 1 or 2; each E is a polypeptide comprising an Fc domain monomer or an albumin protein;T is an integer from 1 to 20; and the squiggly line indicates that L is covalently attached to E.

3. A conjugate, or a pharmaceutically acceptable salt thereof, described by formula (D-lll) or (M-lll):wherein each of C1and C2, independently, has the structure of formula (C):R1is H or phenyl optionally substituted with one or two fluorines;R2is H or phenyl optionally substituted with one or two fluorines; wherein when R1is H, then R2is phenyl optionally substituted with one or two fluorines and when R1is phenyl optionally substituted with one or two fluorines, then R2is H;R3is CF3, C3-C5carbocycle, C3-C4 heteroaryl, or C1-C3alkyl optionally substituted with 1 to 2 oxygen atoms;X1is C3-C6heteroalkyl, C3 heteroaryl, C3-C6heterocycle optionally substituted with sulfonyl or Ci acyl, or C3-C5carbocycle optionally substituted with 1 to 2 fluorines, trifluoromethyl, 1 to 2 methyls, or a six-membered heterocycle substituted with one methyl that forms a spirocycle with the carbocycle, or C1- C3 alkyl optionally substituted with 1 to 2 oxygen atoms;Y is a first linker covalently attached to L or absent;L is a second linker; n is 1 or 2; each E is a polypeptide comprising an Fc domain monomer or an albumin protein;T is an integer from 1 to 20; and the squiggly line indicates that L is covalently attached to E.

4. The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the conjugate is described by formula (D-l):

5. The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the conjugate is described by formula (M-l):

6. The conjugate of claim 2, or a pharmaceutically acceptable salt thereof, wherein the conjugate is described by formula (D-ll):

7. The conjugate of claim 2, or a pharmaceutically acceptable salt thereof, wherein the conjugate is described by formula (M-ll):

8. The conjugate of claim 3, or a pharmaceutically acceptable salt thereof, wherein the conjugate is described by formula (D-lll):

9. The conjugate of claim 3, or a pharmaceutically acceptable salt thereof, wherein the conjugate is described by formula (M-lll):

10. The conjugate of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A1and A2have the structure of formula (A-la):11 . The conjugate of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A1and A2have the structure of formula (A-lb):

12. The conjugate of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A1and A2have the structure of formula (A-lc):

13. The conjugate of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A1and A2have the structure of formula (A-ld):

14. The conjugate of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A1and A2have the structure of formula (A-le):

15. The conjugate of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A1and A2have the structure of formula (A-lf):

16. The conjugate of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A1and A2have the structure of formula (A-lg):

17. The conjugate of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A1and A2have the structure of formula (A-lh):

18. The conjugate of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A1and A2have the structure of formula (A-lla):

19. The conjugate of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A1and A2have the structure of formula (A-llb):

20. The conjugate of claim 6 or 7, or a pharmaceutically acceptable salt thereof, wherein B1and B2have the structure of formula (B-la):21 . The conjugate of claim 6 or 7, or a pharmaceutically acceptable salt thereof, wherein B1and B2have the structure of formula (B-lb):

22. The conjugate of claim 6 or 7, or a pharmaceutically acceptable salt thereof, wherein B1and B2have the structure of formula (B-lc):

23. The conjugate of claim 6 or 7, or a pharmaceutically acceptable salt thereof, wherein B1and B2have the structure of formula (B-ld):

24. The conjugate of claim 6 or 7, or a pharmaceutically acceptable salt thereof, wherein B1and B2have the structure of formula (B-lla):

25. The conjugate of claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein C1and C2have the structure of formula (C-la):

26. The conjugate of claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein C1and C2have the structure of formula (C-lb):

27. The conjugate of claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein C1and C2have the structure of formula (C-lc):

28. The conjugate of claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein C1and C2have the structure of formula (C-ld):

29. The conjugate of any one of claims 1 -10, 12-13, 16-18, or 25-28, or a pharmaceutically acceptable salt thereof, wherein the tropane is in exo form:

30. The conjugate of any one of claims 1 -1 1 , 14-15, or 19-24, or a pharmaceutically acceptable salt thereof, wherein the tropane is in endo form:31 . The conjugate of any one of claims 10-19 or 25-28, or a pharmaceutically acceptable salt thereof, wherein R3is isopropyl.

32. The conjugate of any one of claims 10-19 or 25-28, or a pharmaceutically acceptable salt thereof, wherein R3is methyl.

33. The conjugate of any one of claims 10-19 or 25-28, or a pharmaceutically acceptable salt thereof, wherein R3is ethyl.

34. The conjugate of any one of claims 12, 13, or 16-18, or a pharmaceutically acceptable salt thereof, wherein R4is methyl.

35. The conjugate of any one of claims 12, 13, or 16-18, or a pharmaceutically acceptable salt thereof,37. The conjugate of any one of claims 1-36, wherein Y is:each X3is, independently, N or CH; m is 1 , 2, 3, 4, or 5; p is 1 or 2; and r is 1 or 2.

38. The conjugate of any one of claims 1 -37, or a pharmaceutically acceptable salt thereof, wherein L comprises one or more optionally substituted C1-C40alkylene, optionally substituted C1-C40heteroalkylene, optionally substituted C1-C40alkoxylene, optionally substituted C3-C20cycloalkylene, optionally substituted C2-C20heterocycloalkylene, optionally substituted C5-C15arylene, optionally substituted C2-C15heteroarylene, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino, wherein R' is H, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C3-C20cycloalkyl, optionally substituted C2-C20heterocycloalkyl, optionally substituted C5-C15aryl, or optionally substituted C2-C15heteroaryl.

39. The conjugate of any one of claims 1 -38, or a pharmaceutically acceptable salt thereof, wherein L is oxo substituted.

40. The conjugate of any one of claims 1 -39, or a pharmaceutically acceptable salt thereof, wherein the backbone of L comprises between 1 and 250 atoms.

41. The conjugate of any one of claims 1 -40, or a pharmaceutically acceptable salt thereof, wherein L is capable of forming an amide, a carbamate, a sulfonyl, or a urea linkage.

42. The conjugate of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein L is described by the formula:J1-(Q1)g-(T1)h-(Q2)i-(T2)j-(Q3)k-(T3)|-(Q4)m-(T4)n-(Q5)o-J2wherein J1is a bond attached to Y;J2is a bond attached to E or is a functional group capable of reacting with a functional group conjugated to E; each of Q1, Q2, Q3, Q4, and Q5is, independently, optionally substituted C1-C40alkylene, optionally substituted C1-C40heteroalkylene, optionally substituted C1-C40alkoxylene, optionally substituted C3-C20cycloalkylene, optionally substituted C2-C20heterocycloalkylene, optionally substituted C5-C15arylene, or optionally substituted C2-C15heteroarylene; each of T1, T2, T3, T4is, independently, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, imino, or oximo;R' is H, optionally substituted C1-C20alkyl, optionally substituted C1-C20heteroalkyl, optionally substituted C3-C20cycloalkyl, optionally substituted C2-C20heterocycloalkyl, optionally substituted C5-C15aryl, or optionally substituted C2-C15heteroaryl; and each of g, h, i, j, k, I, m, n, and 0 is, independently, 0, 1 , or 2.

43. The conjugate of claim 42, or a pharmaceutically acceptable salt thereof, wherein Q1is, optionally substituted C1-C40alkylene, optionally substituted C1-C40heteroalkylene, or optionally substituted C3-C20cycloalkylene.

44. The conjugate of claim 42 or 43, or a pharmaceutically acceptable salt thereof, wherein Q2is optionally substituted C3-C20cycloalkyl, optionally substituted C1-C40alkylene, optionally substituted C1- C40 heteroalkylene, optionally substituted C1-C40alkoxylene, or optionally substituted C2-C15heteroarylene.

45. The conjugate of any one of claims 42-44, or a pharmaceutically acceptable salt thereof, wherein Q3is optionally substituted C2-C15heteroarylene or optionally substituted C1-C40heteroalkylene.

46. The conjugate of any one of claims 42-45, or a pharmaceutically acceptable salt thereof, wherein Q4is optionally substituted C1-C40alkylene, optionally substituted C1-C40heteroalkylene, optionally substituted C1-C40alkoxylene, or optionally substituted C2-C15heteroarylene.

47. The conjugate of any one of claims 42-46, or a pharmaceutically acceptable salt thereof, wherein J2is48. A conjugate, or a pharmaceutically acceptable salt thereof, described by a formula of Table 2.

49. The conjugate of any one of claims 1 -48, or a pharmaceutically acceptable salt thereof, wherein the squiggly line connected to E indicates that the L of each A1-L or each A1-L-A2 is covalently attached to a a nitrogen atom of a solvent-exposed lysine of E.

50. The conjugate of any one of claims 1 -48, or a pharmaceutically acceptable salt thereof, the squiggly line connected to E indicates that the L of each Ai-L or each A1-L-A2is covalently attached to a sulfur atom of a solvent-exposed cysteine of E.

51. The conjugate of any one of claims 1 -48, or a pharmaceutically acceptable salt thereof, wherein the squiggly line connected to E indicates that the L of each B1-L or each B1-L-B2is covalently attached to a nitrogen atom of a solvent-exposed lysine of E.

52. The conjugate of any one of claims 1 -48, or a pharmaceutically acceptable salt thereof, the squiggly line connected to E indicates that the L of each B1-L or each B1-L-B2is covalently attached to a sulfur atom of a solvent-exposed cysteine of E.

53. The conjugate of any one of claims 1 -48, or a pharmaceutically acceptable salt thereof, wherein the squiggly line connected to E indicates that the L of each C1-L or each C1-L-C2is covalently attached to a nitrogen atom of a solvent-exposed lysine of E.

54. The conjugate of any one of claims 1 -48 or a pharmaceutically acceptable salt thereof, the squiggly line connected to E indicates that the L of each C1-L or each C1-L-C2is covalently attached to a sulfur atom of a solvent-exposed cysteine of E.

55. The conjugate of any one of claims 1 -54, or a pharmaceutically acceptable salt thereof, wherein n is 2, and each E dimerizes to form an Fc domain.

56. The conjugate of any one of claims 1 -55, or a pharmaceutically acceptable salt thereof, wherein each E is a human lgG1 Fc domain monomer.

57. The conjugate of any one of claims 1 -56, or a pharmaceutically acceptable salt thereof, wherein each E comprises a substitution mutation at N297 selected from N297A, N297G, or N297Q, wherein the amino acid numbering of each Fc domain monomer is according to the Kabat EU index.

58. The conjugate of any one of claims 1 -57, or a pharmaceutically acceptable salt thereof, wherein each E comprises a C220S substitution mutation, wherein the amino acid numbering of each Fc domain monomer is according to the Kabat EU index.

59. The conjugate of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein each E comprises a M252Y, a S254T, and a T256E substitution mutation, wherein the amino acid numbering of each Fc domain monomer is according to the Kabat EU index.

60. The conjugate of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, wherein each E comprises the amino acid sequence of any one of SEQ ID NOs: 1-120 and 283.

61. The conjugate of claim 60, or a pharmaceutically acceptable salt thereof, wherein each E comprises the sequence of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, or SEQ ID NO: 18.

62. The conjugate of claim 60, or a pharmaceutically acceptable salt thereof, wherein each E comprises the sequence of SEQ ID NO: 80, SEQ ID NO: 81 , SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 114, or SEQ ID NO: 118.

63. The polypeptide of any one of claims 1-54, wherein the polypeptide of each E comprises the structure, from N-terminal to C-terminal:wherein VL is an anti-PD-1 light chain variable region;VH is an anti-PD-1 heavy chain variable region;G is an Fc domain monomer; andKi and K2, are each, independently, a peptide linker.

64. The polypeptide of claim 63, whereinVL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 121 , 124, and 125; and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 126, 129, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 130, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 131 , and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 132, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 133, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 134, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 135, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 136, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 130, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 131 , and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 132, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 133, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 134, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 135, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 127, 136, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 130, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 131 , and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 132, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 133, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 134, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 135, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 136, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 130, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 131 , and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 132, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 133, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 134, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 135, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 123, 124, and 125 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 128, 136, and 137;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 138, 139, and 140 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 141 , 142, and 143;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 122, 144, and 145 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 146, 147, and 148;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 149, 150, and 151 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 152, 153, and 154;VL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 155, 156, and 157 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 158, 159, and 160; orVL comprises an LCDR1 , LCDR2, and LCDR3 comprising the sequences set forth in SEQ ID NOs: 161 , 162, and 163 and VH comprises an HCDR1 , HCDR2, and HCDR3 comprising the sequences set forth in SEQ ID NOs: 164, 165, and 166.

65. The polypeptide of claim 63 whereinVL comprises a sequence set forth in SEQ ID NO: 167 and VH comprises a sequence set forth in SEQ ID NO: 176;VL comprises a sequence set forth in SEQ ID NO: 168 and VH comprises a sequence set forth in SEQ ID NO: 177;VL comprises a sequence set forth in SEQ ID NO: 168 and VH comprises a sequence set forth in SEQ ID NO: 178;VL comprises a sequence set forth in SEQ ID NO: 168 and VH comprises a sequence set forth in SEQ ID NO: 179;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 180;VL comprises a sequence set forth in SEQ ID NO: 170 and VH comprises a sequence set forth in SEQ ID NO: 180;VL comprises a sequence set forth in SEQ ID NO: 171 and VH comprises a sequence set forth in SEQ ID NO: 180;VL comprises a sequence set forth in SEQ ID NO: 172 and VH comprises a sequence set forth in SEQ ID NO: 180;VL comprises a sequence set forth in SEQ ID NO: 173 and VH comprises a sequence set forth in SEQ ID NO: 180;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 181 ;VL comprises a sequence set forth in SEQ ID NO: 170 and VH comprises a sequence set forth in SEQ ID NO: 181 ;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 182;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 183;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 184;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 185;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 186;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 187;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 188;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 189;VL comprises a sequence set forth in SEQ ID NO: 174 and VH comprises a sequence set forth in SEQ ID NO: 190;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 191 ;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 192;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 193;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 194;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 195;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 196;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 197;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 198;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 199;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 200;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 201 ;VL comprises a sequence set forth in SEQ ID NO: 175 and VH comprises sequence set forth inSEQ ID NO: 180;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 202;VL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 203; orVL comprises a sequence set forth in SEQ ID NO: 169 and VH comprises a sequence set forth in SEQ ID NO: 204.

66. The polypeptide of any one of claims 63-65, wherein Ki and K2 are each, independently, a peptide linker comprising between 1 and 200 amino acids or a bond.

67. The polypeptide of claim 66, wherein Ki and K2 are each, independently, a peptide linker comprising between 5 and 25 amino acids.

68. The polypeptide of any one of claims 63-67, wherein Ki and K2 are each an independently selected peptide linker comprising the amino acid sequence of any one of (GS)x, (GGS)x, (GGGGS)x, (GGSG)x, (SGGG)x, or (GGGGS)xGGG, wherein x is an integer from 1 to 10.

69. The polypeptide of any one of claims 63-68, wherein the Fc domain monomer is an IgG 1 Fc domain monomer.

70. The polypeptide of any one of claims 63-69, wherein the Fc domain monomer comprises a substitution mutation at N297 selected from N297A, N297G, or N297Q, wherein the amino acid numbering of each Fc domain monomer is according to the Kabat EU index.

71. The polypeptide of any one of claims 63-70, wherein the Fc domain monomer comprises a C220S substitution mutation, wherein the amino acid numbering of each Fc domain monomer is according to the Kabat EU index.

72. The polypeptide of any one of claims 63-71 , wherein the Fc domain monomer comprises a M252Y, a S254T, and a T256E substitution mutation, wherein the amino acid numbering of each Fc domain monomer is according to the Kabat EU index.

73. The polypeptide of any one of claims 63-72 wherein the Fc domain monomer comprises the amino acid sequence of any one of SEQ ID NOs: 1-120 and 283.

74. The polypeptide of claim 73, wherein the Fc domain monomer comprises the amino acid sequence of any one of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 17, or SEQ ID NO: 18.

75. The polypeptide of claim 74, wherein the Fc domain monomer comprises the amino acid sequence of any one of SEQ ID NO: 80, SEQ ID NO: 81 , SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 113, SEQ ID NO: 114, or SEQ ID NO: 118.

76. The polypeptide of any one of claims 63-68, wherein the polypeptide of each E comprises the amino acid sequence of any one of SEQ ID NOs: 205-272 and 284.

77. A dimer comprising: a first polypeptide described by any one of claims 63-76; and a second polypeptide described by any one of claims 63-76; wherein the Fc domain monomer of the first polypeptide and the Fc domain monomer of the second polypeptide dimerize to form an Fc domain.

78. The dimer of claim 77, wherein the first polypeptide and the second polypeptide have the same amino acid sequence and the dimer is a homodimer.

80. The conjugate of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein each E comprises the amino acid sequence of any one of SEQ ID NOs: 273-276.

81. The conjugate of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein T is 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10.

82. A population of conjugates of any one of claims 1-81 , or a pharmaceutically acceptable salt thereof, wherein the average value of T is 1 to 10.

83. A population of conjugates of claim 82, or a pharmaceutically acceptable salt thereof, wherein the average value of T is 1 to 5.

84. A pharmaceutical composition comprising a conjugate or a population of conjugates of any one of claims 1-83, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

85. A pharmaceutical composition comprising the polypeptide of any one of claims 63-76 or the dimer of claim 77 or 78 and a pharmaceutically acceptable carrier.

86. A method of treating a cancer in a subject, the method comprising administering to the subject a conjugate, population of conjugates, or pharmaceutical composition of any one of claims 1-85.

87. The method of claim 86, wherein the cancer is selected from lung cancer, optionally non-small cell lung cancer or small-cell lung cancer; head and neck cancer, optionally squamous cell carcinoma; renal cell carcinoma; breast cancer; ovarian cancer; pancreatic cancer; colorectal cancer; urothelial cancer; bile duct cancer; endometrial cancer; melanoma; prostate cancer; glioma cancer; or esophageal cancer.

88. The method of claim 87, wherein the cancer is PD-L1 negative.

89. The method of claim 87, wherein the breast cancer has wild-type BRCA1 or wild-type BRCA2.

90. The method of claim 87, wherein the breast cancer has a loss-of-function mutation in BRCA1 or BRCA2.91 . The method of any one of claims 87-90, wherein the breast cancer is triple negative breast cancer.

92. The method of claim 91 , wherein the triple negative breast cancer is PD-L1 negative.

93. The method of any one of claims 86-92, wherein the cancer is a solid tumor.

94. The method of any one of claims 86-93, wherein the cancer overexpresses or is known to overexpress CCR5 relative to a non-cancerous cell of the same tissue type.

95. The method of any one of claims 86-94, further comprising administering to the subject a PARP inhibitor or an antibody drug conjugate.

96. The method of claim 95, wherein the PARP inhibitor is olaparib or talazoparib.

97. The method of claim 95, wherein the antibody drug conjugate is Sacituzumab govitecan, Trastuzumab deruxtecan, Datopotamab deruxtecan, Enfortumab vedotin, Tisotumab vedotin, Ladiratumab vedotin, M9140, or ASN004.

98. A method of treating a PD-L1 negative cancer in a subject, the method comprising administering to the subject a conjugate, population of conjugates, or pharmaceutical composition of any one of claims 1 - 85 and an antibody drug conjugate.

99. The method of claim 98, wherein the PD-L1 negative cancer is triple negative breast cancer.

100. The method of claim 99, wherein the PD-L1 negative, triple negative breast cancer has wild-type BRAC1 or wild-type BRCA2.

101. The method of any one of claims 98-100, wherein the antibody drug conjugate is Sacituzumab govitecan, Trastuzumab deruxtecan, Datopotamab deruxtecan, Enfortumab vedotin, Tisotumab vedotin, Ladiratumab vedotin, M9140, or ASN004.

102. A method of treating breast cancer in a subject, the method comprising administering to the subject a conjugate, population of conjugates, or pharmaceutical composition of any one of claims 1 -85 and a PARP inhibitor.

103. The method of claim 102, wherein the breast cancer is triple negative breast cancer.

104. The method of claim 102 or 103, wherein the breast cancer has a loss-of-function mutation in BRCA1 or BRAC2.

105. The method of any one of claims 102-104, wherein the PARP inhibitor is olaparib or talazoparib.

106. A method of treating or preventing a viral infection in a subject, the method comprising administering to the subject a conjugate, population of conjugates, or a pharmaceutical composition of any one of the claims 1-85.

107. The method of claim 106, wherein the viral infection is HIV-1 .

108. A method of treating or preventing an inflammatory disorder in a subject, the method comprising administering to the subject a conjugate, population of conjugates, or a pharmaceutical composition of any one of the claims 1-85.

109. The method of claim 108, wherein the inflammatory disorder is graft-versus-host disease or rheumatoid arthritis.

110. The method of any one of claims 86-109, wherein the conjugate, population of conjugates, or pharmaceutical composition is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically , intraocularally, orally, locally, by inhalation, by injection, or by infusion.

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