Cytotoxic compounds and conjugates thereof

Abstract

Hydrophilic auristatin compounds are described, including drug-linker compounds, ligand-drug conjugate compounds, methods of use, and their preparation. [Figure 1] TIFF2025526648000391.tif90157

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit of priority to U.S. Provisional Application No. 63 / 397,776, filed August 12, 2022, and European Application No. 22202077.8, filed October 18, 2022, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Reference to the Electronic Sequence Listing The contents of the electronic sequence listing (761682007600SEQLIST.xml, size: 966,947 bytes, created on August 10, 2023) are incorporated herein by reference in their entirety. [Background technology]

[0003] Background of the Invention A variety of ligands, including oligopeptides, antibodies and other proteins, have been investigated for the targeted delivery of cytotoxic agents to tumor cells.Although various drug classes have been evaluated for the targeted delivery of these ligands, only a few drug classes have been proven to have sufficient activity as ligand-drug conjugates, while having suitable toxicity profile and other pharmacological properties, to ensure clinical development.Therefore, there is a need for additional cytotoxic agents with improved toxicity profile and other pharmacological properties.

[0004] The techniques and procedures described or referred to herein may generally be found in, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (F.M.A.usubel et al., eds., (2003)); the series METHODS IN ENZYMOLOGY (Academic Press, Inc.); PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames, and G.R. Taylor, eds. (1995)); Greenfield, ed. (2013) Antibodies, A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press; Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney, ed., 1987); Introduction to Cell and Tissue Culture (JP Mather and PERoberts, 1998) Plenum Press; Cell and Tissue Culture Laboratory Procedures (A. Doyle, JB Griffiths, and DG Newell, eds., 1993-98) J. Wiley and Sons; Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JM Miller and MPCalos, 1987; PCR: The Polymerase Chain Reaction (Mullis et al., 1994); Current Protocols in Immunology (JE Coligan et al., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty, ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, ed., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane, Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, ed., Harwood Academic Press, 1999) Publishers, 1995); Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993); and revised editions thereof, are well understood and commonly employed by those skilled in the art using conventional methodologies. Each of the foregoing references in this paragraph is incorporated herein by reference in its entirety. Summary of the Invention [Problem to be solved by the invention]

[0005] [Means for solving the problem]

[0006] Brief Summary of the Invention Compounds of formula (I):

[0007] [ka] or a salt thereof (wherein X b is -NR 1 R 2 and X a teeth,

[0008] [ka] or X a and X b together with the carbon atoms to which they are attached,

[0009] [ka] (where the asterisk represents X a and X b represents a carbon atom of formula (I) bearing a group, R 1 , R 2 , R 3 , R 4 , R a , R b , R 5 , and R 10 are each independently H or C1-C4 alkyl, X is H, OH, or -C(O)NR a R b , -S(O)2R a , -S(O)-R a , S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a and R 6 is a C1-C4 alkyl optionally substituted with OH, R 7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1, When X is H, R 7 , R 8 , R 9 , and R 11 at least two of which contain an OH moiety is provided herein.

[0010] Compounds of formula (II):

[0011] [ka] or a salt thereof (wherein R 1 , R 3 , and R 4 are independently H or C1-C4 alkyl; R 6 is a C1-C4 alkyl optionally substituted with OH, R 7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH, n is 0, 1, or 2; q is 0 or 1) Also provided herein are:

[0012] In some embodiments of Formula (I) and (II), q is 0. In some embodiments, q is 1. In some embodiments, R11 is H. In some embodiments, R 11 is OH.

[0013] In some embodiments of Formula (I), X is OH. In some embodiments, X is —C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a In some embodiments, X b is -NR 1 R 2 and X a teeth,

[0014] [ka] In some embodiments, R 3 is H. In some embodiments, R 4 is H. In some embodiments, n is 0 or 1. In some embodiments, X a and X b together with the carbon atoms to which they are attached,

[0015] [ka] (where the asterisk represents X a and X b In some embodiments, m represents a carbon atom of Formula (I) having a group. In some embodiments, m is 2 or 3.

[0016] In some embodiments of formula (I) or (II), R 1 is H. In some embodiments, R 1 is C1-C4 alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 2is methyl. In some embodiments, R 10 is H. In some embodiments, R 10 is methyl. In some embodiments, R 6 is unsubstituted C1-C4 alkyl. 6 is isopropyl. In some embodiments, R 6 is C1-C4 alkyl substituted with OH. In some embodiments, R 7 is C1-C4 alkyl substituted with OH. In some embodiments, R 7 is —CHOH. In some embodiments, R 7 is H. In some embodiments, R 7 is unsubstituted C1-C4 alkyl. 7 is methyl. In some embodiments, R 7 is a 5-6 membered heteroaryl. 8 is H. In some embodiments, R 8 is OH. In some embodiments, E is phenyl. In some embodiments, ER 9 teeth,

[0017] [ka] where the wavy line indicates the point of attachment of E to the remainder of the compound. In some embodiments, E is a 5-6 membered heteroaryl. In some embodiments, R 9 is H. In some embodiments, R 9 is OH.

[0018] In some embodiments of formula (I), X a teeth,

[0019] [ka] and X bis -NR 1 R 2 and R 1 is H or methyl, R 2 is methyl, X is OH, R 3 and R 4 is H, R 6 is isopropyl, R 7 is -CHOH, R 8 is H, E is phenyl; R 9 is H.

[0020] In some embodiments of Formula (I), the compound is

[0021] [ka] or a salt thereof.

[0022] In some embodiments, the compound is a compound of Table 1.

[0023] Drug-linker compounds of the formula: QD or a salt thereof (wherein Q is (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS * -RL-, (iv) Z'-AS * -RL-Y-, (v) Z'-AB(S * )-RL-, (vi) Z'-AB(S * )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS*-W-, (ix) Z'-AB(S*)-W-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL-; is a linker unit selected from the group consisting of Z' is a Stretcher unit precursor; A is a bond or connector unit, B is the parallel connector unit, S * is a resolving agent, RL is a releasable linker, W is an amino acid unit, Y is a spacer unit, D is a Drug unit of Formula (I'):

[0024] [ka] (In the formula, X b is -NR 2 - # or -N + R 1 R 5 - # where # represents the point of attachment to Q, and X a teeth,

[0025] [ka] or X a and X b together with the carbon atoms to which they are attached,

[0026] [ka] (where the asterisk represents X a and X b represents a carbon atom of formula (I) bearing a group, and # represents the point of attachment to Q), R 1 and R5 are independently C1-C4 alkyl, X is H, OH, or -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a and R 2 , R 3 , R 4 , R 10 , R a , and R b are each independently H or C1-C4 alkyl, R 6 is a C1-C4 alkyl optionally substituted with OH, R 7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1, When X is H, R 7 , R 8 , R 9 , and R 11 at least two of which contain an OH moiety) Also provided herein are:

[0027] In some embodiments, the linker unit Q is of formula (i), (ii), (iii), (iv), (x), or (xi). In some embodiments, the linker unit Q is of formula (v), (vi), (ix), or (xi). In some embodiments, the linker unit Q is of formula (viii), (ix), (x), or (xi).

[0028] In some embodiments, the stretcher unit Z′ is

[0029] [ka] (In the formula, R 17 is -CH2CH2(OCH2CH2) k -, -C1~C 10 Alkylene, C1-C 10 Heteroalkylene-, -C3-C8 carbocyclo-, -O-(C1-C8 alkylene)-, -arylene-, -C1-C 10 Alkylene-arylene-, -arylene-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-, -C3-C8 heterocyclo-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-, -C1~C 10 Alkylene-C(=O)-, C1-C 10 Heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C 10 Alkylene-arylene-C(=O)-, -arylene-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-(C3-C8 carbocyclo)-C(=O)-, -(C3-C8 carbocyclo)-C1-C 10Alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-C(=O)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-NH-, C1-C 10 Heteroalkylene-NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C 10 Alkylene-arylene-NH-, -arylene-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-NH-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-S-, C1-C 10 Heteroalkylene-S-, -C3-C8 carbocyclo-S-, -O-(C1-C8 alkylene)-S-, -arylene-S-, -C1-C 10 Alkylene-arylene-S-, -arylene-C1-C 10 Alkylene-S-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-S-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-S- or -(C3-C8 heterocyclo)-C1-C 10 alkylene-S-, the subscript k is an integer ranging from 1 to 36; R 17 is a basic unit (BU), e.g., an aminoalkyl moiety, e.g., —(CH) x NH2, -(CH2) x NHR a , and -(CH2)x NR a 2, where x is an integer from 1 to 4, and each R a independently, C 1~6 Alkyl and C 1~6 haloalkyl, or two R a groups combined with the nitrogen to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl group; The wavy line indicates the point of covalent attachment to the remainder of the drug-linker compound. is.

[0030] In some embodiments, the stretcher unit Z′ is

[0031] [ka] where the wavy line indicates the point of covalent attachment to the remainder of the Drug-Linker Compound. is.

[0032] In some embodiments, connector unit A is

[0033] [ka] (In the formula, Each R 100 are independently selected from hydrogen or -C1-C3 alkyl; R 111are independently hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-,

[0034] [ka] is selected from the group consisting of each subscript c is independently selected from an integer from 1 to 10; The wavy line indicates the attachment of the connector unit to the remainder of the drug-linker compound. is.

[0035] In some embodiments, connector unit A is

[0036] [ka] and c is an integer ranging from 1 to 6; The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof.

[0037] In some embodiments, A is a bond.

[0038] In some embodiments, B is

[0039] [ka] and each AA is independently a proteinogenic or non-proteinogenic amino acid; The wavy line indicates the point of attachment to the remainder of the Drug-Linker Compound or salt thereof.

[0040] In some embodiments, B is an amino acid.

[0041] [ka] and The wavy line indicates the splitting agent S. * indicates the attachment point to The asterisk indicates the point of attachment to the remainder of the drug-linker structure.

[0042] In some embodiments, the resolving agent S * is a polyethylene glycol (PEG) unit, a cyclodextrin unit, a polyamide, a hydrophilic peptide, a polysaccharide, or a dendrimer. * is a PEG unit containing 4 to 72 (CH2CH2O) subunits. In some embodiments, the PEG unit is

[0043] [ka] and b is selected from the group consisting of 4 to 36; The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof.

[0044] In some embodiments, the releasable linker RL is: -(AA) 1~12 - and Each AA is independently a proteinogenic or non-proteinogenic amino acid.

[0045] In some embodiments, the releasable linker R is -AA1-AA2- or -AA1-AA2-AA3- (wherein AA1 is attached to the Stretcher unit Z' or the Connector unit A). In some embodiments, the releasable linker R is

[0046] [ka] and The wavy line adjacent to the —NH— group indicates attachment to a Stretcher unit Z′ or a Connector unit A, and the wavy line adjacent to a —C(═O)— group indicates attachment to a Spacer unit Y or a Drug unit D.

[0047] In some embodiments, the releasable linker RL is a glycoside.

[0048] [ka] (In the formula, Su is a hexose derived from a monosaccharide, O' represents the oxygen atom of the glycosidic bond that can be cleaved by glycosidase; Single asterisk ( * ) indicates the site of covalent attachment to D, Double asterisk ( ** ) indicates the site of covalent attachment to the rest of Q) is.

[0049] In some embodiments, the releasable linker RL is:

[0050] [ka] and Single asterisk ( * ) indicates the site of covalent attachment to D, Double asterisk ( **The wavy line marked with ) indicates the site of covalent attachment of Q to the rest of the molecule.

[0051] In some embodiments, the spacer unit Y is

[0052] [ka] wherein EWG is an electron-withdrawing group; The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or its salt. is.

[0053] In some embodiments, the spacer unit Y is

[0054] [ka] and The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof.

[0055] In some embodiments, Z' is

[0056] [ka] and R 17 is C1~C 10 is alkylene, A is a bond, R is -AA1-AA2-, AA1 and AA2 are each independently a proteinogenic amino acid; Y is

[0057] [ka] and The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof.

[0058] In some embodiments, Z' is

[0059] [ka] and A is a bond, RL is

[0060] [ka] and Y is

[0061] [ka] is.

[0062] In some embodiments, YD is

[0063] [ka] and The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof.

[0064] In some embodiments, YD is

[0065] [ka] and The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof.

[0066] In some embodiments, the compound is

[0067] [ka] or a salt thereof.

[0068] In some embodiments, the compound is

[0069] [ka] or a salt thereof.

[0070] In some embodiments, the drug-linker compound is a compound in Table 2.

[0071] Ligand-drug conjugate compounds of the formula: L-(QD) p or a pharmaceutically acceptable salt thereof, L is a ligand unit, Q is (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS * -RL-, (iv) Z'-AS * -RL-Y-, (v) Z'-AB(S * )-RL-, (vi) Z'-AB(S * )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS*-W-, (ix) Z'-AB(S*)-W-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL-; is a linker unit selected from the group consisting of Z' is a Stretcher unit precursor; A is a bond or connector unit, B is the parallel connector unit, S * is a resolving agent, RL is a releasable linker, W is an amino acid unit, Y is a spacer unit, D is a Drug unit of Formula (I'):

[0072] [ka] (In the formula, X b is -NR 2 - # or -N + R 1 R 5 - # where # represents the point of attachment to Q, and X a teeth,

[0073] [ka] or X a and X b together with the carbon atoms to which they are attached,

[0074] [ka] (where the asterisk represents X a and X b represents a carbon atom of formula (I) bearing a group, and # represents the point of attachment to Q), R 1 and R 5 are independently C1-C4 alkyl, X is H, OH, or -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a and R 2 , R 3 , R 4 , R 10 , R a , and R b are each independently H or C1-C4 alkyl, R 6 is a C1-C4 alkyl optionally substituted with OH, R 7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1, When X is H, R 7 , R 8 , R 9 , and R 11 at least two of which contain an OH moiety) Also provided herein are:

[0075] In some embodiments, the linker unit Q is of formula (i), (ii), (iii), (iv), (x), or (xi). In some embodiments, the linker unit Q is of formula (v), (vi), (ix), or (xi). In some embodiments, the linker unit Q is of formula (viii), (ix), (x), or (xi).

[0076] In some embodiments, the Ligand unit L and the Stretcher unit Z, when combined, form:

[0077] [ka] (In the formula, R 17 is -CH2CH2(OCH2CH2) k -, -C1~C 10 Alkylene, C1-C 10Heteroalkylene-, -C3-C8 carbocyclo-, -O-(C1-C8 alkylene)-, -arylene-, -C1-C 10 Alkylene-arylene-, -arylene-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-, -C3-C8 heterocyclo-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-, -C1~C 10 Alkylene-C(=O)-, C1-C 10 Heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C 10 Alkylene-arylene-C(=O)-, -arylene-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-(C3-C8 carbocyclo)-C(=O)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-C(=O)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-NH-, C1-C 10 Heteroalkylene-NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C 10 Alkylene-arylene-NH-, -arylene-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-NH-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C 10Alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-S-, C1-C 10 Heteroalkylene-S-, -C3-C8 carbocyclo-S-, -O-(C1-C8 alkylene)-S-, -arylene-S-, -C1-C 10 Alkylene-arylene-S-, -arylene-C1-C 10 Alkylene-S-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-S-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-S- or -(C3-C8 heterocyclo)-C1-C 10 alkylene-S-, the subscript k is an integer ranging from 1 to 36; R 17 is a basic unit (BU), e.g., an aminoalkyl moiety, e.g., —(CH) x NH2, -(CH2) x NHR a , and -(CH2) x NR a 2, where x is an integer from 1 to 4, and each R a independently, C 1~6 Alkyl and C 1~6 haloalkyl, or two R a groups combined with the nitrogen to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl group; The wavy line indicates the point of covalent attachment to the remainder of the ligand-drug conjugate compound. is.

[0078] In some embodiments, the Ligand unit L and the Stretcher unit Z, when combined, form:

[0079] [ka]

[0080] [ka] where the wavy line indicates the point of covalent attachment to the remainder of the ligand-drug conjugate compound. is.

[0081] In some embodiments, connector unit A is

[0082] [ka] (In the formula, Each R 100 are independently selected from hydrogen or -C1-C3 alkyl; R 111 are independently hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-,

[0083] [ka] is selected from the group consisting of each subscript c is independently selected from an integer from 1 to 10; The wavy line indicates the attachment of the connector unit to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof. is.

[0084] In some embodiments, connector unit A is

[0085] [ka] and c is an integer ranging from 1 to 6; The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, A is a bond.

[0087] In some embodiments, B is

[0088] [ka] and each AA is independently a proteinogenic or non-proteinogenic amino acid; The wavy line indicates the point of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, B is an amino acid.

[0090] [ka] and The wavy line indicates the splitting agent S. * indicates the attachment point to The asterisk indicates the point of attachment to the remainder of the Ligand-Drug Conjugate Compound or its pharmaceutically acceptable salt.

[0091] In some embodiments, the resolving agent S *is a polyethylene glycol (PEG) unit, a cyclodextrin unit, a polyamide, a hydrophilic peptide, a polysaccharide, or a dendrimer. * is a PEG unit containing 4 to 72 (CH2CH2O) subunits. In some embodiments, the PEG unit is

[0092] [ka] and b is selected from the group consisting of 4 to 36; The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the releasable linker RL is: -(AA) 1~12 - and Each AA is independently a proteinogenic or non-proteinogenic amino acid.

[0094] In some embodiments, the releasable linker RL is -AA1-AA2- or -AA1-AA2-AA3- (where AA1 is attached to the Stretcher unit Z or the Connector unit A).

[0095] In some embodiments, the releasable linker RL is:

[0096] [ka] and The wavy line adjacent to the -NH- group indicates attachment to a Stretcher unit Z or a Connector unit A, and the wavy line adjacent to a -C(=O)- group indicates attachment to a Spacer unit Y or a Drug unit D.

[0097] In some embodiments, the releasable linker RL is a glycoside.

[0098] In some embodiments, the releasable linker RL is:

[0099] [ka] (In the formula, Su is a hexose derived from a monosaccharide, O' represents the oxygen atom of the glycosidic bond that can be cleaved by glycosidase; Single asterisk ( * ) indicates the site of covalent attachment to D, Double asterisk ( ** ) indicates the site of covalent attachment to the rest of Q) is.

[0100] In some embodiments, the releasable linker RL is:

[0101] [ka] and Single asterisk ( * ) indicates the site of covalent attachment to D, Double asterisk ( ** The wavy line marked with ) indicates the site of covalent attachment of Q to the rest of the molecule.

[0102] In some embodiments, the spacer unit Y is

[0103] [ka] wherein EWG is an electron-withdrawing group; The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof. is.

[0104] In some embodiments, the spacer unit Y is

[0105] [ka] and The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, R 17 is C1~C 10 is alkylene, A is a bond, R is -AA1-AA2-, AA1 and AA2 are each independently a proteinogenic amino acid; Y is

[0107] [ka] and The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, A is a bond, RL is

[0109] [ka] and Y is

[0110] [ka] is.

[0111] In some embodiments, YD is

[0112] [ka] and The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, YD is

[0114] [ka] and The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the compound is

[0116] [ka]

[0117] [ka] or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the ligand-drug conjugate compound is a compound of Table 3.

[0119] In some embodiments, p is an integer ranging from 2 to 6. In some embodiments, p is 4.

[0120] Also provided herein are pharmaceutical compositions comprising the ligand-drug conjugate compounds described herein and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises a plurality of ligand-drug conjugate compounds having an average drug loading of 2 to 8. In some embodiments, the average drug loading is about 4. In some embodiments, the average drug loading is 3.5 to 4.5.

[0121] Also provided herein are methods for treating cancer, comprising administering a therapeutically effective amount of the ligand-drug conjugate compound of any one of claims 66 to 96, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the subject tolerates treatment with the ligand-drug conjugate compound better than treatment with a therapeutically effective dose of another ligand-drug conjugate compound. In some embodiments, the other ligand-drug conjugate compound comprises a monomethyl auristatin E or monomethyl auristatin F drug unit. [Brief explanation of the drawings]

[0122] [Figure 1] FIG. 1 illustrates in vivo mean tumor volume data for various Ag1 ADCs in the A2058 melanoma xenograft model. [Figure 2] FIG. 2 illustrates in vivo mean tumor volume data for various h2A2 ADCs in the Detroit 562 laryngeal carcinoma xenograft model. [Figure 3] FIG. 3 illustrates in vivo median tumor volume data for various cAC10 ADCs in a Karpas / KarpasBVR mixed Hodgkin's lymphoma xenograft model. [Figure 4] FIG. 4 illustrates in vivo mean tumor volume data for various cAC10 ADCs in the Karpas Hodgkin's lymphoma xenograft model. [Figure 5] FIG. 5 illustrates in vivo mean tumor volume data for various cAC10 ADCs in the Karpas Hodgkin's lymphoma xenograft model. [Figure 6] FIG. 6 summarizes plasma neutrophil levels on days 5 and 8 after administration of unconjugated ADC to rats. [Figure 7] FIG. 7 summarizes reticulocyte levels at days 5 and 8 after administration to rats with unconjugated ADC. [Figure 8]FIG. 8 summarizes platelet levels at days 5 and 8 after dosing with unconjugated ADC in rats. [Figure 9] FIG. 9 summarizes aspartate transaminase (AST) levels at day 8 after administration of unconjugated ADC to rats. [Figure 10] FIG. 10 illustrates the efficacy of various hCR011 ADCs and a non-binding control ADC measured in the WM2664 melanoma xenograft model. [Figure 11] FIG. 11 illustrates the efficacy of various hCR011 ADCs and a non-binding control ADC measured in the SKMEL5 melanoma xenograft model. [Figure 12] FIG. 12 illustrates the efficacy of the non-conjugated, Ag2, and hCR011 ADCs measured in the PDX_1 melanoma xenograft model. [Figure 13] Figure 13 illustrates the efficacy of the non-binding, Ag2, and hCR011 ADCs measured in the PDX_4 melanoma xenograft model. [Figure 14] FIG. 14 illustrates the efficacy of the non-conjugated, Ag2, and hCR011 ADCs measured in the PDX_3 NSCLC xenograft model. [Figure 15] Figure 15 illustrates the efficacy of the non-binding, Ag2, and hCR011 ADCs measured in the PDX_2 NSCLC xenograft model. [Figure 16] Figure 16 summarizes the antitumor activity of six hCR011 ADCs using AUC.3. [Figure 17] Figure 17 summarizes plasma neutrophil levels at baseline, 4 days, 15 days, and 29 days after administration of hCR011 ADC to cynomolgus monkeys. [Figure 18] Figure 18 summarizes reticulocyte levels at baseline, 4 days, 15 days, and 29 days after administration of hCR011 ADC to cynomolgus monkeys. [Figure 19]Figure 19 summarizes platelet levels at baseline, 4 days, 15 days, and 29 days after administration of hCR011 ADC to cynomolgus monkeys. [Figure 20] Figure 20 summarizes aspartate transaminase levels at baseline and on day 8 after administration of hCR011 ADC to cynomolgus monkeys. [Figure 21] FIG. 21 shows neutrophil counts from blood samples taken pre-dose and 8 days post-dose. DETAILED DESCRIPTION OF THE INVENTION

[0123] Detailed Description of the Invention One of the target drug classes for use in ligand-drug conjugates is auristatin.Although auristatin has been shown to be an effective payload in some ligand-drug conjugates (LDC), it is believed that their hydrophobicity may contribute to off-target toxicity due to the increased permeability and high bystander activity of free auristatin.In addition, hydrophobic payloads, such as auristatin, may increase the hydrophobicity of LDC, resulting in the rapid clearance of LDC from the subject's body.Therefore, there is a need for auristatin conjugates engineered to have optimized cell permeability, pharmacokinetics, and toxicity profile.

[0124] Without being bound by theory, it is believed that the hydrophilic groups of the auristatin compounds provided herein affect the properties of the compounds and the resulting conjugates (e.g., ligand-drug conjugates). The hydrophilic groups are believed to increase the efficacy of the resulting conjugates in two ways. Conjugates containing hydrophilic auristatin groups may improve tumor exposure to the drug unit due to reduced plasma clearance, and they may simultaneously exhibit reduced off-target toxicity due to reduced cellular permeability of the free drug after release from the conjugate.

[0125] I. Definition Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings: When trade names are used herein, they include product formulations, generic drugs, and active pharmaceutical ingredients of the trade name product unless the context indicates otherwise.

[0126] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by those skilled in the art in the technical field to which this disclosure relates.For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd edition, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 5th edition, 2013, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, 2nd edition, 2006, Oxford University Press provide those skilled in the art with the general dictionary of many of the terms used in this disclosure.

[0127] Unless otherwise required by context or clearly indicated, singular terms shall include pluralities and plural terms shall include the singular.

[0128] It is understood that aspects and embodiments of the invention described herein include "comprising," "consisting of," and / or "consisting essentially of" aspects and embodiments.

[0129] As used herein, the singular forms "a," "an," and "the" should be understood to refer to "one or more" of any named or listed components, unless otherwise indicated.

[0130] The term "about" refers to a value or composition that is within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which depends in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. As will be understood by one of ordinary skill in the art, reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself. For example, a description that refers to "about X" includes a description of "X."

[0131] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and fractions thereof (e.g., tenths and hundredths of integers), where appropriate, unless otherwise indicated.

[0132] When trade names are used herein, reference to a trade name also refers to product formulations, generic drugs, and drug substances of the trade name product, unless the context indicates otherwise.

[0133] The term "and / or," when used herein, should be taken as a specific disclosure of each of the two specified features or components, with or without the other. Thus, when the term "and / or" is used herein in phrases such as "A and / or B," it is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, when the term "and / or" is used in phrases such as "A, B, and / or C," it is intended to encompass each of the following embodiments: A, B, and C; A, B, or C: A or C; A or B; B or C: A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0134] The term "antibody," as used herein, is used in the broadest sense and specifically encompasses intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (i.e., antigen-binding fragments) that retain, at least in part, one or more of the desired biological activities of the full-length antibody, e.g., affinity for its cognate antigen. The native form of an antibody is a tetramer, consisting of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. Within each pair, the light and heavy chain variable regions (V L and V H), together are primarily responsible for binding to antigen. Light and heavy chain variable domains consist of a framework region interrupted by three hypervariable regions, also called "complementarity-determining regions" or "CDRs." In some embodiments, the constant region is recognized by and interacts with the immune system (see, e.g., Janeway et al., 2001, Immunol. Biology, 5th ed., Garland Publishing, New York). Antibodies herein are of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass thereof. In some embodiments, the antibody is derived from a suitable species. In some embodiments, the antibody is of human or murine origin. In some embodiments, the antibody is human, humanized, or chimeric. The antibody can be human, humanized, chimeric, and / or affinity matured, as well as antibodies from other species, such as mouse and rabbit. The term "antibody" therefore includes, for example, polypeptide products of B cells within the immunoglobulin class of polypeptides capable of binding to a specific molecular antigen, composed of two identical pairs of polypeptide chains, each pair having one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), with the respective amino-terminal portions of each chain containing a variable region of about 100 to about 130 or more amino acids, and the respective carboxy-terminal portions of each chain containing a constant region. See, e.g., Antibody Engineering (Borrebaeck, ed., 2nd ed., 1995) and Kuby, Immunology (3rd ed., 1997). The term "antibody" also includes, but is not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies, intrabodies, anti-idiotypic (anti-Id) antibodies, and functional fragments of any of the above (e.g., antigen-binding fragments), which refer to portions of antibody heavy and / or light chain polypeptides that retain some or all of the binding activity of the antibody from which the fragment is derived.Non-limiting examples of functional fragments (e.g., antigen-binding fragments) include single-chain Fvs (scFvs) (including, e.g., monospecific, bispecific, etc.), Fab fragments, F(ab') fragments, F(ab)2 fragments, F(ab')2 fragments, disulfide-linked Fvs (dsFvs), Fd fragments, Fv fragments, diabodies, triabodies, tetrabodies, and minibodies. In particular, antibodies provided herein include immunoglobulin molecules and molecules containing an immunologically active portion of an immunoglobulin molecule, e.g., an antigen-binding domain or antigen-binding site that binds to an antigen (e.g., one or more CDRs of an antibody). Such antibody fragments can be found, for example, in Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers, ed., 1995); Huston et al., 1993, Cell Biophysics 22:189-224; Plueckthun and Skerra, 1989, Meth. Enzymol. 178:497-515; and Day, Advanced Immunochemistry (2nd ed., 1990). The antibodies provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecules.

[0135] The term "monoclonal antibody," as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations, which may, in some embodiments, be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and should not be construed as requiring production of the antibody by any particular method.

[0136] An "intact antibody" is an antibody that contains, where appropriate for the antibody class, an antigen-binding variable region, as well as a light chain constant domain (C L ), and C of the heavy chain constant domain H 1. C H 2. C H 3, and C H 4. In some embodiments, the constant domains are native sequence constant domains (e.g., human native sequence constant domains), while in other embodiments they are amino acid sequence variants thereof.

[0137] "Antibody fragments" include portions of intact antibodies, including the antigen-binding or variable regions thereof. Examples of antibody fragments include Fab, Fab', F(ab'), and Fv fragments, diabodies, triabodies, tetrabodies, linear antibodies, single-chain antibody molecules, scFv, scFv-Fc, multispecific antibody fragments formed from antibody fragments, fragments produced by a Fab expression library, or epitope-binding fragments of any of the above that immunospecifically bind to a target antigen (e.g., a cancer cell antigen, a viral antigen, or a microbial antigen).

[0138] An "antigen-binding fragment" (or simply "fragment") or "antigen-binding domain" of an antigen-binding protein (e.g., an antibody), as used herein, refers to one or more fragments of an antigen-binding protein (e.g., an antibody), regardless of how obtained or synthesized, that retain the ability to specifically bind to an antigen bound to the whole antigen-binding protein. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments. An "Fv" fragment comprises a non-covalently linked dimer of one heavy chain variable domain and one light chain variable domain. A "Fab" fragment comprises the heavy and light chain variable domains of an Fv fragment, as well as the constant domain of the light chain and the first constant domain of the heavy chain (C H1 A "F(ab')2" fragment contains two Fab fragments joined near the hinge region by disulfide bonds.

[0139] An "antigen" is an entity to which an antibody specifically binds.

[0140] The terms "specific binding" and "specifically bind" mean that an antibody or antibody derivative binds in a highly selective manner to its corresponding epitope on a target antigen and does not bind to many other antigens. Typically, an antibody or antibody derivative binds to at least about 1 x 10 -7 M, preferably 10 -8 M~10 -9 M, 10 -10 M, 10 -11 M, or 10 -12 M, and binds to a given antigen with an affinity that is at least two-fold greater than its affinity for binding to a nonspecific antigen other than the given antigen or a closely related antigen (e.g., BSA, casein).

[0141] The term "inhibit" or "inhibition of" means to reduce by a measurable amount or to prevent altogether.

[0142] The term "therapeutically effective amount" refers to an amount of a conjugate effective to treat a disease or disorder in a mammal. In the case of cancer, a therapeutically effective amount of a conjugate may reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow to some extent, and preferably stop) cancer cell invasion into surrounding organs; inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate to some extent one or more symptoms associated with cancer. In some embodiments, the drug inhibits the growth of and / or kills existing cancer cells. In some embodiments, the drug is cytostatic and / or cytotoxic. For cancer therapy, efficacy is measured by commonly available tools. In some embodiments, efficacy is measured by assessing the time to progression (TTP) and / or determining the response rate (RR).

[0143] As used herein, "percent (%) amino acid sequence identity" and "homology" with respect to a peptide, polypeptide, or antigen-binding protein (e.g., antibody) sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a particular peptide or polypeptide sequence, after aligning the sequences and, if necessary, introducing gaps to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms required to achieve maximum alignment across the entire length of the sequences being compared. For example, the % sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (which may alternatively be expressed as a given amino acid sequence A having or comprising a certain % sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y (where X is the number of amino acid residues scored as identical matches by the sequences in the program's alignment of A and B, and Y is the total number of amino acid residues in B. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are calculated according to this formula using the ALIGN-2 computer program. It will be recognized that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % sequence identity of A to B will not equal the % sequence identity of B to A.

[0144] The term "substantial" or "substantially" refers to a majority of a population, mixture, or sample, i.e., >50%, preferably greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the population.

[0145] The term "cytotoxic activity" refers to the cell-killing effect of a drug or a ligand-drug conjugate compound or an intracellular metabolic product of a ligand-drug conjugate compound. In some embodiments, cytotoxic activity is measured by the IC 50 It is expressed as a value, which is the concentration (molar or mass) per unit volume at which half of the cells survive.

[0146] The term "cytostatic activity" refers to the anti-proliferative effect of a drug or a ligand-drug conjugate compound or an intracellular metabolite of a ligand-drug conjugate compound.

[0147] The term "cytotoxic agent," as used herein, refers to a substance that has cytotoxic activity and causes destruction of cells. The term is intended to include chemotherapeutic agents, and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, including synthetic analogs and derivatives thereof.

[0148] The term "cytostatic agent," as used herein, refers to a substance that inhibits cellular function, including cell growth or proliferation. Cytostatic agents include inhibitors, such as protein inhibitors, for example, enzyme inhibitors. Cytostatic agents have cytostatic activity.

[0149] The terms "cancer" and "cancerous" refer to or describe the physiological condition or disorder in mammals that is typically characterized by upregulated cell growth. A "tumor" contains one or more cancerous cells.

[0150] The term "immunoglobulin" refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) low-molecular-weight chains and one pair of heavy (H) chains, all four of which are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, for example, Fundamental Immunology (Paul, W., ed., 7th ed., Raven Press, NY (2013)). Briefly, each heavy chain typically comprises a heavy chain variable region (herein referred to as V H or abbreviated VH) and a heavy chain constant region (C H The heavy chain constant region is typically composed of three domains: C, ... H 1. C H 2, and C H 3. Heavy chains are generally interconnected via disulfide bonds at the so-called "hinge region." Each light chain typically contains a light chain variable region (herein referred to as V L or VL) and a light chain constant region (C L The light chain constant region typically consists of one domain, C L The CL may be of the κ (kappa) or λ (lambda) isotype. The terms "constant domain" and "constant region" are used interchangeably herein. Immunoglobulins may be derived from any of the commonly known isotypes, including, but not limited to, IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those skilled in the art and include, but are not limited to, human IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) encoded by the heavy chain constant region gene.

[0151] The term "hypervariable region" or "HVR," as used herein, refers to each of the regions of an antibody variable domain that are hypervariable in sequence. HVRs can form structurally defined loops ("hypervariable loops"). Native four-chain antibodies generally contain six HVRs: three in the VH (H1, H2, and H3) and three in the VL (L1, L2, and L3). In native antibodies, H3 and L3 are the most diverse of the six HVRs, and H3, in particular, appears to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu, Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003). In fact, naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0152] HVRs generally comprise amino acid residues from hypervariable loops and / or "complementarity-determining regions" (CDRs), which are those with the highest sequence variability and / or involved in antigen recognition. Various schemes for defining the boundaries of a given CDR are known in the art. For example, the Kabat complementarity-determining regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Chothia instead refers to the location of structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). AbM CDRs represent a compromise between Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. "Contact" CDRs are based on analysis of available complex crystal structures. Additional details on the above schemes and other numbering conventions are provided in the following references: Al-Lazikani et al. (1997) J. Mol. Biol. 273:927-948 ("Chothia" numbering scheme); MacCallum et al. (1996) J. Mol. Biol. 262:732-745 (1996) ("Contact" numbering scheme); Lefranc MP. et al. (2003) Dev. Comp. Immunol. 27:55-77 ("IMGT" numbering scheme); and Honegger A. and Pluckthun A. (2001) J. Mol / Biol. 309:657-70 (AHo numbering scheme).

[0153] In some embodiments, the HVR regions and associated sequences are the same as the CDR regions and associated sequences based on one of the numbering conventions described above. As such, residues for exemplary HVRs and / or CDRs are summarized in Table D1 below.

[0154] [Table 1]

[0155] In some embodiments, HVRs may comprise extended HVRs as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in VL, and 26-35 (H1), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in VH. The variable domain residues are numbered according to Kabat et al., supra, for each of these definitions.

[0156] Unless otherwise specified, the terms "CDR" and "complementarity determining region" of a given antibody or region thereof, e.g., a variable region, and the individual CDRs (e.g., CDR-H1, CDR-H2) of an antibody or region thereof, should be understood to encompass complementarity determining regions defined by any of the known schemes described hereinabove. In some instances, schemes for identifying a particular CDR or CDRs are defined, such as CDRs defined by the IMGT, Kabat, AbM, Chothia, or Contact methods. In other instances, specific amino acid sequences of CDRs are provided.

[0157] Thus, in some embodiments, the antigen binding protein comprises CDRs and / or HVRs defined by the IMGT system. In other embodiments, the antigen binding protein comprises CDRs or HVRs defined by the Kabat system. In still other embodiments, the antigen binding protein comprises CDRs or HVRs defined by the AbM system. In further embodiments, the antigen binding protein comprises CDRs or HVRs defined by the Chothia system. In yet other embodiments, the antigen binding protein comprises CDRs or HVRs defined by the IMGT system.

[0158] The term "variable region" or "variable domain" refers to the domain of an antigen-binding protein (e.g., an antibody) heavy or light chain that is involved in binding of the antigen-binding protein (e.g., an antibody) to an antigen. The variable regions or domains of the heavy and light chains of an antigen-binding protein, e.g., an antibody (VH and VL, respectively), can be further subdivided into regions of hypervariability (or hypervariable regions, which can be hypervariable in sequence and / or in the form of structurally defined loops), e.g., hypervariable regions (HVRs) or complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Generally, there are three HVRs (HVR-H1, HVR-H2, HVR-H3) or CDRs (CDR-H1, CDR-H2, CDR-H3) in each heavy chain variable region, and three HVRs (HVR-L1, HVR-L2, HVR-L3) or CDRs (CDR-L1, CDR-L2, CDR-L3) in each light chain variable region. The terms "framework region" and "FR" are known in the art to refer to the non-HVR or non-CDR portions of the heavy and light chain variable regions. Generally, there are four FRs (FR-H1, FR-H2, FR-H3, and FR-H4) in each full-length heavy chain variable region, and four FRs (FR-L1, FR-L2, FR-L3, and FR-L4) in each full-length light chain variable region. Within each VH and VL, the three HVRs or CDRs and four FRs are typically arranged from amino terminus to carboxy terminus in the following order: FR1, HVR1, FR2, HVR2, FR3, HVR3, FR4 for HVRs, or FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 for CDRs (see also Chothia and Lesk J. Mot. Biol., 195, 901-917 (1987)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. In addition, antibodies that bind to a specific antigen can be isolated by screening a library of complementary VL or VH domains using a VH or VL domain derived from an antibody that binds the antigen.See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0159] The term "heavy chain variable region" (VH), as used herein, refers to a region comprising heavy chain HVR-H1, FR-H2, HVR-H2, FR-H3, and HVR-H3. For example, a heavy chain variable region can comprise heavy chain CDR-H1, FR-H2, CDR-H2, FR-H3, and CDR-H3. In some embodiments, the heavy chain variable region also comprises at least a portion of FR-H1 and / or at least a portion of FR-H4.

[0160] The term "heavy chain constant region" as used herein refers to a region comprising at least three heavy chain constant domains C H 1. C H 2, and C H The heavy chain constant region refers to a region containing 3. Non-limiting exemplary heavy chain constant regions include γ, δ, and α. Non-limiting exemplary heavy chain constant regions also include ε and μ. Each heavy constant region corresponds to an antibody isotype. For example, an antibody containing a γ constant region is an IgG antibody, an antibody containing a δ constant region is an IgD antibody, and an antibody containing an α constant region is an IgA antibody. Furthermore, an antibody containing a μ constant region is an IgM antibody, and an antibody containing an ε constant region is an IgE antibody. A particular isotype can be further subdivided into subclasses. For example, IgG antibodies include, but are not limited to, IgG1 (containing a gamma 1 constant region), IgG2 (containing a gamma 2 constant region), IgG3 (containing a gamma 3 constant region), and IgG4 (containing a gamma 4 constant region) antibodies; IgA antibodies include, but are not limited to, IgA1 (containing an alpha 1 constant region) and IgA2 (containing an alpha 2 constant region) antibodies; and IgM antibodies include, but are not limited to, IgM1 and IgM2.

[0161] The term "heavy chain" (HC), as used herein, refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. The term "full-length heavy chain," as used herein, refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.

[0162] The term "light chain variable region" (VL), as used herein, refers to the region comprising light chain HVR-L1, FR-L2, HVR-L2, FR-L3, and HVR-L3. In some embodiments, the light chain variable region comprises light chain CDR-L1, FR-L2, CDR-L2, FR-L3, and CDR-L3. In some embodiments, the light chain variable region also comprises FR-L1 and / or FR-L4.

[0163] The term "light chain constant region" as used herein refers to a light chain constant domain C L Non-limiting exemplary light chain constant regions include lambda and kappa.

[0164] The term "light chain" (LC), as used herein, refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. The term "full-length light chain," as used herein, refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.

[0165] The "EU numbering system" or "EU index" is generally used when referring to residues in an immunoglobulin heavy chain constant region (e.g., the EU index as reported in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md., 1991). The "EU index in Kabat" refers to the residue numbering of the human IgG1 EU antibody. Unless otherwise stated herein, references to residue numbers in the constant domain of an antibody refer to residue numbering according to the EU numbering system.

[0166] The term "derivative" refers to a molecule (e.g., an antigen binding protein, e.g., an antibody or fragment thereof) that contains a chemical modification other than an amino acid (or nucleic acid) insertion, deletion, or substitution. In certain embodiments, a derivative includes a covalent modification, including, but not limited to, chemical bonding with a polymer, lipid, or other organic or inorganic moiety. In certain embodiments, a derivative of a particular antigen binding protein may have a longer circulating half-life than the antigen binding protein that has not been chemically modified. In certain embodiments, a derivative may have improved targeting ability to a desired cell, tissue, and / or organ. In some embodiments, a derivative of an antigen binding protein includes, but is not limited to, The polymer is not limited to, but may be covalently modified to contain one or more polymers, including monomethoxy-polyethylene glycol, dextran, cellulose, or other carbohydrate-based polymers, poly-(N-vinylpyrrolidone)-polyethylene glycol, propylene glycol homopolymer, polypropylene oxide / ethylene oxide copolymer, polyoxyethylated polyol (e.g., glycerol) and polyvinyl alcohol, and mixtures of such polymers.See, for example, U.S. Patent Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192, and 4,179,337.

[0167] The term "compete," when used in the context of antigen-binding proteins (e.g., antibodies or fragments thereof) competing for the same epitope, refers to competition between the antigen-binding proteins, as determined by an assay in which the antigen-binding protein (e.g., antibody or fragment thereof) being tested (e.g., test antibody) prevents or inhibits (partially or completely) the specific binding of a reference antigen-binding protein (e.g., reference antibody) to a common antigen (e.g., gpNMB or a fragment thereof). Numerous types of competitive binding assays can be used to determine whether one antigen-binding protein competes with another, including various label-free biosensor approaches, such as surface plasmon resonance (SPR) analysis (see, e.g., Abdiche et al., 2009, Anal. Biochem. 386:172-180; Abdiche et al., 2012, J. Immunol. Methods 382:101-116; and Abdiche et al., 2014, PLoS One 9:e92451). Other assays that can be used include solid-phase direct or indirect radioimmunoassays (RIA), solid-phase direct or indirect enzyme immunoassays (EIA), sandwich competition assays (see, e.g., Stahl et al., 1983, Methods in Enzymology 9:242-253), solid-phase direct biotin-avidin EIA (see, e.g., Kirkland et al., 1986, J. Immunol. 137:3614-3619), solid-phase direct labeled assays, solid-phase direct labeled sandwich assays (see, e.g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1989). Press), solid-phase direct labeling RIA using I-125 label (see, e.g., Morel et al., 1988, Mol. Immunol. 25:7-15), solid-phase direct biotin-avidin EIA (see, e.g., Cheung et al., 1990, Virology 176:546-552), and direct labeling RIA (Moldenhauer et al., 1990, Scand. J. Immunol. 32:77-82).Typically, the test antigen-binding protein is present in excess (e.g., at least 2-fold, 5-fold, 10-fold, 20-fold, or 100-fold). Usually, when a competing antigen-binding protein is present in excess, it inhibits the specific binding of the reference antigen-binding protein to a common antigen by at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In instances where each antigen-binding protein (e.g., an antibody or fragment thereof) detectably inhibits the binding of the other antigen-binding protein to its cognate epitope, whether to the same, greater, or lesser extent, the antigen-binding proteins are said to "cross-compete" with each other or "cross-block" each other for binding of their respective epitopes. Typically, such cross-competition studies are performed using the conditions and methods described above for competition studies, and the degree of blocking is, for each method, at least 30%, at least 40%, or at least 50%.

[0168] An "affinity matured" antibody refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs) compared to a parent antibody lacking such alterations, which alterations result in an improvement in the affinity of the antibody for the antigen. In some instances, an affinity matured antibody refers to an antibody with one or more alterations in one or more complementarity determining regions (CDRs) compared to a parent antibody lacking such alterations, which alterations result in an improvement in the affinity of the antibody for the antigen.

[0169] As used herein, the terms "specifically bind," "binding," or simply "bind," or other related terms, in the context of binding of an antigen-binding protein to its target antigen, mean that the antigen-binding protein exhibits substantial background binding to non-target molecules. An antigen-binding protein that specifically binds to a target antigen (e.g., gpNMB) will, however, cross-react with corresponding proteins (such as gpNMB) from different species.

[0170] "K DThe term "(M)" as used herein refers to the dissociation equilibrium constant of a particular antigen-binding protein-antigen interaction (e.g., an antibody-antigen interaction). As used herein, affinity and K D is inversely proportional, so that higher affinity corresponds to lower K D A lower affinity is intended to refer to a higher K D is intended to refer to.

[0171] An "antibody-drug conjugate" or simply "ADC" refers to an antibody conjugated to a cytotoxic or cytostatic agent. The antibody-drug conjugate typically binds to a target antigen (e.g., gpNMB) on the cell surface, followed by internalization of the antibody-drug conjugate into the cell, where the drug is released.

[0172] A "cytotoxic effect" refers to the depletion, elimination and / or killing of target cells.

[0173] A "cytotoxic agent" refers to an agent that has a cytotoxic effect on cells.

[0174] A "cytostatic effect" refers to the inhibition of cell proliferation.

[0175] A "cytostatic agent" refers to an agent that has a cytostatic effect on cells, thereby inhibiting the growth and / or expansion of a specific subset of cells. The cytostatic agent may be conjugated to an antibody or administered in combination with an antibody.

[0176] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxy terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md., 1991.

[0177] A "functional Fc region" possesses the "effector functions" of a native sequence Fc region. Exemplary "effector functions" include Fc receptor binding, C1q binding, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), down-regulation of cell surface receptors (e.g., B cell receptor, BCR), and the like. Such effector functions generally require that the Fc region be combined with a binding domain (e.g., an antibody variable domain), and can be assessed using a variety of assays.

[0178] A "native-sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native-sequence human Fc regions include native-sequence human IgG1 Fc regions (non-A and A allotypes), native-sequence human IgG2 Fc regions, native-sequence human IgG3 Fc regions, and native-sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0179] A "variant Fc region" comprises an amino acid sequence that differs from that of a native sequence Fc region by virtue of at least one amino acid modification.

[0180] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. In some embodiments, the FcγR is a native human FcR. In some embodiments, the FcR binds IgG antibodies (gamma receptors) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain (see, e.g., Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs have been reviewed, for example, in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those identified in the future, are encompassed by the term "FcR" herein. The term "Fc receptor" or "FcR" also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) and for regulating immunoglobulin homeostasis. Methods for measuring binding to FcRn are known (see, e.g., Ghetie and Ward, Immunol. Today 18(12):592-598 (1997); Ghetie et al., Nature Biotechnology 15(7):637-640 (1997); Hinton et al., J. Biol. Chem. 279(8):6213-6216 (2004); WO2004 / 92219 (Hinton et al.)).

[0181] "Effector function" refers to the biological activity attributable to the Fc region of an antibody, which varies depending on the antibody isotype. Examples of antibody effector functions include Clq binding and complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), down-regulation of cell surface receptors (e.g., B cell receptors), and B cell activation. Such functions can be influenced, for example, by binding of the Fc effector domain to Fc receptors on immune cells with phagocytic or lytic activity, or by binding of the Fc effector domain to components of the complement system. Typically, effects mediated by Fc-binding cells or complement components result in the inhibition and / or depletion of CD33-targeted cells. The Fc region of an antibody can recruit Fc receptor (FcR)-expressing cells and bring them into juxtaposition with antibody-coated target cells. Cells expressing surface FcRs for IgG, including FcγRIII (CD16), FcγRII (CD32), and FcγRIII (CD64), can act as effector cells for the destruction of IgG-coated cells. Such effector cells include monocytes, macrophages, natural killer (NK) cells, neutrophils, and eosinophils. Engagement of FcγRs by IgG activates antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP). ADCC activates CD16 through the secretion of membrane pore-forming proteins and proteases. + Phagocytosis is mediated by effector cells, but not by CD32 + and CD64 + Mediated by effector cells (see, e.g., Fundamental Immunology, 4th ed., Paul, ed., Lippincott-Raven, NY, 1997, Chapters 3, 17, and 30; Uchida et al., 2004, J. Exp. Med. 199:1659-69; Akewanlop et al., 2001, Cancer Res. 61:4061-65; Watanabe et al., 1999, Breast Cancer Res. Treat. 53:199-207).

[0182] "Human effector cells" are leukocytes that express one or more FcRs and perform effector function. In certain embodiments, the cells express at least FcγRIII and perform ADCC effector function. Examples of human leukocytes that mediate ADCC include peripheral blood mononuclear cells (PBMCs), natural killer (NK) cells, monocytes, cytotoxic T cells, and neutrophils. Effector cells can be isolated from a native source, for example, from blood.

[0183] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a cytotoxic mechanism in which the Fc region of an antibody bound to an antigen on the cell surface of a target cell interacts with Fc receptors (FcRs) present on certain cytotoxic effector cells (e.g., NK cells, neutrophils, and macrophages). This interaction enables these cytotoxic effector cells to subsequently kill the target cell with cytotoxins. NK cells, the primary cells for mediating ADCC, express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess the ADCC activity of a molecule of interest, an in vitro ADCC assay can be performed, such as those described in U.S. Patent Nos. 5,500,362 or 5,821,337, or U.S. Patent No. 6,737,056 (Presta). Useful effector cells for such assays include PBMCs and NK cells. The ADCC activity of a molecule of interest can also be assessed in vivo, for example, in an animal model, such as that disclosed in Clynes et al., Proc. Natl. Acad. Sci. (USA) 95:652-656 (1998). Additional polypeptide variants with altered Fc region amino acid sequences (polypeptides with variant Fc regions) and increased or decreased ADCC activity are described, for example, in U.S. Patent Nos. 7,923,538 and 7,994,290.

[0184] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to the Fc region (of the appropriate subclass) of an antibody, which binds to its cognate antigen on the target cell. This binding activates a series of enzymatic reactions that culminate in the formation of pores in the target cell membrane and subsequent cell death. Complement activation can also result in the deposition of complement components on the target cell surface, which promote ADCC by binding to complement receptors (e.g., CR3) on leukocytes. To assess complement activation, a CDC assay can be performed, for example, as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996). Polypeptide variants having altered Fc region amino acid sequences (polypeptides, e.g., antibodies having variant Fc regions) and having increased or decreased C1q binding ability are described, for example, in U.S. Patent No. 6,194,551 B1, U.S. Patent No. 7,923,538, U.S. Patent No. 7,994,290, and WO 1999 / 51642. See also, for example, Idusogie et al., J. Immunol. 164:4178-4184 (2000).

[0185] The term "antibody-dependent cellular phagocytosis," or simply "ADCP," refers to the process by which antibody-coated cells are internalized, either in whole or in part, by phagocytic immune cells (e.g., macrophages, neutrophils, and dendritic cells) that bind the Fc region of Ig.

[0186] A polypeptide variant (e.g., an antibody) with "altered" FcR binding affinity or ADCC activity is one that has enhanced or decreased FcR binding activity and / or ADCC activity compared to a parent polypeptide or a polypeptide comprising a native-sequence Fc region. A polypeptide variant that "exhibits increased binding" to an FcR binds to at least one FcR with better affinity than the parent polypeptide. A polypeptide variant that "exhibits reduced binding" to an FcR binds to at least one FcR with lower affinity than the parent polypeptide. In some embodiments, such variants that exhibit reduced binding to an FcR may have little or no appreciable binding to an FcR, e.g., 0-20% binding to an FcR, compared to a native-sequence IgG Fc region.

[0187] The terms "substantially similar" or "substantially the same," as used herein, refer to a substantially high degree of similarity between two or more numerical values, such that one of skill in the art would consider the difference between the two or more values to have little or no biological and / or statistical significance within the context of the biological characteristic measured by the values. In some embodiments, two or more substantially similar values differ by no more than about any one of 5%, 10%, 15%, 20%, 25%, or 50%.

[0188] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K d Affinity can be measured by methods commonly known in the art, including those described herein.

[0189] "Autoimmune disease," as used herein, refers to a disease or disorder arising from and directed against an individual's own tissues or proteins.

[0190] "Patient" as used herein refers to a subject to be administered the ligand-drug conjugate compound of the present invention.Patients include, but are not limited to, humans, rats, mice, guinea pigs, non-human primates, pigs, goats, horses, cows, dogs, cats, birds, and poultry.Typically, patients are rats, mice, dogs, humans, or non-human primates, more typically humans.

[0191] The term "treat" or "treatment," unless otherwise indicated by context, refers to therapeutic and prophylactic treatments in which the objective is to inhibit or slow (reduce) the development or spread of an undesired physiological change or disorder, such as cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, reduction in the extent of disease, stabilized (i.e., not worsening) disease, delay or slowing of disease progression, improvement or alleviation of disease state, and remission (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder.

[0192] In the context of cancer, the term "treating" includes any or all of killing tumor cells, inhibiting the growth of tumor cells, cancer cells, or tumors, inhibiting tumor or cancer cell replication, reducing overall tumor burden or the number of cancerous cells, and ameliorating one or more symptoms associated with the disease.

[0193] In the context of autoimmune disease, the term "treating" includes any or all of inhibiting the replication of cells associated with the autoimmune disease state, including, but not limited to, cells that produce autoimmune antibodies, reducing the amount of autoimmune antibodies, and ameliorating one or more symptoms of the autoimmune disease.

[0194] "Compound," as used herein, refers to and includes the chemical compound itself, named or represented by its structure and its salt forms, whether explicitly stated or not, unless the context explicitly states that such salt forms are to be excluded. The term "compound" also encompasses solvated forms of the compound, where the solvent is non-covalently associated with the compound or reversibly covalently associated with the compound, such as when a carbonyl group of the compound is hydrated to form a gem-diol. Solvated forms include the compound itself and its salt forms, and refer to hemisolvates, monosolvates, and disolvates, including hydrates, where the compound is associated with two or more solvent molecules, and where the two or more solvent molecules are the same or different.

[0195] In some instances, the compounds of the invention include an explicit reference to one or more of the above forms, e.g., salts and solvates; this does not mean any solid-state form of the compound; however, this reference is for emphasis only and should not be construed as excluding any other form identified above. Furthermore, if an explicit reference to salts and / or solvates of a compound or ligand drug conjugate composition is not made, the omission should not be construed as excluding salts and / or solvates of the compound or conjugate, unless the context makes clear that such salts and / or solvates are excluded.

[0196] The phrase "salt thereof," as used herein, refers to a salt form of a compound (e.g., a drug, a drug-linker compound, or a ligand-drug conjugate compound). The salt form of a compound may be one or more internal salt forms and / or may include the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. The counterion in the salt form of a compound is typically an organic or inorganic moiety that stabilizes the charge of the parent compound. The salt form of a compound has one or more charged atoms in its structure. In instances where multiple charged atoms are part of the salt form, multiple counterions and / or multiple charged counterions exist. Thus, the salt form of a compound typically has one or more charged atoms and one or more counterions corresponding to those of the non-salt form of the compound. In some embodiments, the non-salt form of a compound contains at least one amino group or other basic moiety, and therefore, in the presence of an acid, an acid addition salt with the basic moiety is obtained. In other embodiments, the non-salt form of the compound contains at least one carboxylic acid group or other acidic moiety, and therefore, in the presence of a base, a carboxylate or other anionic moiety is obtained. Exemplary salts include, but are not limited to, sulfate, trifluoroacetate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, perphosphate, isonicotinate, lactate, salicylate, percitrate, tartrate, oleate, tannate, pantothenate, acid tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)).

[0197] Pharmaceutically acceptable salts are salt forms of the compounds described herein that are suitable for administration to a subject, and in some embodiments, contain a countercation or counteranion as described in P.H. Stahl and C.G. Wermuth (eds.), Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002.

[0198] A "Linker unit," as used herein, is a bifunctional moiety that connects or can connect a Drug unit to a Ligand unit in a Ligand-Drug conjugate compound. The Linker unit of the present invention, in some embodiments, comprises two or more components selected from the group consisting of a Stretcher unit having a basic unit, a Connector unit, a Parallel Connector unit, a Releasable Linker, and a Spacer unit.

[0199] "PEG," "PEG unit," or "polyethylene glycol," as used herein, refers to an organic moiety containing repeating ethylene-oxy subunits, and may be polydisperse, monodisperse, or discrete (i.e., having a discrete number of ethylene-oxy subunits). Polydisperse PEGs are heterogeneous mixtures of sizes and molecular weights, while monodisperse PEGs are typically purified from heterogeneous mixtures and thus provide a single chain length and molecular weight. Preferred PEG units are discrete PEGs, which are compounds synthesized in a sequential manner and not via a polymerization process. Discrete PEGs provide single molecules with defined and prescribed chain lengths.

[0200] The PEG units provided herein comprise one or more polyethylene glycol chains, each containing one or more ethyleneoxy subunits covalently attached to one another. The polyethylene glycol chains may be linked to one another in any pattern (e.g., linear, branched, or star-shaped configurations). Typically, at least one of the polyethylene glycol chains, prior to incorporation into the ligand-drug conjugate compound, is derivatized at one end with an alkyl moiety substituted with an electrophilic group for covalent attachment to the carbamate nitrogen of the methylene carbamate unit (i.e., representing an instance of R). Typically, the terminal ethyleneoxy subunit in each polyethylene glycol chain that is not involved in covalent attachment to the remainder of the linker unit is modified with a PEG capping unit, typically H, or an optionally substituted alkyl, such as -CH3, -CH2CH3, or -CH2CH2CO2H. Preferred PEG units have a single polyethylene glycol chain having 4 to 24 -CH2CHO- subunits covalently attached in sequence, terminated at one end with a PEG capping unit.

[0201] "Halogen," as used herein by itself or in combination with another term, refers to fluorine, chlorine, bromine, or iodine, unless otherwise stated or implied by context, and is typically -F or -Cl.

[0202] Unless otherwise indicated, the term "alkyl," alone or as part of another term, refers to a straight-chain or branched saturated hydrocarbon having the indicated number of carbon atoms (e.g., "-C1-C4 alkyl," "-C1-C8 alkyl," or "-C1-C 10("Alkyl" refers to alkyl groups having 1 to 4, 1 to 8, or 1 to 10 carbon atoms, respectively. If the number of carbon atoms is not specified, the alkyl group has 1 to 8 carbon atoms. Representative straight-chain "-C1-C8 alkyl" groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, and -n-octyl, while branched -C3-C8 alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and -2-methylbutyl.

[0203] Unless otherwise indicated, "alkylene," alone or as part of another term, refers to a saturated, branched, straight-chain, or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane, of the stated number of carbon atoms, typically 1 to 4, 1 to 8, or 1 to 10 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH-), 1,2-ethylene (-CHCH-), 1,3-propylene (-CHCHCH-), 1,4-butylene (-CHCHCHCH-), and the like. In preferred embodiments, the alkylene is a branched or straight-chain hydrocarbon (i.e., it is not a cyclic hydrocarbon).

[0204] "Alkenyl," as used herein alone or as part of another term, unless otherwise stated or implied by context, refers to an organic moiety, substituent, or group containing one or more double-bond functional groups (e.g., —CH═CH— moieties), or 1, 2, 3, 4, 5, or 6 or more, typically 1, 2, or 3, such functional groups, more typically 1 such functional group; in some embodiments, an alkenyl substituent, moiety, or group may contain non-aromatically linked, usually secondary, tertiary, or cyclic carbon atoms, i.e., linear, branched, cyclic, or any combination thereof, as part of the base moiety, so long as it is a vinyl moiety (e.g., —CH═CH moiety). Alkenyl moieties, groups, or substituents having multiple double bonds may have the double bonds positioned vicinal (e.g., 1,3-butadienyl moiety) or nonvicinal to one or more intervening saturated carbon atoms, or combinations thereof, provided that the cyclic vicinal arrangement of the double bonds does not form a 4n+2 electron cyclic vicinal system (i.e., not aromatic).

[0205] An alkenyl moiety, group, or substituent has at least one sp 1 carbon atom that is divalent and double-bonded to another organic moiety or Markush structure to which it is associated. 2 Contains carbon atoms or sp 2 At least two adjacent sp atoms in which one of the carbon atoms is monovalent and is single-bonded to another related organic moiety or Markush structure 2 Typically, when alkenyl is used as a Markush group (i.e., is a substituent), it refers to the sp of the alkene functional group of the alkenyl moiety. 2 The carbon atom is a single bond to the Markush or another organic moiety associated therewith. In some embodiments, when an alkenyl moiety is defined, the species is preferably a substituted or unsubstituted alkenyl group. 2 The carbon atom is monovalent and the monovalent portion is the sp 2The term "alkenyl" refers to a group having one or more endocyclic double bonds derived from the removal of a hydrogen atom from a carbon atom, and corresponding to any of the optionally substituted alkyl or carbocyclyl group moieties or substituents described herein. Such monovalent moieties are exemplified by, but not limited to, vinyl (-CH=CH), allyl, 1-methylvinyl, butenyl, isobutenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, and cyclohexenyl. In some embodiments, the term "alkenyl" refers to a group having all carbon-containing moieties that are not sp 2 These include those containing at least one double bond functionality in which one of the carbon atoms is monovalent, and / or other linear, cyclic and branched chains.

[0206] The number of carbon atoms in the alkenyl moiety is determined by the sp of the alkene functional group that defines it as an alkenyl substituent. 2 The number of carbon atoms, and the carbon atoms of the alkenyl moiety are those from the variable groups and optional substituents on the alkenyl moiety, not including any carbon atoms of other moieties or Markush structures. 2 It is defined by the total number of adjacent non-aromatic carbon atoms attached to each carbon. This number ranges from 1 to 50 or 1 to 30, typically 1 to 20 or 1 to 12, more typically 1 to 8, 1 to 6, or 1 to 4 carbon atoms when the double-bonded functional group is double-bonded to a Markush structure (e.g., =CH2), or from 2 to 50, typically 2 to 30, 2 to 20, or 2 to 12, more typically 2 to 8, 2 to 6, or 2 to 4 carbon atoms when the double-bonded functional group is single-bonded to a Markush structure (e.g., -CH=CH2). For example, C2-C8 alkenyl or C2-C8 alkenyl is an alkyl group having at least two adjacent sp carbon atoms, one of which is monovalent and adjacent to each other. 2 C2-C6 alkenyl or C2-C6 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, where at least two of these carbon atoms are monovalent and adjacent to each other are sp2 In some embodiments, the alkenyl moiety contains 2, 3, 4, 5, or 6 carbon atoms, where one of the carbon atoms is monovalent and two adjacent sp 2 The alkenyl moiety is a C2-C6 or C2-C4 alkenyl moiety containing only carbon atoms. Typically, the alkenyl substituents are two sp 2 It is a C2-C6 or C2-C4 alkenyl moiety containing only carbon. If the number of carbon atoms is not specified, the alkenyl moiety contains 2 to 8 carbon atoms.

[0207] "Alkenylene," as used herein by itself or as part of another term, unless otherwise stated or implied by context, refers to a group of alkene functional groups in a parent alkene having the stated number of carbon atoms, with the same or two different sp 2 It refers to an organic moiety, substituent, or group containing one or more double bond moieties, as previously described for alkenyl, with two radical centers derived by the removal of two hydrogen atoms from a carbon atom or two hydrogen atoms from two separate alkene functional groups. In some embodiments, the alkenylene moiety refers to an organic moiety, substituent, or group containing one or more double bond moieties, as previously described for alkenyl, with two radical centers derived by the removal of two hydrogen atoms from a carbon atom or two separate alkene functional groups. In some embodiments, the alkenylene moiety refers to an organic moiety, substituent, or group containing one or more double bond moieties, as previously described for alkenyl, where the hydrogen atoms are the same or different sp of the double bond functional groups of the alkenyl radical. 2 sp from a carbon atom or from different double-bonded moieties to provide a diradical 2 The alkenylene moiety is an alkenyl radical as described herein, removed from a carbon atom. Typically, the alkenylene moiety is -C=C- or -C=CX 1 -C=C- structure (wherein X 1 is absent or is alkylene as defined herein, typically C1-C6 alkylene). The number of carbon atoms in the alkenylene moiety is determined by the sp of the alkene functional group that defines it as an alkenylene moiety. 2 The number of carbon atoms and its sp in which the alkenyl moiety occurs as a variable, not including any carbon atoms of other moieties or Markush structures. 2It is defined by the total number of adjacent non-aromatic carbon atoms attached to each carbon. This number ranges from 2 to 50 or 2 to 30, typically 2 to 20 or 2 to 12, more typically 2 to 8, 2 to 6, or 2 to 4 carbon atoms, unless otherwise specified. For example, C2-C8 alkenylene or C2-C8 alkenylene is an alkylene group having at least two adjacent non-aromatic carbon atoms, one of which is divalent or both of which are monovalent, sp 2 C2-C6 alkenylene or C2-C6 alkenylene means an alkenylene moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, where C2-C6 alkenylene or C2-C6 alkenylene means at least two adjacent sp 2 In some embodiments, the alkenylene moiety is an alkenyl moiety containing 2, 3, 4, 5, or 6 carbon atoms, where the alkenylene moiety is an alkyl group. 2 Two sp atoms adjacent to each other, where the carbon atoms are monovalent 2 It is a C2-C6 or C2-C4 alkenylene having carbon atoms. If the number of carbon atoms is not specified, the alkenylene moiety has 2 to 8 carbon atoms.

[0208] "Alkynyl," as the term is used herein alone or as part of another term, unless otherwise stated or implied by context, refers to an organic moiety, substituent, or group that contains one or more triple bond functional groups (e.g., -C≡C- moieties), or 1, 2, 3, 4, 5, or 6 or more, typically 1, 2, or 3 or more such functional groups, more typically 1 such functional group. Alkynyl moieties, groups, or substituents having multiple triple bonds may have the triple bonds positioned vicinal or non-vicinity with one or more intervening saturated or unsaturated carbon atoms, or combinations thereof, provided that the cyclic vicinal arrangement of the triple bonds does not form a cyclic vicinal system of 4n+2 electrons (i.e., not aromatic).

[0209] An alkynyl moiety, group, or substituent contains at least two sp carbon atoms, the carbon atoms being adjacent to one another and one of the sp carbon atoms being single-bonded to another organic moiety or Markush structure with which it is associated. When alkynyl is used as a Markush group (i.e., a substituent), the alkynyl is single-bonded to the Markush formula or another organic moiety with which it is associated through the triple-bonded carbon (i.e., sp carbon) of the terminal alkyne functional group. In some embodiments, when an alkynyl moiety, group, or substituent is defined, the species includes any of the alkyl or carbocyclyl group moieties or substituents described herein that have one or more endo triple bonds and in which the monovalent moiety is derived from the removal of a hydrogen atom from an sp carbon of the parent alkyne compound. Such monovalent moieties are exemplified by, but not limited to, -C≡CH, -C≡C-CH3, and -C≡C-Ph.

[0210] The number of carbon atoms in an alkynyl substituent is defined by the number of sp carbon atoms of the alkene functional group that defines it as an alkynyl substituent and the total number of adjacent non-aromatic carbon atoms attached to each of these sp carbons, not including any carbon atoms of other moieties or Markush structures in which the alkenyl moiety is a variable. That number can vary from 2 to 50, typically 2 to 30, 2 to 20, or 2 to 12, more typically 2 to 8, 2 to 6, or 2 to 4 carbon atoms when triple bond functionality is single-bonded to a Markush structure (e.g., -CH≡CH). For example, C2-C8 alkynyl or C2-C8 alkynyl refers to an alkynyl moiety containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms, at least two of which are sp carbon atoms, one of which is monovalent and adjacent to each other; C2-C6 alkynyl or C2-C6 alkynyl refers to an alkynyl moiety containing 2, 3, 4, 5, or 6 carbon atoms, at least two of which are sp carbon atoms, one of which is monovalent and adjacent to each other. In some embodiments, an alkynyl substituent or group is a C2-C6 or C2-C4 alkynyl moiety having two sp carbon atoms, one of which is monovalent and adjacent to each other. If the number of carbon atoms is not specified, the alkynyl moiety, group, or substituent has from 2 to 8 carbon atoms.

[0211] The term "prodrug," as used herein, refers to a less biologically active or inactive compound that is converted into a more biologically active compound in the body through a chemical or biological process (i.e., chemical reaction or enzymatic biotransformation). Typically, a biologically active compound is rendered less biologically active (i.e., converted into a prodrug) by chemically modifying the compound with a prodrug moiety. In some embodiments, the prodrug is a type II prodrug, which is bioactivated extracellularly, for example, in digestive fluids, or in the body's circulatory system, for example, in blood. Exemplary prodrugs are esters and β-D-glucopyranosides.

[0212] Unless otherwise indicated, "aryl," alone or as part of another term, means a monovalent carbocyclic aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system of the stated number of carbon atoms, typically 6 to 20 carbon atoms. Some aryl groups are represented in the exemplary structures as "Ar." Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. An exemplary aryl group is the phenyl group.

[0213] Unless otherwise indicated, "arylene" alone or as part of another term is an aryl group, as defined above, having two covalent bonds (i.e., is divalent), and may be ortho, meta, or para oriented, as shown in the following structure with phenyl as an exemplary group:

[0214] [ka]

[0215] Unless otherwise indicated, "C3-C8 heterocycle," alone or as part of another term, refers to a monovalent aromatic or non-aromatic monocyclic or bicyclic ring system having 3 to 8 carbon atoms (also referred to as ring members) and 1 to 4 heteroatom ring members independently selected from N, O, P, or S, derived by the removal of one hydrogen atom from a ring atom of the parent ring system. In some embodiments, one or more N, C, or S atoms in the heterocycle are oxidized. In some embodiments, the ring containing the heteroatom is aromatic or non-aromatic. A heterocycle in which all ring atoms participate in aromaticity is referred to as heteroaryl; otherwise, it is referred to as heterocarbocycle.

[0216] Unless otherwise stated, a heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. In some embodiments, heteroaryl is bonded through an aromatic carbon in its aromatic ring system and is referred to as a C-linked heteroaryl. In other embodiments, heteroaryl is bonded through a non-double-bonded N atom in its aromatic ring system (i.e., not =N-) and is referred to as an N-linked heteroaryl. Thus, nitrogen-containing heterocycles are C-linked or N-linked, and include pyrrole moieties, such as pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked), and imidazole moieties, such as imidazol-1-yl and imidazol-3-yl (both N-linked), and imidazol-2-yl, imidazol-4-yl, and imidazol-5-yl moieties (all of which are C-linked).

[0217] Unless otherwise indicated, a "C3-C8 heteroaryl" is an aromatic C3-C8 heterocycle, where the subscript represents the total number of carbons in the cyclic ring system of the heterocycle or the total number of aromatic carbons in the aromatic ring system of the heteroaryl, and does not denote the size of the ring system or the presence or absence of ring fusion. Representative examples of C3-C8 heterocycles include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, pyrrolyl, thiophenyl (thiophene), furanyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, isothiazolyl, and isoxazolyl.

[0218] When explicitly stated, the size of a heterocyclic or heteroaryl ring system is indicated by the total number of atoms in the ring. For example, a designation of a 5- or 6-membered heteroaryl indicates the total number of aromatic atoms (i.e., 5 or 6) in the heteroaromatic ring system of the heteroaryl, but does not refer to the number of aromatic heteroatoms or aromatic carbon atoms in the ring system. Fused heteroaryls are either explicitly stated as such or implied by context and are typically indicated by the number of aromatic atoms in each aromatic ring fused to each other to form the fused heteroaromatic ring system. For example, a 5,6-membered heteroaryl is an aromatic 5-membered ring fused to an aromatic 6-membered ring, where one or both rings have an aromatic heteroatom or the heteroatom is shared between the two rings.

[0219] A heterocycle fused to an aryl or heteroaryl, where the heterocycle remains non-aromatic and is part of a larger structure through attachment to the non-aromatic portion of the fused ring system, is an example of a heterocycle where the heterocycle is substituted by ring fusion with an aryl or heteroaryl. Similarly, an aryl or heteroaryl fused to a heterocycle or carbocycle, where the heterocycle is part of a larger structure through attachment to the aromatic portion of the fused ring system, is an example of an aryl or heterocycle where the aryl or heterocycle is substituted by ring fusion with a heterocycle or carbocycle.

[0220] Unless otherwise indicated, "C3-C8 heterocyclo," alone or as part of another term, refers to a C3-C8 heterocycle, as defined above, where one of the heterocycle's hydrogen atoms is replaced with a bond (i.e., it is divalent). Unless otherwise indicated, "C3-C8 heteroarylene," alone or as part of another term, refers to a C3-C8 heteroaryl group, as defined above, where one of the heteroaryl group's hydrogen atoms is replaced with a bond (i.e., it is divalent). When explicitly given, the size of a heteroarylene ring system is indicated by the total number of atoms in the ring. For example, a designation of a 5- or 6-membered heteroarylene indicates the total number of atoms in the heterocyclic ring system of the heterocycle (i.e., 5 or 6), but does not refer to the number of heteroatoms or carbon atoms in the ring system.

[0221] Unless otherwise indicated, a "C3-C8 carbocycle," alone or as part of another term, is a 3-, 4-, 5-, 6-, 7-, or 8-membered monovalent saturated or unsaturated non-aromatic monocyclic or bicyclic carbocycle derived by the removal of one hydrogen atom from a ring atom of a parent ring system. Representative -C3-C8 carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctyl, and cyclooctadienyl.

[0222] Unless otherwise indicated, "C3-C8 carbocyclo" alone or as part of another term refers to a C3-C8 carbocyclic group, as defined above, in which another one of the carbocyclic group's hydrogen atoms is replaced with a bond (i.e., is divalent).

[0223] Unless otherwise indicated, the term "heteroalkyl," alone or in combination with another term, means, unless otherwise stated, a stable linear or branched hydrocarbon, or combination thereof, fully saturated or containing 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and 1 to 10, preferably 1 to 3, heteroatoms selected from the group consisting of O, N, Si, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatoms O, N, and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. When explicitly given, the number of atoms in a heteroalkyl or heteroarylene group is indicated by the total number of atoms in the group. For example, a designation of C1-C2 heteroalkyl refers to the total number of atoms in the heteroalkyl group (i.e., 1 or 2), but does not refer to the number of heteroatoms or carbon atoms in the group.

[0224] Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -NH-CH2-CH2-NH-C(O)-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=NO-CH3, and -CH=CH-N(CH3)-CH3. In some embodiments, two heteroatoms are consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Typically, a C1-C4 heteroalkyl or heteroalkylene has 1 to 4 carbon atoms and 1 or 2 heteroatoms, with C 1~ A C3 heteroalkyl or heteroalkylene has 1 to 3 carbon atoms and 1 or 2 heteroatoms. In some embodiments, the heteroalkyl or heteroalkylene is saturated.

[0225] Unless otherwise indicated, the term "heteroalkylene," alone or in combination with another term, refers to a divalent group derived from a heteroalkyl (as discussed above), as exemplified by -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini. Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.

[0226] Unless otherwise indicated, "aminoalkyl," alone or in combination with another term, refers to a heteroalkyl in which the alkyl portion is substituted with an amino, alkylamino, dialkylamino, or cycloalkylamino group, as defined herein. Exemplary non-limiting aminoalkyls are -CHNH, -CHCHNH, -CHCHNHCH, and -CHCHN(CH), further including branched species such as -CH(CH)NH and -C(CH)CHNH in the (R)- or (S)-configuration. Alternatively, an aminoalkyl may be a heteroalkyl in which no sp carbon atom other than the radical carbon atom of the alkyl portion is present. 3 The carbon is replaced with an amino or alkylamino moiety, and the sp 3 The nitrogen atom must be at least one sp 3 sp in the alkyl moiety, provided that the carbon atom remains the same 3 is an alkyl moiety, group, or substituent, as defined herein, replacing a carbon. When referring to an aminoalkyl moiety as a substituent on a larger structure or another moiety, the aminoalkyl is covalently attached to the structure or moiety through a carbon radical of the alkyl portion of the aminoalkyl.

[0227] "Hydroxyalkyl," as used herein alone or in combination with another term, refers to an alkyl moiety, group, or substituent having a hydroxyl radical in place of one or more hydrogen atoms of the alkyl moiety, group, or substituent, unless otherwise stated or implied by context. In some embodiments, one or two hydrogen atoms are replaced with hydroxyl substituents, respectively, in a hydroxyalkyl group. Hydroxyalkyl is typically represented by the number of adjacent carbon atoms in its alkyl or alkylene portion. Thus, a C hydroxyalkyl is exemplified by, but not limited to, -CH OH, and a C hydroxyalkyl is exemplified by, but not limited to, -CH CH OH or -CH (OH) CH .

[0228] "Haloalkyl," as the term is used herein alone or in combination with another term, refers to an alkyl moiety, group, or substituent having a halogen atom in place of one or more hydrogen atoms of the alkyl moiety, group, or substituent, unless otherwise stated or implied by context. In some embodiments, one or two hydrogen atoms are each replaced with a halogen atom in a haloalkyl group. Haloalkyls are typically represented by the number of adjacent carbon atoms in the alkyl or alkylene portion. Thus, C haloalkyls are exemplified by, but not limited to, -CHF, -CHCl, -CHBr, or -CHI, and C haloalkyls are exemplified by, but not limited to, -CHCHF, -CHCHCl, -CHCHBr, -CHCHI, -CH(F)CH, -CH(Cl)CH, -CH(Br)CH, or -CH(I)CH. In some embodiments, the term "haloalkyl" refers to an alkyl moiety, group, or substituent having halogens in place of two or more hydrogen atoms. For example, a C haloalkyl is also exemplified by, but not limited to, -CHF, -CHCl, -CHBr, or -CHI, and a C haloalkyl is exemplified by, but not limited to, -CHCHF, -CHCHCl, -CHCHBr, -CHCHI, -CH(F)CH, -CH(Cl)CH, -CH(Br)CH, or -CH(I)CH. In some embodiments, the term "haloalkyl" refers to an alkyl moiety, group, or substituent having halogens in place of all hydrogen atoms. Thus, in some embodiments, the term "haloalkyl" encompasses fully halogenated alkyl moieties, groups, or substituents. For example, a C haloalkyl is also exemplified by, but not limited to, -CF, -CCl, -CBr, or -CI.

[0229] Unless otherwise indicated, "alkylamino" and "cycloalkylamino", alone or in combination with other terms, refer to at least one sp of an alkyl or cycloalkyl radical. 3"means an alkyl or cycloalkyl radical as described herein in which a radical carbon atom of the alkyl or cycloalkyl radical is replaced with a nitrogen radical, provided that the carbon atom remains intact. In those instances in which an alkylamino is substituted at the nitrogen with another alkyl moiety, the resulting substituted radical may be referred to as a dialkylamino moiety, group, or substituent, in which the alkyl moieties substituting the nitrogen are independently selected.

[0230] Exemplary and non-limiting amino, alkylamino, and dialkylamino substituents include those having the structure -N(R')2, where R' in these examples is independently hydrogen or C 1~6 While alkyl is typically hydrogen or methyl, cycloalkylamines include those with heterocycloalkyl, where both R', together with the nitrogen to which they are attached, define a heterocyclic ring. When both R' are hydrogen or alkyl, the moiety may be described as a primary amino group and a tertiary amine group, respectively. When one R' is hydrogen and the other is alkyl, the moiety may be described as a secondary amino group. Primary and secondary alkylamino moieties are typically more reactive as nucleophiles toward carbonyl-containing electrophilic centers, while tertiary amines are typically more basic.

[0231] The term "substituted" means that the specified group or moiety bears one or more substituents. Exemplary substituents include, but are not limited to, -X, -R", -OH, -OR", -SR", -N(R"), -N(R"), =NR", -CX, -CN, -NO, -NR"C(=O)R", -C(=O)R", -C(=O)N(R"), -S(=O)R", -S(=O)NR", -S(=O)R", -OP(=O)(OR"), -P(=O)(OR"), -PO = , PO3H2, -C(=O)R'', -C(=S)R'', -CO2R'', -CO2 -, -C(=S)OR'', -C(=O)SR'', -C(=S)SR'', -C(=O)N(R'')2, -C(=S)N(R'')2, and -C(=NR)N(R'')2, wherein each X is independently selected from the group consisting of halogen: -F, -Cl, -Br, and -I; and each R'' is independently selected from the group consisting of -H, -C1 to -C 20 Alkyl, -C6~C 20 Aryl, -C3~C 14 It is selected from the group consisting of a heterocycle, a protecting group, and a prodrug moiety.

[0232] More typically, the substituents are selected from the group consisting of -X, -R", -OH, -OR", -SR", -N(R")2, -N(R")3, =NR", -NR"C(=O)R", -C(=O)R", -C(=O)N(R")2, -S(=O)2R", -S(=O)2NR", -S(=O)R", -C(=O)R", -C(=S)R", -C(=O)N(R")2, -C(=S)N(R")2, and -C(=NR)N(R")2, wherein each X is independently , -F and -Cl, or selected from the group consisting of -X, -R", -OH, -OR", -N(R")2, -N(R")3, -NR"C(=O)R", -C(=O)N(R")2, -S(=O)2R", -S(=O)2NR", -S(=O)R", -C(=O)R", -C(=O)N(R")2, -C(=NR)N(R")2, protecting groups, and prodrug moieties; 20 Alkyl, -C6~C 20 Aryl, -C3~C 14 It is selected from the group consisting of a heterocycle, a protecting group, and a prodrug moiety.

[0233] In some embodiments, substituents on the alkyl, alkenyl, or alkynyl are selected from the group consisting of -N(R'')2, -N(R'')3, and -C(=NR)N(R'')2, where R'' is hydrogen and -C1-C 20In some embodiments, the alkyl, alkenyl, or alkynyl groups are substituted with a series of ethyleneoxy moieties to define the PEG units described herein. In some embodiments, the alkylene, carbocycle, carbocyclo, arylene, heteroalkyl, heteroalkylene, heterocycle, heterocyclo, heteroaryl, and heteroarylene groups described above are similarly substituted.

[0234] The term "unsubstituted" means that a specified group has no substituents. When the term "substituted" is used to describe a structural system, substitution occurs at any valency-allowed position in the system. When a group or moiety has more than one substituent, it is understood that the substituents can be the same or different from one another. In some embodiments, a substituted group or moiety has 1 to 5 substituents. In some embodiments, a substituted group or moiety has 1 substituent. In some embodiments, a substituted group or moiety has 2 substituents. In some embodiments, a substituted group or moiety has 3 substituents. In some embodiments, a substituted group or moiety has 4 substituents. In some embodiments, a substituted group or moiety has 5 substituents.

[0235] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples in which the event or circumstance occurs and examples in which it does not occur. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. With respect to any group containing one or more substituents, it will be understood by those skilled in the art that it is not intended to introduce any substitution or substitution pattern in which such group is sterically infeasible, synthetically impractical, and / or inherently unstable. When a group or moiety is optionally substituted, it will also be understood that the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0236] "Protecting group," as used herein, means a moiety that prevents or reduces the ability of the atom or functional group with which it is associated to participate in undesired reactions. Typical protecting groups for atoms or functional groups are given in Greene (1999), "Protective Groups In Organic Synthesis, 3rd Edition," Wiley Interscience, which is incorporated herein by reference. Protecting groups for heteroatoms such as oxygen, sulfur, and nitrogen are used in some instances to minimize or prevent their undesired reactions with electrophilic compounds. In other instances, protecting groups are used to reduce or eliminate the nucleophilicity and / or basicity of the unprotected heteroatom. A non-limiting example of a protected oxygen is -OR. PR (In the formula, R PRis a protecting group for hydroxyl), where hydroxyl is typically protected as an ester (e.g., acetate, propionate, or benzoate). Other protecting groups for hydroxyl avoid nucleophilic interference with organometallic or other highly basic reagents, where hydroxyl is typically protected as an ether, including alkyl or heterocycloalkyl ethers (e.g., methyl or tetrahydropyranyl ethers), alkoxymethyl ethers (e.g., methoxymethyl or ethoxymethyl ethers), optionally substituted aryl ethers, and silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]-methylsilyl (SEM)). Nitrogen protecting groups include -NHR PR or -N(R PR )2-(wherein, R PR at least one of R is a nitrogen atom protecting group, or both R PR (which together constitute a protecting group) for primary or secondary amines.

[0237] A protecting group is suitable if it can prevent or avoid undesired side reactions or premature loss of the protecting group under the reaction conditions required to effect the desired chemical transformation elsewhere in the molecule, or during purification of the newly formed molecule if desired, and is removable under conditions that do not adversely affect the structure or stereochemical integrity of the newly formed molecule. By way of example and not limitation, suitable protecting groups include those previously described for protecting otherwise reactive functional groups. Suitable protecting groups are sometimes those used in peptide coupling reactions.

[0238] "Electron-withdrawing group," as used herein, means a functional group or electronegative atom that attracts electron density away from the atom to which it is bonded, either inductively and / or through resonance, whichever is more dominant (i.e., in some embodiments, the functional group or atom is inductively electron-withdrawing but overall electron-donating through resonance), tending to stabilize the anion or electron-rich moiety. The electron-withdrawing effect is typically transferred inductively, albeit in a weakened form, to other atoms attached to the bonded atom made electron-deficient by the electron-withdrawing group (EWG), thus affecting the electrophilicity of the more distant reactive center. Exemplary electron-withdrawing groups include, but are not limited to, -C(=O), -CN, -NO, -CX, -X, -C(=O)OR', -C(=O)N(R'), -C(=O)R', -C(=O)X, -S(=O)R', -S(=O)OR', -S(=O)NHR', -S(=O)N(R'), -P(=O)(OR'), -P(=O)(CH)NHR', -NO, -N(R') + wherein X is —F, —Br, —Cl, or —I, and R′, in some embodiments, at each occurrence, is independently selected from hydrogen and C 1~6 alkyl, as well as certain O-linked moieties described herein, such as acyloxy.

[0239] Exemplary EWGs may also include aryl groups (e.g., phenyl) and certain heteroaryl groups (e.g., pyridine), depending on the substituents on the aromatic ring. Thus, the term "electron-withdrawing group" also includes aryls or heteroaryls that are further substituted with electron-withdrawing groups. Typically, electron-withdrawing groups on aryls or heteroaryls are -C(=O), -CN, -NO2, -CX3, and -X (wherein X is independently selected from halogens, typically -F or -Cl). Depending on their substituents, alkyl moieties may also be electron-withdrawing groups.

[0240] As used herein, a "succinimide moiety" refers to an organic moiety containing a succinimide ring system, typically present in one type of Stretcher unit (Z), which further contains an alkylene-containing moiety attached to the imide nitrogen of that ring system. The succinimide moiety typically results from the Michael addition of a sulfhydryl group of a Ligand unit to the maleimide ring system of a Stretcher unit precursor (Z') in a Drug Linker Compound or its maleimide-containing intermediate. The succinimide moiety thus contains a thio-substituted succinimide ring system, and when present in a Ligand-Drug Conjugate Compound, has its imide nitrogen substituted with the remainder of the Linker unit of the Ligand-Drug Conjugate Compound, optionally substituted with a substituent that was present on the maleimide ring system of Z'.

[0241] "Succinic acid-amide moiety," as used herein, refers to a succinic acid moiety in which one of the two carboxylic acid groups is replaced with an amide substituent resulting from the thio-substituted succinimide ring system of the succinimide moiety defined herein, which undergoes hydrolysis to break one of its carbonyl-nitrogen bonds. In some embodiments, the succinic acid-amide moiety has the structure:

[0242] [ka] where the left wavy line indicates attachment to a Ligand unit or hydrogen atom, and the right wavy line indicates attachment to the remainder of the Ligand-Drug Conjugate Compound, Drug-Linker Compound, Intermediate, or fragment thereof. Hydrolysis resulting in a succinic acid-amide moiety provides a lower likelihood of the Linker unit undergoing premature loss of the Ligand unit to which it is attached due to elimination of the antibody-thio substituent. Hydrolysis of the succinimide ring system of the thio-substituted succinimide moiety is expected to provide regiochemical isomers of the acid-amide moiety due, at least in part, to the difference in reactivity of the two carbonyl carbons of the succinimide ring system that contribute to any substituents present on the maleimide ring system of the Stretcher unit precursor and the thio substituent introduced by the targeting ligand that is the precursor to the Ligand unit.

[0243] In many instances, the conjugates, linkers, and component assemblies described herein will refer to reactive groups. A "reactive group" or RG is a group containing a reactive site (RS) that can form a bond with either a component of the linker unit Q or the drug unit D. RS is a reactive site within the reactive group (RG). Reactive groups include sulfhydryl groups that form disulfide or thioether bonds, aldehyde, ketone, or hydrazine groups that form hydrazone bonds, carboxylic acids or amino groups that form peptide bonds, carboxylic acids or hydroxy groups that form ester bonds, sulfonic acids that form sulfonamide bonds, alcohols that form carbamate bonds, and amines that form sulfonamide or carbamate bonds.

[0244] The following table describes reactive groups, reactive sites, and exemplary functional groups that can be formed after reaction of the reactive sites. The table is non-limiting. Those skilled in the art will recognize the R * and R ** It will be recognized that the moiety is effectively any organic moiety (e.g., an alkyl group, an aryl group, a heteroaryl group, or a substituted alkyl, aryl, or heteroaryl group) that is compatible with the bond formation provided to convert RG into one of the exemplary functional groups. As applied to the various aspects of the present invention, R * represents one or more components of a self-stabilizing linker, or optionally a secondary linker; R ** It will also be appreciated that represents one or more components of a secondary linker, drug unit, stabilizing unit, or detection unit, depending on the selection.

[0245] [Table 2]

[0246] II. Embodiment A. Auristatin Compounds The present application is based, in part, on the surprising discovery that the properties of auristatin-containing ligand-drug conjugate compounds can be improved by adjusting the hydrophilicity of the auristatin drug with polar moieties, e.g., hydroxyl groups. The hydrophobicity of auristatin drugs is a known obstacle to their implementation in pharmaceuticals containing ligand-drug conjugates due to the potential for high bystander activity and off-target toxicity resulting from rapid clearance of the drug from the subject's body. The compounds of the present application reduce the hydrophobicity of the Drug unit, which in turn reduces the drug's off-target toxicity and rapid clearance. The use of Drug units with polar moieties at certain positions in the auristatin scaffold results in reduced permeability and cellular potency of the free drug, thus reducing off-target effects during treatment without sacrificing the efficacy of the intact ligand-drug conjugate compound incorporating the Drug unit.

[0247] In some embodiments herein, provided are auristatin compounds comprising at least one polar moiety on the auristatin skeleton. In some embodiments, provided are drug-linker compounds comprising an auristatin moiety as described herein. In some embodiments, provided are ligand-drug conjugate compounds comprising an auristatin moiety as described herein. In some embodiments, provided are methods for treating cancer using the ligand-drug conjugate compounds described herein. In some embodiments, provided are auristatin compounds comprising at least one hydrophilic moiety, the drug-linker, and intermediates thereof, as well as methods for making the ligand-drug conjugate compounds. In some embodiments, the polar moiety is a polar moiety other than a carboxylate. In some embodiments, the polar moiety is a hydroxyl group.

[0248] In some embodiments, the compound of formula (I):

[0249] [ka] or a salt thereof (wherein X b is -NR 1 R 2 and X a teeth,

[0250] [ka] or X a and X b together with the carbon atoms to which they are attached,

[0251] [ka] (where the asterisk represents X a and X b represents a carbon atom of formula (I) bearing a group, R 1 , R 2 , R 3 , R 4 , R a , R b , R 5 , and R 10 are each independently H or C1-C4 alkyl, X is H, OH, or -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a and R 6 is a C1-C4 alkyl optionally substituted with OH, R 7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8 , R 9 , and R 11 are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1, When X is H, R 7 , R 8 , R 9 , and R 11 at least two of which contain an OH moiety is provided.

[0252] In some embodiments, the compound of formula (Iz):

[0253] [ka] or a salt thereof (wherein X b is -NR 1 R 2 and X a teeth,

[0254] [ka] or X a and X b together with the carbon atoms to which they are attached,

[0255] [ka] (where the asterisk represents X a and X b represents a carbon atom of formula (I) bearing a group, R 1 , R 2 , R 3 , R 4 , R a , R b , R 5 , and R 10are each independently H or C1-C4 alkyl, X is OH, -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a and R 6 is a C1-C4 alkyl optionally substituted with OH, R 7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1) is provided.

[0256] In some embodiments, the compound of formula (II):

[0257] [ka] or a salt thereof (wherein R 1 , R 3 , and R 4 are independently H or C1-C4 alkyl; R 6 is a C1-C4 alkyl optionally substituted with OH, R 7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH, n is 0, 1, or 2; q is 0 or 1) is provided.

[0258] In some embodiments of Formula (I), q is 0. In some embodiments of Formula (I), q is 1. In some embodiments of Formula (II), q is 0. In some embodiments of Formula (II), q is 1.

[0259] In some embodiments of formula (I) or (Iz), X b is -NR 1 R 2 and X a teeth,

[0260] [ka] In some embodiments, R 1 and R 2 are each independently C1-C4 alkyl. 1 and R 2 and are both H. In some embodiments, R 1 and R 2 are each independently n-propyl, isopropyl, ethyl, or methyl. 1 and R 2 are each independently ethyl or methyl. 1 and R 2 and are both methyl. In some embodiments, R 1 is H and R 2 is C1-C4 alkyl. In some embodiments, R 1 is H and R 2 is n-propyl, isopropyl, ethyl, or methyl.1 is H and R 2 is ethyl or methyl. In some embodiments, R 1 is H and R 2 is methyl. In some embodiments, R 3 and R 4 are each independently C1-C4 alkyl. 3 is H and R 4 is C1-C4 alkyl. In some embodiments, R 3 and R 4 is H. In some embodiments, R 3 is H and R 4 is methyl. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, R 1 is H and R 2 is methyl and R 3 is H and R 4 is H and n is 0. In some embodiments, R 1 is methyl and R 2 is methyl and R 3 is H and R 4 is H and n is 0.

[0261] In some embodiments of formula (I) or (Iz), X a and X b together with the carbon atoms to which they are attached,

[0262] [ka] (where the asterisk represents X a and X b In some embodiments, R represents a carbon atom of formula (I) having a 5is H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 5 is H, ethyl, or methyl. In some embodiments, R 5 is H or methyl. In some embodiments, R 5 is ethyl or methyl. In some embodiments, R 5 is H. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is methyl. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 2. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0 or 1 and m is 0, 1, or 2. In some embodiments, n is 0 and m is 2. In some embodiments, n is 1 and m is 1. In some embodiments, m is 2 and n is 1. In some embodiments, X is H or OH. In some embodiments, X is H. In some embodiments, X is OH.

[0263] In some embodiments of Formula (I), X is H, OH, —C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a In some embodiments, X is OH, —S(O)R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R aIn some embodiments, X is H or OH. In some embodiments, X is OH. In some embodiments, X is OH, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is OH, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is -NHS(O)R a , or -NHC(O)R a In some embodiments, X is -S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, OH, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is H, OH, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is H, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, OH, or —C(O)NR a R b In some embodiments, X is OH or —C(O)NR a R b In some embodiments, X is H or —C(O)NR a R b In some embodiments, R a and R b is independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra and R b is independently H, ethyl, or methyl. In some embodiments, R a and R b is independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. a is H and R b is methyl.

[0264] In some embodiments of Formula (Iz), X is OH, —C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a In some embodiments, X is OH. In some embodiments, X is OH, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is OH, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is -NHS(O)R a , or -NHC(O)R a In some embodiments, X is -S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is OH or —C(O)NR a R b In some embodiments, X is —C(O)NR a R b In some embodiments, R a and R bis independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b is independently H, ethyl, or methyl. In some embodiments, R a and R b is independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. a is H and R b is methyl.

[0265] In some embodiments of formula (I) or (Iz), X b is -NR 1 R 2 and X a teeth,

[0266] [ka] and X is OH and R 1 is H or methyl, and R 2 is methyl and R 3 is H and R 4 is H and n is 0. In some embodiments, X is OH and R 1 is methyl and R 2 is methyl and R 3 is H and R 4 is H and n is 0. In some embodiments, X is OH and R 1 is H and R 2 is methyl and R 3 is H and R 4 is H and n is 0. In some embodiments, X is OH and R 3 and R 4 is H and n is 0. In some embodiments, X is OH and R 1 is H and R 2 is H and R3 is H and R 4 is H and n is 0.

[0267] In some embodiments of Formula (II), R 1 is H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 1 is H, ethyl, or methyl. In some embodiments, R 1 is H or methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is H. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0.

[0268] In some embodiments of Formula (II), R 3 and R 4 is H. In some embodiments, R 3 and R 4 is methyl. In some embodiments, R 3 is H and R 4 is methyl.

[0269] In some embodiments of formula (I), (Iz), or (II), R 6 is n-propyl, isopropyl, ethyl, or methyl. 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6is a methyl substituted with OH.

[0270] In some embodiments of formula (I), (Iz), or (II), R 7 is C1-C4 alkyl substituted with OH. In some embodiments, R 7 is a C1-C4 alkyl substituted by two OH moieties. 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 7 is C1-C4 alkyl. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl. 7 is methyl. In some embodiments, R 7 is —CHCHOH or CHOH. In some embodiments, R 7 is —CHOH. In some embodiments, R 7 is a 5-6 membered heteroaryl. 7 is a 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl.

[0271] In some embodiments of formula (I), (Iz), or (II), R 8 , R 9 , and R 11 is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is H. In some embodiments, R 8 and R 9 are OH and R, respectively. 11 is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is OH. In some embodiments, R 8 is H and R 9is H and R 11 is OH.

[0272] In some embodiments of Formula (I), (Iz), or (II), E is a 6-membered ring. In some embodiments, E is pyridine or phenyl. In some embodiments, E is phenyl.

[0273] In some embodiments of formula (I), (Iz), or (II), R 7 is -CHOH, and R 8 is H and R 9 is H and E is phenyl.

[0274] In some embodiments, the compound of formula (Ia):

[0275] [ka] or a salt thereof (wherein R 1 , R 2 , R 3 , R 4 , R a , and R b are each independently H or C1-C4 alkyl, X is H, OH, or -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a and R 6 is C1-C4 alkyl, R 7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH, q is 0 or 1, When X is H, R 7 , R 8 , R 9 , and R 11 at least two of which contain an OH moiety is provided.

[0276] In some embodiments of Formula (Ia), q is 0. In some embodiments, q is 1.

[0277] In some embodiments of Formula (Ia), R 1 is H and R 2 is C1-C4-alkyl. In some embodiments, R 1 is H and R 2 is n-propyl, isopropyl, ethyl, or methyl. 1 is H and R 2 is ethyl or methyl. In some embodiments, R 1 is H and R 2 is methyl. In some embodiments, R 1 and R 2 are each independently C1-C4 alkyl. 1 and R 2 are each independently n-propyl, isopropyl, ethyl, or methyl. 1 and R 2 are each independently ethyl or methyl. 1 and R 2 is methyl. In some embodiments, R 1 and R 2 are both H.

[0278] In some embodiments of Formula (Ia), X is H, OH, —C(O)NR a R b , -S(O)2R a , -S(O)-R a, -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a In some embodiments, X is OH, —S(O)R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a In some embodiments, X is H or OH. In some embodiments, X is OH. In some embodiments, X is OH, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is OH, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is -NHS(O)R a , or -NHC(O)R a In some embodiments, X is -S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, OH, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is H, OH, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is H, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, OH, or —C(O)NRa R b In some embodiments, X is OH or —C(O)NR a R b In some embodiments, X is H or —C(O)NR a R b In some embodiments, R a and R b is independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b is independently H, ethyl, or methyl. In some embodiments, R a and R b is independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. a is H and R b is methyl.

[0279] In some embodiments of Formula (Ia), X is OH, —C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a In some embodiments, X is OH. In some embodiments, X is OH, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is OH, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is -NHS(O)R a , or -NHC(O)R a In some embodiments, X is -S(O)Ra , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is OH or —C(O)NR a R b In some embodiments, X is —C(O)NR a R b In some embodiments, R a and R b is independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b is independently H, ethyl, or methyl. In some embodiments, R a and R b is independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. a is H and R b is methyl.

[0280] In some embodiments of Formula (Ia), R 6 is n-propyl, isopropyl, ethyl, or methyl. 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is a methyl substituted with OH.

[0281] In some embodiments of Formula (Ia), R 7is C1-C4 alkyl substituted with OH. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 7 is —CHCHOH or CHOH. In some embodiments, R 7 is —CHOH. In some embodiments, R 7 is C1-C4 alkyl. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl. 7 is methyl. In some embodiments, R 7 is a 5-6 membered heteroaryl. 7 is a 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl.

[0282] In some embodiments of Formula (Ia), R 8 , R 9 , and R 11 is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is H. In some embodiments, R 8 and R 9 are OH and R, respectively. 11 is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is OH.

[0283] In some embodiments of Formula (Ia), X is OH and R 3 is H or methyl, and R 1 is H or C1-C4 alkyl, and R 2 is C1-C4 alkyl, R6 is C1-C4 alkyl, and R 7 is a C1-C4 alkyl optionally substituted with OH, and R8 is H or C1-C4 alkyl, and R 9 is H and q is 0. In some embodiments, X is OH and R 3 is H and R 1 is H or methyl, and R 2 is methyl and R 6 is isopropyl, and R 7 is CHOH, and R 8 is H and R 9 is H and q is 0.

[0284] In some embodiments, the compound of formula (Ib):

[0285] [ka] or a salt thereof, wherein the variables are as defined for formula (I).

[0286] In some embodiments of Formula (Ib), X is H. In some embodiments, X is H or OH. In some embodiments, R 5 is H or methyl. In some embodiments, R 5 is H. In some embodiments, m is 1 or 2. In some embodiments, m is 2. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, m is 2 and n is 0. In some embodiments, m is 1 and n is 1.

[0287] In some embodiments of Formula (Ib), R 6 is n-propyl, isopropyl, ethyl, or methyl. 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is a methyl substituted with OH.

[0288] In some embodiments of Formula (Ib), R 7 is C1-C4 alkyl substituted with OH. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 7 is C1-C4 alkyl. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl. 7 is methyl. In some embodiments, R 7 is —CHCHOH or CHOH. In some embodiments, R 7 is —CHOH. In some embodiments, R 7 is a 5-6 membered heteroaryl. 7 is a 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl.

[0289] In some embodiments of Formula (Ib), R 8 , R 9 , and R 11 are each H. In some embodiments, R 8 is OH and R 9 is H and R 11 is H. In some embodiments, R 8 and R 9 are OH and R, respectively. 11 is H. In some embodiments, R 8 is OH and R9 is H and R 11 is OH. In some embodiments, R 8 is H and R 9 is H and R 11 is OH.

[0290] In some embodiments of Formula (Ib), E is a 6-membered ring. In some embodiments, E is pyridine or phenyl. In some embodiments, E is phenyl.

[0291] In some embodiments of Formula (Ib), R 7 is -CHOH, and R 8 is H and R 9 is H and E is phenyl.

[0292] In some embodiments of Formula (Ib), R 7 is -CHOH, and R 8 is H and R 9 is H. In some embodiments, m is 2, n is 0, X is H, and R 10 is methyl and R 6 is isopropyl, and R 7 is H and R 8 is OH and R 9 In some embodiments, m is 1, n is 1, X is H, and R 10 is methyl and R 6 is isopropyl, and R 7 is H and R 8 is OH and R 9 In some embodiments, m is 2, n is 1, X is H, and R 10 is methyl and R 6 is isopropyl, and R 7 is H and R 8 is OH and R 9 is OH.

[0293] In some embodiments, the compound of formula (Ic):

[0294] [ka] or a salt thereof, wherein the variables are as defined for formula (I), (Iz), or (Ia).

[0295] In some embodiments, the compound of formula (Id):

[0296] [ka] or a salt thereof, wherein the variables are as defined for formula (I), (Iz), or (Ia).

[0297] In some embodiments, the compound of formula (Ie):

[0298] [ka] or a salt thereof, wherein the variables are as defined for formula (I), (Iz), or (Ia).

[0299] In some embodiments, the compound of formula (Id):

[0300] [ka] or a salt thereof, wherein the variables are as defined for formula (I), (Iz), or (Ia).

[0301] In some embodiments of formula (Ic), (Id), (Ie), or (If), R 1 and R 1 are both H. R 1 is H and R 2 is C1-C4-alkyl. In some embodiments, R 1 is H and R2 is n-propyl, isopropyl, ethyl, or methyl. 1 is H and R 2 is ethyl or methyl. In some embodiments, R 1 is H and R 2 is methyl. In some embodiments, R 1 and R 2 are each independently C1-C4 alkyl. 1 and R 2 are each independently n-propyl, isopropyl, ethyl, or methyl. 1 and R 2 are each independently ethyl or methyl. 1 and R 2 is methyl.

[0302] In some embodiments of Formula (Ic), (Id), (Ie), or (If), X is H, OH, —C(O)NR a R b , or -NHC(O)R a In some embodiments, X is H, OH, —C(O)NR a R b , or -NHC(O)R a In some embodiments, X is H or OH. In some embodiments, X is OH. In some embodiments, R 3 is H or C1-C4 alkyl. In some embodiments, R 3 is H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 3 is H, ethyl, or methyl. In some embodiments, X is H or OH and R 3 is H or methyl. In some embodiments, X is OH and R 3 is H. In some embodiments, X is OH and R 3 is methyl. In some embodiments, Ra is ethyl or methyl. In some embodiments, R a is methyl.

[0303] In some embodiments of formula (Ic), (Id), (Ie), or (If), R 6 is n-propyl, isopropyl, ethyl, or methyl. 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is a methyl substituted with OH.

[0304] In some embodiments of formula (Ic), (Id), (Ie), or (If), R 7 is C1-C4 alkyl substituted with OH. In some embodiments, R 7 is a C1-C4 alkyl substituted by two OH moieties. 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 7 is —CHCHOH or CHOH. In some embodiments, R 7 is —CHOH. In some embodiments, R 7 is C1-C4 alkyl. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl. 7 is methyl. In some embodiments, R 7 is a 5-6 membered heteroaryl. 7is a 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl.

[0305] In some embodiments of formula (Ic) or (Ie), R 8 and R 9 is H. In some embodiments, R 8 is OH and R 9 is H. In some embodiments, R 8 and R 9 are OH, respectively.

[0306] In some embodiments of formula (Id) or (If), R 8 , R 9 , and R 11 is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is H. In some embodiments, R 8 and R 9 are OH and R, respectively. 11 is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is OH. In some embodiments, R 8 is H and R 9 is H and R 11 is OH.

[0307] In some embodiments of Formula (Ic), (Id), (Ie), or (If), X is OH and R 3 is H or methyl, and R 1 is H or C1-C4 alkyl, and R 2 is C1-C4 alkyl, R6 is C1-C4 alkyl, and R 7 is a C1-C4 alkyl optionally substituted with OH, and R 8 is H or C1-C4 alkyl, and R 9 is H. In some embodiments, X is OH and R3 is H and R 1 is H or methyl, and R 2 is methyl and R 6 is isopropyl, and R 7 is CHOH, and R 8 is H and R 9 is H.

[0308] In some embodiments of Formula (Ic), R 7 is -CHOH, and R 8 is H and R 9 is H.

[0309] In some embodiments, the compound of formula (IIa):

[0310] [ka] or a salt thereof, wherein the variables are as defined for formula (II).

[0311] In some embodiments of Formula (IIa), q is 0. In some embodiments, q is 1.

[0312] In some embodiments of Formula (IIa), R 1 is H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 1 is H, ethyl, or methyl. In some embodiments, R 1 is H or methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is H. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0.

[0313] In some embodiments of Formula (IIa), R 6is n-propyl, isopropyl, ethyl, or methyl. 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is a methyl substituted with OH.

[0314] In some embodiments of Formula (IIa), R 7 is C1-C4 alkyl substituted with OH. In some embodiments, R 7 is a C1-C4 alkyl substituted by two OH moieties. 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 7 is C1-C4 alkyl. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl. 7 is methyl. In some embodiments, R 7 is —CHCHOH or CHOH. In some embodiments, R 7 is —CHOH. In some embodiments, R 7 is a 5-6 membered heteroaryl. 7 is a 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl.

[0315] In some embodiments of Formula (IIa), R 8 , R 9 , and R 11is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is H. In some embodiments, R 8 and R 9 are OH and R, respectively. 11 is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is OH. In some embodiments, R 8 is H and R 9 is H and R 11 is OH.

[0316] In some embodiments of Formula (IIa), E is a 6-membered ring. In some embodiments, E is pyridine or phenyl. In some embodiments, E is phenyl.

[0317] In some embodiments of Formula (IIa), R 7 is -CHOH, and R 8 is H and R 9 is H and R 11 is H.

[0318] In some embodiments, a compound of Table 1, or a salt thereof (eg, a pharmaceutically acceptable salt) is provided.

[0319] [Table 3-1]

[0320] [Table 3-2]

[0321] [Table 3-3]

[0322] [Table 3-4]

[0323] [Table 3-5]

[0324] [Table 3-6]

[0325] [Table 3-7]

[0326] [Table 3-8]

[0327] [Table 3-9]

[0328] Drug-Linker Compounds In some embodiments, when preparing the Ligand-Drug Conjugate Compounds described herein, it may be desirable to synthesize the complete Drug-Linker Compound prior to conjugation to a targeting agent, which will become the Ligand unit of the Ligand-Drug Conjugate Compound. In such embodiments, the Drug-Linker Compounds described herein are intermediate compounds. In these embodiments, the Stretcher unit in the Drug-Linker Compound is not yet covalently attached to the Ligand unit (i.e., the Stretcher unit precursor, Z') and therefore has a functional group for conjugation to a targeting agent. In one embodiment, the Drug-Linker Compound comprises an auristatin moiety (represented herein as Formulas (I) and (II), or any subformula thereof), or / and a Linker unit (Q) through which the Ligand unit is connected to the Drug unit.

[0329] In another embodiment, the Drug-Linker Compound comprises, as the Drug unit, an auristatin compound of Formula (I) or any subformula thereof, and a Linker unit (Q) comprising a releasable linker (RL) other than a glycoside (e.g., glucuronide) unit through which the Ligand unit is connected to the conjugated auristatin compound. In addition to RL, the Linker unit comprises a Stretcher unit precursor (Z') that contains a functional group for conjugation to a targeting agent, which is a precursor to the Ligand unit, and thus can connect RL (directly or indirectly) to the Ligand unit. In some of these embodiments, the Parallel Connector unit (B) comprises a Resolving Agent (S) as a side chain appendage. * In any one of these embodiments, the connector unit (A) is present when it is desired to add a longer distance between the stretcher unit and the RL.

[0330] In one group of embodiments, the Drug-Linker Compound comprises an auristatin compound of Formula (I) or any sub-formula thereof, and a Linker unit (Q), where Q is attached either directly to a Stretcher unit precursor (Z') or to an intervening component (i.e., A, S * and / or B(S * )) indirectly attached to Z', where Z' comprises a functional group capable of forming a covalent bond to a targeting agent.

[0331] In another group of embodiments, the Drug-Linker Compound comprises an auristatin of Formula (I) or any sub-formula thereof, and a Linker unit (Q), wherein Q is attached either directly to a Stretcher unit precursor (Z') or to an intervening component (i.e., A, S * and / or B(S * )))))))))))))))))))))))))))))))))))))))))))))))))))

[0332] In some embodiments, the drug-linker compound has the formula: QD or a salt thereof (wherein Q is (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS * -RL-, (iv) Z'-AS * -RL-Y-, (v) Z'-AB(S * )-RL-, (vi) Z'-AB(S * )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS*-W-, (ix) Z'-AB(S*)-W-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL-; is a linker unit selected from the group consisting of Z' is a Stretcher unit precursor; A is a bond or connector unit, B is the parallel connector unit, S * is a resolving agent, RL is a releasable linker, W is an amino acid unit, Y is a spacer unit, D is a Drug unit of Formula (I'):

[0333] [ka] (In the formula, X b is -NR 2 - # or -N + R 1 R 5 - # where # represents the point of attachment to Q, and X a teeth,

[0334] [ka] or X a and X b together with the carbon atoms to which they are attached,

[0335] [ka] (where the asterisk represents X a and X b represents a carbon atom of formula (I) bearing a group, and # represents the point of attachment to Q), R 1 and R5 are independently C1-C4 alkyl, X is H, OH, or -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a and R 2 , R 3 , R 4 , R 10 , R a , and R b are each independently H or C1-C4 alkyl, R 6 is a C1-C4 alkyl optionally substituted with OH, R 7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1, When X is H, R 7 , R 8 , R 9 , and R 11 at least two of which contain an OH moiety) It has.

[0336] In the context of drug-linker compounds, the assembly is best described in terms of its constituent parts. Although some procedures for the preparation of drug-linker compounds are described herein, the order of assembly and general conditions for preparing the compounds will be well understood by those skilled in the art in view of the teachings of this application.

[0337] Component Group 1. Drug Unit D The Drug unit of a Drug-Linker Compound or Ligand-Drug conjugate thereof provided herein is the auristatin portion of the compounds disclosed herein and is referred to herein as the Drug unit.

[0338] In some embodiments, the Drug unit D has the formula (I'), as described above.

[0339] In some embodiments of Formula (I'), q is 0. In some embodiments, q is 1.

[0340] In some embodiments, the Drug unit D has the formula (Iz'):

[0341] [ka] (In the formula, X b is -NR 2 - # or -N + R 1 R 5 - # where # represents the point of attachment to Q, and X a teeth,

[0342] [ka] or X a and X b together with the carbon atoms to which they are attached,

[0343] [ka] (where the asterisk represents X a and X b represents a carbon atom of formula (I) bearing a group, and # represents the point of attachment to Q), R 1 and R 5 are independently C1-C4 alkyl, X is OH, -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a and R 2 , R 3 , R 4 , R 10 , R a , and R b are each independently H or C1-C4 alkyl, R 6 is a C1-C4 alkyl optionally substituted with OH, R 7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1) It has.

[0344] In some embodiments of formula (I') or (Iz'), q is 0. In some embodiments, q is 1.

[0345] In some embodiments of formula (I') or (Iz'), X b is -NR 2 - # or -N + R 1 R 5 - #where # represents the point of attachment to Q, and X a teeth,

[0346] [ka] In some embodiments, R 1 and R 2 are each independently C1-C4 alkyl. 1 and R 5 are each independently n-propyl, isopropyl, ethyl, or methyl. 1 and R 5 are each independently ethyl or methyl. 1 and R 5 is methyl. In some embodiments, R 3 and R 4 are each independently C1-C4 alkyl. 3 is H and R 4 is C1-C4 alkyl. In some embodiments, R 3 and R 4 is H. In some embodiments, R 3 is H and R 4 is methyl. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, R 1 is methyl and R 5 is methyl and R 3 is H and R 4 is H and n is 0. In some embodiments, R 2 is n-propyl, isopropyl, ethyl, or methyl. 2 is ethyl or methyl. In some embodiments, R 2is methyl. In some embodiments, R 2 is H.

[0347] In some embodiments of formula (I') or (Iz'), X a and X b together with the carbon atoms to which they are attached,

[0348] [ka] (where the asterisk represents X a and X b represents a carbon atom of formula (I) bearing a group, and # represents the point of attachment to Q). 5 is n-propyl, isopropyl, ethyl, or methyl. 5 is ethyl or methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is methyl. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 2. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, m is 1 or 2 and n is 0 or 1.

[0349] In some embodiments of Formula (I'), X is H, OH, -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a In some embodiments, X is OH, —S(O)R a , -S(O)-R a , -S(O)NR a Rb , -NHS(O)2R a , or -NHC(O)R a In some embodiments, X is H or OH. In some embodiments, X is OH. In some embodiments, X is OH, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is OH, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is -NHS(O)R a , or -NHC(O)R a In some embodiments, X is -S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, OH, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is H, OH, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is H, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, OH, or —C(O)NR a R b In some embodiments, X is OH or —C(O)NR a R b In some embodiments, X is H or —C(O)NR a R b In some embodiments, R a and Rb is independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b is independently H, ethyl, or methyl. In some embodiments, R a and R b is independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. a is H and R b is methyl.

[0350] In some embodiments of Formula (Iz'), X is OH, -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a In some embodiments, X is OH. In some embodiments, X is OH, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is OH, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is -NHS(O)R a , or -NHC(O)R a In some embodiments, X is -S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is OH or —C(O)NR a R b In some embodiments, X is —C(O)NR a R bIn some embodiments, R a and R b is independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b is independently H, ethyl, or methyl. In some embodiments, R a and R b is independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. a is H and R b is methyl.

[0351] In some embodiments of formula (I') or (Iz'), X b -N + R 1 R 5 - # and X a teeth,

[0352] [ka] and X is OH and R 1 is methyl or methyl, and R 5 is methyl and R 3 is H and R 4 is H and n is 0. In some embodiments, X is OH and R 1 is methyl and R 5 is methyl and R 3 is H and R 4 is H and n is 0. In some embodiments, X is OH and R 3 and R 4 is H and n is 0.

[0353] In some embodiments of formula (I') or (Iz'), X b is -NR 2 -# and X a teeth,

[0354] [ka] and X is OH and R 2 is H or C1-C4 alkyl. b is -NR 2 - # and X a teeth,

[0355] [ka] and X is OH and R 2 is H. In some embodiments, X b is -NR 2 - # and X a teeth,

[0356] [ka] and X is OH and R 2 is C1-C4 alkyl.

[0357] In some embodiments of formula (I') or (Iz'), R 6 is n-propyl, isopropyl, ethyl, or methyl. 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is a methyl substituted with OH.

[0358] In some embodiments of formula (I') or (Iz'), R 7 is C1-C4 alkyl substituted with OH. In some embodiments, R 7 is a C1-C4 alkyl substituted by two OH moieties. 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 7 is C1-C4 alkyl. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl. 7 is methyl. In some embodiments, R 7 is —CHCHOH or CHOH. In some embodiments, R 7 is —CHOH. In some embodiments, R 7 is a 5-6 membered heteroaryl. 7 is a 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl.

[0359] In some embodiments of formula (I') or (Iz'), R 8 , R 9 , and R 11 is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is H. In some embodiments, R 8 and R 9 are OH and R, respectively. 11 is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is OH. In some embodiments, R 8 is H and R 9 is H and R 11 is OH.

[0360] In some embodiments of formula (I') or (Iz'), E is an optionally substituted 6-membered ring. In some embodiments, E is pyridine or phenyl, each of which is optionally substituted. In some embodiments, E is an optionally substituted phenyl. In some embodiments, E is an optionally substituted 5- to 6-membered heteroaryl. In some embodiments, E is an optionally substituted 5-membered heteroaryl. In some embodiments, E is pyridine or phenyl, each of which is unsubstituted. In some embodiments, E is an unsubstituted phenyl. In some embodiments, E is an unsubstituted 5- to 6-membered heteroaryl. In some embodiments, E is an unsubstituted 5-membered heteroaryl.

[0361] In some embodiments of formula (I') or (Iz'), R 7 is -CHOH, and R 8 is H and R 9 is H and E is phenyl.

[0362] In some embodiments, the Drug unit D has the formula (Ia') or (Ia''):

[0363] [ka] or a salt thereof (wherein R 1 and R 5 are independently C1-C4 alkyl, X is H, OH, or -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a and R 2 , R 3 , R a, and R b are each independently H or C1-C4 alkyl, R 6 is C1-C4 alkyl, R 7 is H, C1-C4 alkyl optionally substituted with OH, or 5- or 6-membered heteroaryl, R 8 , R 9 , and R 11 are each independently H or OH, q is 0 or 1, The wavy line is the site of attachment to the rest of the drug-linker compound. It has.

[0364] In some embodiments of Formula (Ia') and (Ia''), q is 0. In some embodiments, q is 1.

[0365] In some embodiments of Formula (Ia'), R 2 is C1-C4-alkyl. In some embodiments, R 2 is n-propyl, isopropyl, ethyl, or methyl. 2 is ethyl or methyl. 2 is methyl. In some embodiments, R 2 is H. In some embodiments, R 2 is ethyl, methyl, or H. In some embodiments, R 2 is methyl or H.

[0366] In some embodiments of Formula (Ia″), R 1 and R 5 are each independently n-propyl, isopropyl, ethyl, or methyl. 1 and R 5 are each independently ethyl or methyl. 1 and R 5 are each methyl. In some embodiments, R1 is methyl and R 5 is n-propyl, isopropyl, ethyl, or methyl. 1 is methyl and R 5 is ethyl or methyl. In some embodiments, R 1 and R 5 is methyl.

[0367] In some embodiments of formula (Ia') and (Ia''), X is H, OH, -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a In some embodiments, X is OH, —S(O)R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a In some embodiments, X is H or OH. In some embodiments, X is OH. In some embodiments, X is OH, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is OH, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is -NHS(O)R a , or -NHC(O)R a In some embodiments, X is -S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, OH, —NHS(O)R a, or -NHC(O)R a In some embodiments, X is H, OH, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, —NHS(O)R a , or -NHC(O)R a In some embodiments, X is H, —S(O)R a , -S(O)-R a , or -S(O)NR a R b In some embodiments, X is H, OH, or —C(O)NR a R b In some embodiments, X is OH or —C(O)NR a R b In some embodiments, X is H or —C(O)NR a R b In some embodiments, R a and R b is independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b is independently H, ethyl, or methyl. In some embodiments, R a and R b is independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. a is H and R b is methyl.

[0368] In some embodiments of formula (Ia′) and (Ia″), R 3 is H or methyl. In some embodiments, R 3 is H. In some embodiments, R 3 is methyl.

[0369] In some embodiments of formula (Ia′) and (Ia″), R 6 is n-propyl, isopropyl, ethyl, or methyl. 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is a methyl substituted with OH.

[0370] In some embodiments of formula (Ia′) and (Ia″), R 7 is C1-C4 alkyl substituted with OH. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. 7 is —CHCHOH or CHOH. In some embodiments, R 7 is —CHOH. In some embodiments, R 7 is C1-C4 alkyl. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl. 7 is methyl. In some embodiments, R 7 is a 5-6 membered heteroaryl. 7 is a 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl.

[0371] In some embodiments of formula (Ia′) and (Ia″), R 8 , R 9, and R 11 is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is H. In some embodiments, R 8 and R 9 are OH and R, respectively. 11 is H. In some embodiments, R 8 is OH and R 9 is H and R 11 is OH. In some embodiments, R 8 is H and R 9 is H and R 11 is OH.

[0372] In some embodiments of Formula (Ia'), X is OH and R 3 is H or methyl, and R 2 is C1-C4 alkyl, R6 is C1-C4 alkyl, and R 7 is a C1-C4 alkyl optionally substituted with OH, and R 8 is H or C1-C4 alkyl, and R 9 is H. In some embodiments, q is 0, X is OH, and R 3 is H or methyl, and R 2 is C1-C4 alkyl, R6 is C1-C4 alkyl, and R 7 is a C1-C4 alkyl optionally substituted with OH, and R 8 is H or C1-C4 alkyl, and R 9 is H.

[0373] In some embodiments of Formula (Ia″), X is OH and R 3 is H or methyl, and R 1 is C1-C4 alkyl, and R 5 is C1-C4 alkyl, R6 is C1-C4 alkyl, and R 7 is a C1-C4 alkyl optionally substituted with OH, and R 8is H or C1-C4 alkyl, and R 9 is H. In some embodiments, q is 0, X is OH, and R 3 is H or methyl, and R 1 is C1-C4 alkyl, and R 5 is C1-C4 alkyl, R6 is C1-C4 alkyl, and R 7 is a C1-C4 alkyl optionally substituted with OH, and R 8 is H or C1-C4 alkyl, and R 9 is H.

[0374] In some embodiments, the Drug unit D has the formula (Ib') or (Ib''):

[0375] [ka] where the variables are as defined for Formula (Ib) and the wavy line is the site of attachment to the remainder of the Drug-Linker Compound.

[0376] In some embodiments of formula (Ib') and (Ib''), R 7 is -CHOH, and R 8 is H and R 9 is H.

[0377] In some embodiments, the Drug unit D has the formula (Ic') or (Ic''):

[0378] [ka] where the variables are as defined for Formula (Ic) and the wavy line is the site of attachment to the remainder of the Drug-Linker Compound.

[0379] In some embodiments of formula (Ic') or (Ic''), X is OH and R 3 is H. In some embodiments, R 7 is -CHOH, and R8 is H and R 9 is H. In some embodiments, X is OH and R 7 is -CHOH, and R 8 is H and R 9 is H. In some embodiments, X is OH and R 3 is H and R 7 is -CHOH, and R 8 is H and R 9 is H.

[0380] In some embodiments, the Drug unit D has the formula (Id') or (Id''):

[0381] [ka] where the variables are as defined for Formula (Id) and the wavy line is the site of attachment to the remainder of the Drug-Linker Compound.

[0382] In some embodiments, the Drug unit D has the formula (Ie′) or (Ie″):

[0383] [ka] where the variables are as defined for Formula (Ie) and the wavy line is the site of attachment to the remainder of the Drug-Linker Compound.

[0384] In some embodiments, the Drug unit D has the formula (Id') or (Id''):

[0385] [ka] where the variables are as defined for formula (If) and the wavy line is the site of attachment to the remainder of the Drug-Linker Compound.

[0386] In some embodiments of formula (Id'), (Id''), (If'), or (If''), X is OH and R 3 is H. In some embodiments, R 7 is -CHOH, and R 8 is H and R 9 is H. In some embodiments, X is OH and R 7 is -CHOH, and R 8 is H and R 9 is H. In some embodiments, X is OH and R 3 is H and R 7 is -CHOH, and R 8 is H and R 9 is H.

[0387] In some embodiments of Formula (Ia"), (Ic"), (Id"), (Ie"), or (If"), the quaternized nitrogen atom prevents cyclization of the Drug unit. In some embodiments, the quaternized nitrogen atom prevents premature release of the Drug unit from a Drug-Linker compound or moiety (e.g., in a Ligand-Drug conjugate compound). In some embodiments, the quaternized nitrogen atom prevents cyclization of and premature release of the Drug unit from a Drug-Linker compound or moiety (e.g., in a Ligand-Drug conjugate compound).

[0388] 2. Linker unit Q As described above, in some embodiments, the linker unit Q is (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS * -RL-, (iv) Z'-AS * -RL-Y-, (v) Z'-AB(S * )-RL-, (vi) Z'-AB(S * )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS*-W-, (ix) Z'-AB(S*)-W-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL-; where Z' is a stretcher unit, A is a bond or connector unit, B is a parallel connector unit, and S * is a resolving agent, RL is a releasable linker, W is an amino acid unit, and Y is a spacer unit. having a formula selected from the group consisting of:

[0389] In other embodiments, the linker unit Q is (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS * -RL-, (iv) Z'-AS * -RL-Y-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL- having a formula selected from the group consisting of:

[0390] In some embodiments, the linker unit Q is (v) Z'-AB(S * )-RL-, (vi) Z'-AB(S * )-RL-Y-, (ix) Z'-AB(S*)-W-, and (xi) Z'-AB(S*)-W-RL- having a formula selected from the group consisting of:

[0391] In some embodiments, the linker unit Q is (iii) Z'-AS * -RL-, (iv) Z'-AS * -RL-Y-, (v) Z'-AB(S * )-RL-, (vi) Z'-AB(S * )-RL-Y-, (viii) Z'-AS*-W-, (ix) Z'-AB(S*)-W-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL- having a formula selected from the group consisting of:

[0392] In some embodiments, the linker unit Q is (viii) Z'-AS*-W-, (ix) Z'-AB(S*)-W-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL- having a formula selected from the group consisting of:

[0393] 3. Stretcher unit Z' The Stretcher unit (Z) is the building block of the Ligand-Drug Conjugate that acts to connect the Ligand unit to the rest of the conjugate. The Stretcher unit Precursor (Z') is the building block of the Drug-Linker Compound, or an intermediate thereof, that has a functional group that can form a bond with a functional group of the targeting Ligand to form the Stretcher unit (Z).

[0394] In some embodiments, the Stretcher unit precursor (Z') has an electrophilic group that can interact with a reactive nucleophilic group present on a Ligand unit (e.g., an antibody) to provide a covalent bond between the Ligand unit and the Stretcher unit of the Linker unit. Nucleophilic groups on antibodies that have this capability include, but are not limited to, sulfhydryl, hydroxyl, and amino functional groups. In some aspects, the heteroatom of the nucleophilic group of the antibody can be reactive to an electrophilic group on the Stretcher unit precursor to provide a covalent bond between the Ligand unit and the Stretcher unit of the Linker unit or Drug-Linker moiety. Useful electrophilic groups for this purpose include, but are not limited to, maleimide, haloacetamide groups, and NHS esters. The electrophilic group provides a convenient site for antibody attachment to form a Ligand-Drug conjugate compound or a Ligand unit-Linker intermediate compound.

[0395] In other embodiments, the Stretcher unit precursor has a reactive site bearing a nucleophilic group that is reactive toward an electrophilic group present on a Ligand unit (e.g., an antibody). Useful electrophilic groups on antibodies for this purpose include, but are not limited to, aldehyde and ketone carbonyl groups. The heteroatom of the nucleophilic group of the Stretcher unit precursor can react with an electrophilic group on the antibody to form a covalent bond to the antibody. Useful nucleophilic groups on the Stretcher unit precursor for this purpose include, but are not limited to, hydrazide, hydroxylamine, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide. The electrophilic group on the antibody provides a convenient site for antibody attachment to form a Ligand-Drug conjugate compound or a Ligand unit-Linker intermediate compound.

[0396] In some embodiments, the sulfur atom of the Ligand unit is linked to the succinimide ring system of the Stretcher unit formed by reaction of a thiol functional group of the Targeting Ligand with the maleimide moiety of the corresponding Stretcher unit precursor, hi other embodiments, the thiol functional group of the Ligand unit reacts with an alpha haloacetamide moiety to provide a sulfur-linked Stretcher unit by nucleophilic displacement of its halogen substituent.

[0397] An exemplary Stretcher unit prior to conjugation to a Ligand unit (i.e., a Stretcher unit precursor) comprises a maleimide moiety and has the formula Z'a

[0398] [ka] (wherein the wavy line adjacent to the carbonyl carbon represents B, A, or S in the above formula depending on the presence or absence of A and / or B. * indicates adhesion to R 17 is -(CH2) 1~5 -or-CH2CH2(OCH2CH2) 1~36 In some embodiments, R 17 is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -CH2CH2OCH2CH2-, -CH2CH2(OCH2CH2)2-, -CH2CH2(OCH2CH2)3-, -CH2CH2(OCH2CH2)4-, -CH2CH2(OCH2CH2)5-, -CH2CH2(OCH2CH2)6-, -CH2CH2(OCH2CH2)7-, -CH2CH2(OCH2CH2)8-, -CH2CH2(OCH2CH2) 10 -, -CH2CH2(OCH2CH2) 12 -, -CH2CH2(OCH2CH2) 14 -, -CH2CH2(OCH2CH2) 16 -, -CH2CH2(OCH2CH2) 18-, -CH2CH2(OCH2CH2) 20 -, -CH2CH2(OCH2CH2) 24 -, -CH2CH2(OCH2CH2) 28 -, -CH2CH2(OCH2CH2) 32 -,or -CH2CH2(OCH2CH2) 36 -It is.

[0399] Another exemplary Stretcher unit prior to conjugation to a Ligand unit (i.e., a Stretcher unit precursor) comprises a maleimide moiety and has the formula Z'a-BU

[0400] [ka] (wherein the wavy line adjacent to the carbonyl carbon atom represents B, A, or S in the above formula, depending on the presence or absence of A and / or B. * indicates adhesion to R 17 is a basic unit (BU), such as an optionally substituted aminoalkyl, e.g., —(CH) x NH2, -(CH2) x NHR a , and -(CH2) x N(R a )2, where the subscript x is an integer from 1 to 4, substituted with —(CH2) 1~5 -or-CH2CH2(OCH2CH2) 1~5 -, preferably R 17 is -CH2- or -CH2CH2-, the subscript X is 1 or 2, and each R a independently, C 1~6 Alkyl and C 1~6 haloalkyl, or two R a The groups, in combination with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, or piperidinyl group. It is represented by a structure containing the structure of

[0401] In some embodiments of Formula Z'a, the Stretcher unit precursor (Z') has the following structure:

[0402] [ka] wherein the wavy line adjacent to the carbonyl is as defined for Z'a or Z'a-BU. is represented by one of the following:

[0403] In other embodiments, the Stretcher unit precursor (Z') comprises a maleimide moiety:

[0404] [ka] wherein the wavy line adjacent to the carbonyl is as defined for Z'a, and the amino group may be protonated or protected by an amino-protecting group.

[0405] It will be understood that in a Stretcher unit having a BU moiety, the amino functionality of the moiety is typically protected during synthesis by an amino protecting group, such as an acid-labile protecting group (e.g., BOC).

[0406] The structure of Z'a or Z'a-BU (where -R 17 -or-R 17 Exemplary Stretcher unit precursors covalently attached to Connector units comprising (BU)- are -CH-, -CHCH-, or -CH(CHNH)- have the following structures:

[0407] [ka] wherein the wavy line adjacent to the carbonyl is as defined for Z'a or Z'a-BU. It has.

[0408] Other Stretcher unit precursors attached to the Connector unit (A) have the structures shown above, where A in any one of the Z'-A- and Z'(BU)-A- structures shown above is

[0409] [ka] where the subscript m ranges from 1 to 6, n ranges from 8 to 24, and R PEG is a PEG capping unit, preferably H, -CH, or -CHCHCOH, and an asterisk ( * ) indicates a covalent attachment to the corresponding Stretcher unit precursor in the structure to formula Z'a, and the wavy line indicates a covalent attachment to RL) and a splitter (-B(S * In examples such as those shown herein, the PEG groups shown are meant to be exemplary of various splitting agents containing PEG groups of different lengths, and other splitting agents either directly attached or modified for attachment to parallel connector units.

[0410] In some embodiments of the invention, the Stretcher unit has a mass of about 1000 daltons or less, about 500 daltons or less, about 200 daltons or less, about 30, 50, or 100 daltons to about 1000 daltons, about 30, 50, or 100 daltons to about 500 daltons, or about 30, 50, or 100 daltons to about 200 daltons.

[0411] 4. Connector unit (A) In some embodiments, a connector unit (A) is included in the drug-linker compound in instances where it is desired to add further distance between the Stretcher unit precursor (Z') and the releasable linker. In some embodiments, the additional distance aids in activation within the RL. Thus, the connector unit (A), when present, spans the framework of the linker unit. In that regard, the connector unit (A) is covalently bonded to a Stretcher unit (or its precursor) at one end and optionally to a parallel connector unit or a separating agent (S) at the other end. * ) covalently bonded to

[0412] Those skilled in the art will recognize that a connector unit is any group that serves to provide attachment of the releasable linker to the remainder of the linker unit (Q). A connector unit can include, for example, one or more (e.g., 1 to 10, preferably 1, 2, 3, or 4) proteinogenic or non-proteinogenic amino acids, amino alcohols, amino aldehydes, diamino residues. In some embodiments, the connector unit is a single proteinogenic or non-proteinogenic amino acid, amino alcohol, amino aldehyde, or diamino residue. An exemplary amino acid that can serve as a connector unit is β-alanine.

[0413] In some of these embodiments, the connector unit has the formula represented below:

[0414] [ka] where the wavy line indicates the attachment of a connector unit in the drug-linker compound, and R 111are independently hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-,

[0415] [ka] is selected from the group consisting of Each R 100 are independently selected from hydrogen or -C1-C3 alkyl, preferably hydrogen or CH3, and the subscript c is independently selected from integers 1 to 10, preferably 1 to 3. It has.

[0416] Splitting agent (S * ) or -B(S * Representative connector units having a carbonyl group for attachment to the )- are as follows:

[0417] [ka] (wherein, in each instance, R 13 are independently -CH2CH2(OCH2CH2) k -, -C1-C6 alkylene-, -C3-C8 carbocyclo-, -arylene-, -C1-C 10 Heteroalkylene-, -C3-C8 heterocyclo-, -C1-C 10 Alkylene-arylene-, -arylene-C1-C 10 Alkylene-, -C1~C 10Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 heterocyclo)-, and -(C3-C8 heterocyclo)-C1-C 10 alkylene-, where the subscript k is an integer ranging from 1 to 36, and the subscript c is an integer ranging from 1 to 4. In some embodiments, R 13 is —C1-C6 alkylene, and c is 1.

[0418] Splitting agent (S * ) or -B(S * Another representative connector unit having a carbonyl group for attachment to the - is:

[0419] [ka] (In the formula, R 13 is -CH2CH2(OCH2CH2) k -, -C1-C6 alkylene-, -C3-C8 carbocyclo-, -arylene-, -C1-C 10 Heteroalkylene-, -C3-C8 heterocyclo-, -C1-C 10 Alkylene-arylene-, -arylene-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 heterocyclo)- or -(C3-C8 heterocyclo)-C1-C 10 alkylene-, and the subscript k is an integer ranging from 1 to 36. 13 is —C1 to C6 alkylene.

[0420] Splitting agent (S * ) or -B(S * Representative connector units having an NH moiety attached to a )- are as follows:

[0421] [ka] (wherein, in each instance, R 13 are independently -CH2CH2(OCH2CH2) k -, -C1-C6 alkylene-, -C3-C8 carbocyclo-, -arylene-, -C1-C 10 Heteroalkylene-, -C3-C8 heterocyclo-, -C1-C 10 Alkylene-arylene-, -arylene-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 heterocyclo)-, and -(C3-C8 heterocyclo)-C1-C 10 alkylene-, where the subscript k is an integer ranging from 1 to 36, and the subscript c is an integer ranging from 1 to 36. 13 is -C1-C6 alkylene, and the subscript c is 1.

[0422] Splitting agent (S * ) or -B(S * Another representative connector unit having an NH moiety attached to a )- is:

[0423] [ka] (In the formula, R 13 is -CH2CH2(OCH2CH2) k -, -C1-C6 alkylene-, -C3-C8 carbocyclo-, -arylene-, -C1-C 10 Heteroalkylene-, -C3-C8 heterocyclo-, -C1-C 10 Alkylene-arylene-, -arylene-C1-C 10 Alkylene-, -C1~C 10Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C 10 alkylene-, -C(=O)C1-C6 alkylene-, or -C1-C6 alkylene-C(=O)-C1-C6 alkylene, where the subscript k is an integer ranging from 1 to 36.

[0424] Selected embodiments of the connector unit have the following structure:

[0425] [ka] where the wavy line adjacent to the nitrogen indicates covalent attachment to the Stretcher unit (Z) (or its precursor Z'), and the wavy line adjacent to the carbonyl indicates covalent attachment to the resolving agent (S * ) or -B(S * )-, where m is an integer ranging from 1 to 6, preferably from 2 to 6, and more preferably from 2 to 4. Includes those having the following.

[0426] 5. Releasable Linker (RL) The releasable linker (RL) can be linked to the spacer unit (Y) or the drug unit (D). The RL contains a cleavable bond (i.e., a reactive site) that releases free drug upon action by enzymes present in hyperproliferative cells or hyperactivated immune cells or the characteristic immediate environment of these abnormal or unwanted cells compared to normal cells, or upon non-enzymatic action due to conditions likely experienced by hyperproliferative cells. Alternatively, the RL contains a cleavable bond that is more likely to act intracellularly in hyperproliferative cells or hyperactivated immune cells due to preferential entry into such cells compared to normal cells.

[0427] Peptide Releasable Linkers In some embodiments, the releasable linker is a peptide releasable linker. In some embodiments, the peptide releasable linker (RL) comprises one or more contiguous or noncontiguous sequences of amino acids (e.g., such that the RL has 1-12 or fewer amino acids). The peptide releasable linker can comprise or consist of, for example, an amino acid, dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide, or dodecapeptide unit. In some embodiments, in the presence of an enzyme (e.g., a tumor-associated protease), the amide linkage between the amino acids is cleaved, which ultimately results in the release of the free drug.

[0428] Each amino acid may be proteinogenic or non-proteinogenic, and / or D- or L-isomer, provided that R contains a cleavable bond that, upon cleavage, initiates release of the Drug unit. In some embodiments, the peptide releasable linker contains only proteinogenic amino acids. In some aspects, the peptide releasable linker has 1-12 or fewer amino acids in a contiguous sequence.

[0429] In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, selenocysteine, ornithine, penicillamine, β-alanine, aminoalkanoic acids, aminoalkynic acids, aminoalkanedioic acids, aminobenzoic acids, amino-heterocyclo-alkanoic acids, heterocyclo-carboxylic acids, citrulline, statins, diaminoalkanoic acids, and derivatives thereof. In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, and selenocysteine. In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, and valine. In some embodiments, each amino acid is selected from proteinogenic or non-proteinogenic amino acids.

[0430] In another embodiment, each amino acid is independently selected from the group consisting of the following L-(proteinogenic) amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan, and valine.

[0431] In another embodiment, each amino acid is independently selected from the group consisting of the D-isomers of the following proteinogenic amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan, and valine.

[0432] In certain embodiments, the peptide releasable linker comprises only proteinogenic amino acids. In other embodiments, the peptide releasable linker comprises only non-proteinogenic amino acids. In some embodiments, the peptide releasable linker comprises a proteinogenic amino acid attached to a non-proteinogenic amino acid. In some embodiments, the peptide releasable linker comprises a proteinogenic amino acid attached to a D-isomer of the proteinogenic amino acid.

[0433] In another embodiment, each amino acid is independently selected from the group consisting of β-alanine, N-methylglycine, glycine, lysine, valine, and phenylalanine.

[0434] Exemplary peptide releasable linkers include dipeptides or tripeptides having -Val-Lys-Gly-, -Val-Cit-, -Phe-Lys-, or -Val-Ala-.

[0435] Useful peptide releasable linkers are designed and optimized for their selectivity for enzymatic cleavage by specific enzymes, such as tumor-associated proteases. In some embodiments, cleavage of the linkage is catalyzed by cathepsin B, C, or D, or plasmin proteases.

[0436] In some embodiments, the peptide releasable linker (RL) is -(-AA-) 1~12 - or (-AA-AA-) 1~6wherein AA, at each occurrence, is independently selected from a proteinogenic or non-proteinogenic amino acid. In one embodiment, AA, at each occurrence, is independently selected from a proteinogenic amino acid. In another embodiment, R is represented by the formula: AAA1-AA2-AA3, where AAA1, AA2, and AA3 are each independently an amino acid, AAA1 is attached to -NH-, and AA3 is attached to S * In another embodiment, AA3 is a tripeptide having a nucleotide sequence (attached to ). In another embodiment, AA3 is gly or β-ala.

[0437] In some embodiments, the peptide releasable linker has the formula represented below in square brackets, where the subscript w is an integer ranging from 1 to 12, or w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, or w is 2, 3, or 4, or w is 3, or w is 4:

[0438] [ka] (In the formula, R 19 is, in each instance, independently hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl,

[0439] [ka] In some embodiments, the subscript w is not 3.

[0440] In some embodiments, each R 19 is independently hydrogen, methyl, isopropyl, isobutyl, sec-butyl, —(CH)NH, or —(CH)NH. 19 are independently hydrogen, isopropyl, or —(CH 2 ) 4 NH 2 .

[0441] Exemplary peptide releasable linkers have the formulas (Pa), (Pb) and (Pc):

[0442] [ka] (In the formula, R 20 and R 21 is as follows:

[0443] [Table 4] is)

[0444] [ka] (In the formula, R 20 , R 21 and R 22 is as follows:

[0445] [Table 5] is)

[0446] [ka] (In the formula, R 20 , R 21 , R 22 and R 23 is as follows:

[0447] [Table 6] is) is expressed by

[0448] In some embodiments, the RL comprises a peptide selected from the group consisting of gly-gly, gly-gly-gly, gly-gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, gly-val-lys-gly, val-lys-gly-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly, gly-gly-phe-gly, gly-gly-phe-gly-gly, val-gly, and val-lys-β-ala.

[0449] In other embodiments, the RL comprises a peptide selected from the group consisting of gly-gly-gly, gly-gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, gly-val-lys-gly, val-lys-gly-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly, gly-gly-phe-gly, and val-lys-β-ala.

[0450] In still other embodiments, the RL comprises a peptide selected from the group consisting of gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly, and val-lys-β-ala.

[0451] In yet other embodiments, the RL comprises a peptide selected from the group consisting of gly-gly-gly-gly, gly-val-lys-gly, val-lys-gly-gly, and gly-gly-phe-gly.

[0452] In other embodiments, RL is a peptide selected from the group consisting of val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly and val-lys-β-ala.

[0453] In still other embodiments, RL is val-lys-gly.

[0454] In still other embodiments, RL is val-lys-β-ala.

[0455] In some embodiments, the releasable linker RL is:

[0456] [ka] wherein the wavy line adjacent to the -NH- group indicates attachment to Stretcher unit Z' or Connector unit A, and the wavy line adjacent to the -C(=O)- group indicates attachment to Spacer unit Y or Drug unit D. is.

[0457] Glycoside Unit Releasable Linker In some embodiments, the releasable linker is a glycoside (e.g., glucuronide) unit. In such embodiments, the self-immolative cascade is activated by the action of a glycosidase on the carbohydrate moiety of the glycoside (e.g., glucuronide) unit. Several sugars are useful in the embodiments described herein. Specific carbohydrate moieties include galactose, glucose, mannose, xylose, arabinose, mannose-6-phosphate, fucose, rhamnose, gulose, allose, 6-deoxy-glucose, lactose, maltose, cellobiose, gentiobiose, maltotriose, GlcNAc, GalNAc, and maltohexaose.

[0458] A glycoside (e.g., glucuronide) unit typically comprises a sugar moiety (Su) linked to a self-immolative spacer via an oxygen glycosidic bond. Cleavage of the oxygen glycosidic bond initiates a self-immolative reaction sequence that results in the release of the free drug. In some embodiments, the self-immolative sequence is activated from cleavage of a glycoside (e.g., glucuronide) unit, an exemplary glycoside unit, by β-glucuronidase. A glycoside (e.g., glucuronide) unit comprises an activation unit and a self-immolative spacer unit. A glycoside (e.g., glucuronide) unit comprises a sugar moiety (Su) linked to a self-immolative spacer unit via an oxygen glycosidic bond.

[0459] In some embodiments, the glycoside (e.g., glucuronide) unit is a self-immolative unit (SP) of the formula:

[0460] [ka] (In the formula, the wavy line represents a connector unit (A) or a parallel connector unit (B), a resolving agent (S *), or a Drug unit or Spacer unit attached to a Drug unit and to a Stretcher unit precursor (Z'), or a sugar moiety (Su) linked via an oxygen glycosidic bond (-O'-) to a Drug unit or Spacer unit, or a Drug unit attached to a Stretcher unit precursor (Z'), directly or indirectly through a combination of a Connector unit and a Parallel Connector unit, or a covalent attachment to a Drug unit.

[0461] The oxygen glycosidic bond (-O'-) is typically a β-glucuronidase cleavage site (ie, Su is from the glucuronide), eg, a glycosidic bond cleavable by human lysosomal β-glucuronidase.

[0462] In some embodiments, the glycoside (e.g., glucuronide) unit has the formula Ga, Gb, or Gc:

[0463] [ka] (wherein Su is a sugar moiety, -O'- represents an oxygen glycosidic bond, and R 1S , R 2S and R 3S are independently hydrogen, halogen, -CN, -NO2, or other electron-withdrawing or electron-donating groups, and R BZ is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, PEG unit, cyclodextrin unit, polyamide, hydrophilic peptide, polysaccharide, and dendrimer, a wavy line indicates attachment to a Stretcher unit precursor (Z') directly or indirectly through a connector unit or a parallel connector unit or a connector unit and a parallel connector unit, and a # indicates attachment to a Drug unit or Spacer (directly or indirectly through an intervening functional group or other moiety).

[0464] In some embodiments, R 1S , R 2S , and R 3S is independently selected from hydrogen, halogen, —CN, or —NO.1S , R 2S and R 3S are each hydrogen. 2S is an electron-withdrawing group, preferably NO2, and R 1S and R 3S are hydrogen atoms.

[0465] In some such embodiments, the activatable self-immolative group capable of glycosidase cleavage to initiate a self-immolative reaction sequence has the formula Gd:

[0466] [ka] (In the formula, R 4S is CHOH or —COH, a wavy line indicates covalent attachment to a Stretcher unit (Z) (or its precursor Z′) directly or indirectly through a connector unit or a parallel connector unit or a connector unit and a parallel connector unit, and a hash mark (#) indicates covalent attachment to a methylene carbamate unit.

[0467] In some embodiments, the activatable self-immolative moiety comprises a glycoside (e.g., glucuronide) unit, which has the following formula Ge:

[0468] [ka] where the wavy line indicates covalent attachment to the Stretcher unit (Z) (or its precursor Z') directly or indirectly through a connector unit or a parallel connector unit or a connector unit and a parallel connector unit, and the hash mark (#) indicates covalent attachment of the benzylic carbon of a spacer or functional group attached to the Drug unit. In some embodiments, the structure of formula Ge is represented by + ), where the nitrogen atom is from a tertiary amine functional group on the unconjugated Drug unit.

[0469] Another type of releasable linker that provides a mechanism for separation of the Drug unit from the Ligand unit and other components of the Linker unit by activation of a self-immolative cascade within the Linker unit contains a p-aminobenzoyloxycarbonyl (PAB) moiety, the phenylene component of which is J m where the subscript m, indicating the number of substituents, is an integer ranging from 0 to 4, and each J is independently -C1-C8 alkyl, -O-(C1-C8 alkyl), -halogen, -nitro, or -cyano.

[0470] In some embodiments, R is a self-immolative group that can release -D without the need for a separate hydrolysis step or subsequent self-immolative event. In some embodiments, -R is a PAB moiety linked to the carbonyl of -W- through the amino nitrogen atom of the PAB group and directly connected to -D through a carbonate group. In related embodiments, -R is linked to -A-, -S- through the amino nitrogen atom of the PAB group. * -B- or -B-, and directly connected to -D through a carbonate group. Without being bound by any particular theory or mechanism, a possible mechanism of drug release from a RL containing a PAB moiety, in which the RL is directly attached to -D through a carbonate group, is shown in Toki et al. (2002) J Org. Chem. 67:1866-1872.

[0471] In some embodiments, the RL unit containing the PAB moiety has the formula:

[0472] [ka] wherein the subscript m is an integer ranging from 0 to 4, and each J is independently -C1-C8 alkyl, -O-(C1-C8 alkyl), -halogen, -nitro, or -cyano.

[0473] Other examples of self-immolative groups include, but are not limited to, aromatic compounds electronically similar to the PAB moiety, such as 2-aminoimidazole-5-methanol derivatives (Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and ortho- or para-aminobenzyl acetals. Other RLs, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al., Chemistry Biology, 1995, 2, 223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm et al., J. Amer. Chem. Soc., 1972, 94, 5815), and 2-aminophenylpropionic acid amides (Amsberry et al., J. Org. Chem., 1990, 55, 5867), undergo cyclization upon hydrolysis of the amide bond.

[0474] In one embodiment, RL is a branched bis(hydroxymethyl)styrene (BHMS) unit.

[0475] In some embodiments, R L has the formula:

[0476] [ka] (In the formula, ** The wavy line marked with indicates the attachment site to D. * The wavy line marked with indicates the point of attachment of Q to an additional linker component. In some embodiments, the PAB-containing RL is attached directly to the Drug Unit.

[0477] 6. Splitting Agent S * The ligand-drug conjugates described herein may contain a resolving agent (S * ) The resolving agent moiety is useful, for example, to mask the hydrophobicity of a particular Drug Unit or Linking Unit component.

[0478] Representative resolving agents include polyethylene glycol (PEG) units, cyclodextrin units, polyamides, hydrophilic peptides, polysaccharides, and dendrimers.

[0479] When a polyethylene glycol (PEG) unit, cyclodextrin unit, polyamide, hydrophilic peptide, polysaccharide, or dendrimer is included in Q, the group can be present as an "in-line" component, or as a side chain or branched component. For those embodiments in which a branched version exists, the linker unit can include a lysine residue (or parallel connector unit, B) that provides simple functional conjugation of, for example, a PEG unit to the remainder of the linking unit.

[0480] Polyethylene glycol (PEG) units When present, polydisperse PEG, monodisperse PEG and individual PEG are used as the resolving agent portion in the compound of the present invention.Polydisperse PEG is a heterogeneous mixture of size and molecular weight, while monodisperse PEG is typically purified from a heterogeneous mixture, thus providing a single chain length and molecular weight.Preferred PEG unit is individual PEG, which is a compound that is synthesized in a sequential manner and is not subjected to a polymerization process.Individual PEG provides a single molecule with a defined and specified chain length.

[0481] The PEG units provided herein can include one or more polyethylene glycol chains. The polyethylene glycol chain is composed of at least two ethylene oxide (CH2CHO) subunits. In some embodiments, the polyethylene glycol chains are linked to each other, for example, in a linear, branched, or star configuration. Typically, at least one of the PEG chains is derivatized at one end for covalent attachment to an appropriate site on a linker unit (e.g., B) component, or is derivatized at the other end for covalent attachment to an appropriate site on a linker unit component (e.g., ZAS). * -RL-, ZAS *-RL-Y-) is used as an in-line (e.g., bifunctional) linking group within the two covalent bonds. Exemplary attachment within the linker unit is by a non-conditionally cleavable linkage or via a conditionally cleavable linkage. Exemplary attachment is via an amide linkage, an ether linkage, an ester linkage, a hydrazone linkage, an oxime linkage, a disulfide linkage, a peptide linkage, or a triazole linkage. In some embodiments, attachment within the linker unit is by a non-conditionally cleavable linkage. In some embodiments, attachment within the linker unit is not via an ester linkage, a hydrazone linkage, an oxime linkage, or a disulfide linkage. In some embodiments, attachment within the linker unit is not via a hydrazone linkage.

[0482] A conditionally cleavable linkage refers to a linkage that is not substantially susceptible to cleavage while circulating in plasma, but is susceptible to cleavage in an intracellular or intratumor environment. A non-conditionally cleavable linkage is one that is not substantially susceptible to cleavage in any biological environment. Chemical hydrolysis of hydrazones, reduction of disulfides, and enzymatic cleavage of peptide bonds or glycosidic linkages are examples of conditionally cleavable linkages.

[0483] In some embodiments, the PEG unit is directly attached to the parallel connector unit B, where the other end (or ends) of the PEG unit are free, untethered, and may take the form of a methoxy, carboxylic acid, alcohol, or other suitable functional group. The methoxy, carboxylic acid, alcohol, or other suitable functional group acts as a cap for the terminal PEG subunit of the PEG unit. Untethered means that the PEG unit is not attached to a drug unit, antibody, or another linking component at its untethered site. Those skilled in the art will understand that a PEG unit, in addition to comprising repeating ethylene glycol subunits, can also contain non-PEG material (e.g., to facilitate coupling of multiple PEG chains to each other). Non-PEG material refers to atoms in the PEG unit that are not part of the repeating -CHCHO- subunits. In some embodiments provided herein, the PEG unit comprises two monomeric PEG chains attached to each other via a non-PEG element. In other embodiments provided herein, the PEG unit comprises two linear PEG chains attached to a central core or parallel connector unit (i.e., the PEG unit itself is branched).

[0484] There are many methods of PEG attachment available to those skilled in the art [e.g., Goodson et al. (1990) Bio / Technology 8:343 (PEGylation of interleukin-2 at its glycosylation site after site-directed mutagenesis); EP 0401384 (coupling PEG to G-CSF); Malik et al. (1992) Exp. Hematol. 20:1028-1035 (PEGylation of GM-CSF using tresyl chloride); PCT Publication No. WO 90 / 12874 (PEGylation of erythropoietin containing a recombinantly introduced cysteine residue using cysteine-specific mPEG derivatives); U.S. Patent No. 5,757,078 (PEGylation of EPO peptides); U.S. Patent No. 5,672,662 (Poly(ethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications); U.S. Patent No. 6,077,939 (PEGylation of an N-terminal alpha-carbon of a peptide); Veronese et al. (1985) Appl. Biochem. Biotechnol 11:141-142 (PEGylation of an N-terminal alpha-carbon of a peptide with PEG-nitrophenylcarbonate ("PEG-NPC") or PEG-trichlorophenylcarbonate); and Veronese (2001) Biomaterials 22:405-417 (Review article on peptide and protein PEGylation)].

[0485] For example, PEG may be covalently bound to an amino acid residue via a reactive group. The reactive group is one to which an activated PEG molecule can be attached (e.g., a free amino or carboxyl group). For example, the N-terminal amino acid residue and lysine (K) residue have a free amino group, and the C-terminal amino acid residue has a free carboxyl group. Thiol groups (e.g., found on cysteine residues) can also be useful as reactive groups for attaching PEG. In addition, enzyme-assisted methods have been described for specifically introducing activated groups (e.g., hydrazide, aldehyde, and aromatic amino groups) into the C-terminus of polypeptides (see Schwarz et al. (1990) Methods Enzymol. 184:160; Rose et al. (1991) Bioconjugate Chem. 2:154; and Gaertner et al. (1994) J. Biol. Chem. 269:7224).

[0486] In some embodiments, PEG molecules may be attached to amino groups using methoxylated PEGs ("mPEG") with different reactive moieties. Non-limiting examples of such reactive moieties include succinimidyl succinate (SS), succinimidyl carbonate (SC), mPEG-imidate, para-nitrophenyl carbonate (NPC), succinimidyl propionate (SPA), and cyanuric chloride. Non-limiting examples of such mPEGs include mPEG-succinimidyl succinate (mPEG-SS), mPEG2-succinimidyl succinate (mPEG2-SS), mPEG-succinimidyl carbonate (mPEG-SC), mPEG2-succinimidyl carbonate (mPEG2-SC), mPEG-imidate, mPEG-para-nitrophenyl carbonate (mPEG-NPC), mPEG-imidate, mPEG2-para-nitrophenyl carbonate mPEG-NPC, mPEG-succinimidyl propionate (mPEG-SPA), mPEG2-succinimidyl propionate (mPEG2-SPA), mPEG-N-hydroxy-succinimide (mPEG-NHS), mPEG2-N-hydroxy-succinimide (mPEG2-NHS), mPEG-cyanuric chloride, mPEG2-cyanuric chloride, mPEG2-lysinol-NPC, and mPEG2-Lys-NHS.

[0487] Generally, at least one of the PEG chains that make up the PEG unit is functionalized to allow it to be covalently attached to other linker unit components.

[0488] Functionalization can include, for example, via amine, thiol, NHS ester, maleimide, alkyne, azide, carbonyl, or other functional groups. In some embodiments, the PEG unit further comprises a non-PEG material (i.e., a material that does not comprise -CHCHO-) to provide for coupling to other linker unit components or to facilitate the coupling of two or more PEG chains.

[0489] The presence of a PEG unit (or other resolving agent) in a linker unit can have two possible effects on the pharmacokinetics of the resulting ligand-drug conjugate. The desired effect is a decrease in clearance (and subsequent increase in exposure) resulting from a reduction in nonspecific interactions induced by exposed hydrophobic elements of the ligand-drug conjugate or the drug unit itself. The second effect is a decrease in volume and rate of distribution, which is undesirable and may result from an increase in the molecular weight of the ligand-drug conjugate.

[0490] Increasing the number of PEG subunits increases the hydrodynamic radius of the conjugate, typically resulting in decreased diffusivity. This decreased diffusivity, in turn, typically reduces the ability of the ligand-drug conjugate to penetrate tumors (Schmidt and Wittrup, Mol Cancer Ther 2009, 8:2861-2871). Because of these two competing pharmacokinetic effects, it is desirable to use PEG that is large enough to reduce ligand-drug conjugate clearance and thus increase plasma exposure, but not so large that it significantly reduces the diffusivity of the ligand-drug conjugate, preventing it from reaching the intended target cell population. For methodologies for selecting the optimal PEG size for a particular drug-linker, see the examples (e.g., Examples 1, 18, and 21) of US2016 / 0310612, which are incorporated herein by reference.

[0491] In one group of embodiments, the PEG unit comprises one or more linear PEG chains each having at least 2 subunits, at least 3 subunits, at least 4 subunits, at least 5 subunits, at least 6 subunits, at least 7 subunits, at least 8 subunits, at least 9 subunits, at least 10 subunits, at least 11 subunits, at least 12 subunits, at least 13 subunits, at least 14 subunits, at least 15 subunits, at least 16 subunits, at least 17 subunits, at least 18 subunits, at least 19 subunits, at least 20 subunits, at least 21 subunits, at least 22 subunits, at least 23 subunits, or at least 24 subunits. In some embodiments, the PEG unit comprises a total of at least 4 subunits, at least 6 subunits, at least 8 subunits, at least 10 subunits, or at least 12 subunits. In some such embodiments, the PEG unit comprises a total of about 72 or fewer subunits, preferably a total of about 36 or fewer subunits.

[0492] In one group of embodiments, the PEG units comprise one or more linear PEG chains each having 2 subunits, 3 subunits, 4 subunits, 5 subunits, 6 subunits, 7 subunits, 8 subunits, 9 subunits, 10 subunits, 11 subunits, 12 subunits, 13 subunits, 14 subunits, 15 subunits, 16 subunits, 17 subunits, 18 subunits, 19 subunits, 20 subunits, 21 subunits, 22 subunits, 23 subunits, or 24 subunits. In some embodiments, the PEG units comprise a total of 4 subunits, 6 subunits, 8 subunits, 10 subunits, or 12 subunits. In some such embodiments, the PEG units comprise a total of about 72 or fewer subunits, preferably a total of about 36 or fewer subunits.

[0493] In another group of embodiments, the PEG units may be a total of 4 to 72, 4 to 60, 4 to 48, 4 to 36, or 4 to 24 subunits, 5 to 72, 5 to 60, 5 to 48, 5 to 36, or 5 to 24 subunits, 6 to 72, 6 to 60, 6 to 48, 6 to 36, or 6 to 24 subunits, 7 to 72, 7 to 60, 7 to 48, 7 to 36, or 7 to 24 subunits, 8 to 72, 8 to 60, 8 to 48, 8 to 36, or 8 to 24 subunits, 9 to 72, 9 to 60, 9 to 48, 9 to 36, or 9 to 24 subunits, 10 to 72, 10 to 60, 10 to 48, 10 to 36, or 10 to 24 subunits, 11 to 72, 11 to 60, 11 to 48, 11 to 36, or 11 to 24 subunits, 12 to 72, 12 to 60, 12 to 48, 12 to 36, or 12 to 24 subunits, 13 to 72, 13 to 60, 13 to 48, 13 to 36, or 13 to 24 subunits, 14 to 72, 14 to 60, 14 to 48, 14 to 36, or 14 to 24 subunits, 15 to 72, 15 to 60, 15 to 48, 15 to 36, or 15 to 24 subunit ~48, 9~36 or 9~24 subunits, 10~72, 10~60, 10~48, 10~36 or 10~24 subunits, 11~72, 11~60, 11~48, 11~36 or 11~24 subunits, 12~72, 12~60, 12~48, 12~36 or 12~24 subunits, 13~72, 13~60, 13~48, 13~36 or 13~24 subunits, 14~72, 14~60, 14~48, 14~36 or Subunits of 14-24, 15-72, 15-60, 15-48, 15-36 or 15-24, subunits of 16-72, 16-60, 16-48, 16-36 or 16-24, subunits of 17-72, 17-60, 17-48, 17-36 or 17-24, subunits of 18-72, 18-60, 18-48, 18-36 or 18-24, subunits of 19-72, 19-60, 19-48, 19-36 or 19-24 subunits, 20-72, 20-60, 20-48, 20-36 or 20-24 subunits, 21-72, 21-60, 21-48, 21-36 or 21-24 subunits, 22-72, 22-60, 22-48, 22-36 or 22-24 subunits, 23-72, 23-60, 23-48, 23-36 or 23-24 subunits, or 24-72, 24-60, 24-48, 24-36 or 24 subunits.

[0494] In some embodiments, the resolving agent S *is a linear PEG unit comprising 2 to 20, or 2 to 12, or 4 to 12, or 4, 8, or 12 -CH2CH2O- subunits. In some embodiments, the linear PEG unit is connected to an R L unit at one end of the PEG unit and to a Stretcher / Connector unit (ZA-) at the other end of the PEG unit. In some embodiments, the PEG unit is connected to an R L unit through a -CH2CH2C(O)- group that forms an amide bond with the R L unit (e.g., -(CH2CHO) n -CH2CH2C(O)-RL), which is connected to the Stretcher / Connector unit (ZA-) via an -NH- group that forms an amide bond with the ZA- moiety (e.g., ZA-NH-(CH2CH2O) n -).

[0495] An exemplary embodiment for a PEG unit connected to a RL and a stretcher / connector unit (ZA-) is shown below:

[0496] [ka] In certain embodiments, the PEG units are

[0497] [ka] wherein the left wavy line indicates the site of attachment to ZA-, the right wavy line indicates the site of attachment to RL, and each b is independently selected from 2 to 72, 4 to 72, 6 to 72, 8 to 72, 10 to 72, 12 to 72, 2 to 24, 4 to 24, 6 to 24, or 8 to 24, 2 to 12, 4 to 12, 6 to 12, and 8 to 12. In some embodiments, subscript b is 2, 4, 8, 12, or 24. In some embodiments, subscript b is 2. In some embodiments, subscript b is 4. In some embodiments, subscript b is 8. In some embodiments, subscript b is 12.

[0498] In some embodiments, a linear PEG unit is connected to a parallel connector unit at one end and includes an end cap at the other end. In some embodiments, the PEG unit is connected to the parallel connector unit through a carbonyl group that forms an amide bond with the amino group of a lysine residue in the parallel connector unit (e.g., -CH2CH2(OCH2CH2) k -C(O)-B-, where k is an integer of 1 to 36, C 1~4 Alkyl and C 1~4 In some embodiments, the resolving agent S * is a linear PEG unit containing 4, 8, or 12 -CH2CH2O- subunits and a terminal methyl cap.

[0499] Exemplary linear PEG units for use in any of the embodiments provided herein are as follows:

[0500] [ka] In certain embodiments, the PEG units are

[0501] [ka] where the wavy line indicates the site of attachment to the parallel connector unit (B), and each n is independently selected from 4 to 72, 6 to 72, 8 to 72, 10 to 72, 12 to 72, 6 to 24, or 8 to 24. In some embodiments, the subscript b is about 4, about 8, about 12, or about 24.

[0502] As used herein, the terms "PEG2," "PEG4," "PEG8," and "PEG12" refer to specific embodiments of PEG units containing that number of PEG subunits (i.e., the number of subscripts "b"). For example, "PEG2" refers to an embodiment of a PEG unit containing two PEG subunits, "PEG4" refers to an embodiment of a PEG unit containing four PEG subunits, "PEG8" refers to an embodiment of a PEG unit containing eight PEG subunits, and "PEG12" refers to an embodiment of a PEG unit containing twelve PEG subunits.

[0503] As described herein, PEG units are selected so that they improve the clearance of the resulting ligand-drug conjugate, but do not significantly affect the ability of the conjugate to penetrate tumors. In embodiments, PEG units selected for use preferably have from 2 subunits to about 24 subunits, from 4 subunits to about 24 subunits, and more preferably from about 4 subunits to about 12 subunits.

[0504] In some embodiments of the present disclosure, the PEG unit is about 300 daltons to about 5 kilodaltons, about 300 daltons to about 4 kilodaltons, about 300 daltons to about 3 kilodaltons, about 300 daltons to about 2 kilodaltons, or about 300 daltons to about 1 kilodalton. In some such embodiments, the PEG unit has at least 6 subunits, or at least 8, 10, or 12 subunits. In some such embodiments, the PEG unit has at least 6 subunits, or at least 8, 10, or 12 subunits, but no more than 72 subunits, preferably no more than 36 subunits.

[0505] It will be appreciated that when referring to PEG subunits, and depending on the context, the number of subunits may be expressed as an average number, for example, when referring to a population of ligand-drug conjugates or drug-linker compounds and / or when using polydisperse PEGs.

[0506] 7. Parallel connector unit (B) In some embodiments, the Ligand-Drug Conjugates and Drug-Linker Compounds contain parallel connector units to provide points of attachment to the resolving agent (in the linker units, -B(S * In some embodiments, the PEG unit is attached to a parallel connector unit, e.g., a lysine, as shown below, where the wavy line and asterisk indicate a covalent linkage within the linker unit of the ligand-drug conjugate or drug-linker compound:

[0507] [ka]

[0508] In some embodiments, a parallel connector unit (B) and a resolving agent (S * )(Together, -B(S * )-)teeth,

[0509] [ka] (wherein m is a number ranging from 0 to 6, n is a number ranging from 2 to 24, and R PEG is a PEG capping unit, preferably H, -CH, or -CHCHCOH, and an asterisk ( * ) indicates covalent attachment to the corresponding connector unit A in formula Za, Za', Zb', or Zc', and the wavy line indicates covalent attachment to a releasable linker (RL). In some embodiments, the structure is attached to a connector unit A in formula Za or Za'. In some embodiments, n is 2, 4, 8, or 12. In examples such as those shown herein, the PEG groups shown are meant to be illustrative of various splitting agents containing PEG groups of different lengths, and other splitting agents directly attached or modified for attachment to parallel connector units.

[0510] 8. Spacer unit (Y) In some embodiments, the Ligand-Drug conjugates provided herein have a spacer (Y) between the releasable linker (RL) and the Drug unit. The spacer unit is a functional group that facilitates attachment of the RL to the Drug unit, or provides an additional structural component (e.g., a methylene carbamate unit or a self-immolative para-aminobenzyl (PAB) component) to further facilitate release of the Drug unit from the remainder of the conjugate.

[0511] In these embodiments to further facilitate release of the Drug unit as free drug, the Spacer unit Y has the following formula:

[0512] [ka] where EWG represents an electron-withdrawing group and the wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof. In some embodiments, EWG is represented by one of: -CN, -NO, -CX, -X, -C(=O)OR', -C(=O)N(R'), -C(=O)R', -C(=O)X, -S(=O)R', -S(=O)OR', -S(=O)NHR', -S(=O)N(R'), -P(=O)(OR'), -P(=O)(CH)NHR', -NO, -N(R') + wherein X is -F, -Br, -Cl, or -I, and R' is independently selected from the group consisting of hydrogen and C1-C6 alkyl.

[0513] In some embodiments, the spacer unit-drug unit group (-YT * -D) has the following formula:

[0514] [ka] where the adjacent wavy line is the point of covalent attachment to RL and T * is as defined above, and D' represents the remainder of the Drug unit, where T* and D' together form a Drug Unit of Formula (Ia) or any sub-formula thereof).

[0515] In some embodiments, the spacer unit has the formula:

[0516] [ka] where the wavy line adjacent to the nitrogen atom is the point of covalent attachment to R L as defined above, and the wavy line next to the benzyl carbon atom connects to the Drug unit. In some embodiments, the Drug unit is attached to the benzyl carbon atom through the quaternized tertiary amine (N) of D.

[0517] In yet other embodiments, the spacer unit has the formula:

[0518] [ka] where the wavy line adjacent to the nitrogen atom is the point of covalent attachment to R L as defined above, and the wavy line next to the -O-C(O)- group connects to the Drug unit. In some embodiments, the Drug unit is attached via a primary or secondary amine.

[0519] In some embodiments, provided herein are Drug-Linker compounds in Table 2, or salts thereof.

[0520] [Table 7-1]

[0521] [Table 7-2]

[0522] [Table 7-3]

[0523] [Table 7-4]

[0524] [Table 7-5]

[0525] Ligand-drug conjugate compounds In the context of Ligand-Drug Conjugate Compounds, the assembly is described by the building blocks described for Drug-Linker Compounds, except for the Stretcher unit Z and the Ligand unit L. The Stretcher unit Z is coordinated with the Ligand unit L in the Ligand-Drug Conjugate Compound, as described below. While some procedures for the preparation of Ligand-Drug Conjugate Compounds are described herein, the order of assembly and general conditions for preparing the compounds will be well understood by those skilled in the art.

[0526] In some embodiments, the Ligand-Drug conjugate compound comprises an auristatin compound of Formula (I) or any sub-formula thereof, a Linker unit (Q) comprising a releasable linker (RL) other than a glycoside (e.g., glucuronide) unit through which the Ligand unit is connected to the conjugated auristatin compound, and a Ligand unit (L). In addition to RL, the Linker unit can comprise a Stretcher unit (Z) connected to the Ligand unit, connecting RL (directly or indirectly) to the Ligand unit. In some embodiments, the Parallel Connector unit (B) comprises a Resolving Agent (S) as a side chain appendage. * In any one of these embodiments, the connector unit (A) is present when it is desired to add a longer distance between the stretcher unit and the RL.

[0527] In some embodiments, the Ligand-Drug Conjugate Compound comprises an auristatin compound of Formula (I) or any sub-formula thereof, and a Linker Unit (Q), wherein Q is attached directly to a Stretcher Unit (Z) or to an intervening component (i.e., A, S * and / or B(S * ) ...

[0528] In another group of embodiments, the Ligand-Drug conjugate compound comprises an auristatin of Formula (I) or any sub-formula thereof, a linker unit (Q), where Q is attached either directly to a Stretcher unit (Z) or to an intervening component (i.e., A, S) of the Linker unit of the Ligand-Drug conjugate compound. * and / or B(S * ))))))))))))))))))))))))))))))))))))))))))))))))))))))))

[0529] In some embodiments, the ligand-drug conjugate compound has the formula: L-(QD) p or a pharmaceutically acceptable salt thereof, L is a ligand unit, Q is (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS * -RL-, (iv) Z'-AS * -RL-Y-, (v) Z'-AB(S * )-RL-, (vi) Z'-AB(S * )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS*-W-, (ix) Z'-AB(S*)-W-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL-; is a linker unit selected from the group consisting of Z' is a Stretcher unit precursor; A is a bond or connector unit, B is the parallel connector unit, S * is a resolving agent, RL is a releasable linker, W is an amino acid unit, Y is a spacer unit, D is a Drug unit of Formula (I'):

[0530] [ka] (In the formula, X b is -NR 2 - # or -N + R 1 R 5 - # where # represents the point of attachment to Q, and X a teeth,

[0531] [ka] or X a and X b together with the carbon atoms to which they are attached,

[0532] [ka] (where the asterisk represents X a and X brepresents a carbon atom of formula (I) bearing a group, and # represents the point of attachment to Q), R 1 and R 5 are independently C1-C4 alkyl, X is H, OH, or -C(O)NR a R b , -S(O)2R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a and R 2 , R 3 , R 4 , R 10 , R a , and R b are each independently H or C1-C4 alkyl, R 6 is a C1-C4 alkyl optionally substituted with OH, R 7 is H, C1-C4 alkyl optionally substituted with OH, or 5- or 6-membered heteroaryl, E is phenyl or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1, p is an integer ranging from 1 to 12; When X is H, R 7 , R 8 , R 9 , and R 11 at least two of which contain an OH moiety) It has.

[0533] In some embodiments, the formula L-(QD) pwherein the Drug unit D is a ligand-drug conjugate compound of the formula (Iz * ):

[0534] [ka] (In the formula, X b is -NR 2 - # or -N + R 1 R 5 - # where # represents the point of attachment to Q, and X a teeth,

[0535] [ka] or X a and X b together with the carbon atoms to which they are attached,

[0536] [ka] (where the asterisk represents X a and X b represents a carbon atom of formula (I) bearing a group, and # represents the point of attachment to Q), R 1 and R 5 are independently C1-C4 alkyl, X is OH, -S(O)R a , -S(O)-R a , -S(O)NR a R b , -NHS(O)2R a , or -NHC(O)R a and R 2 , R 3 , R 4 , R 10 , R a , and R b are each independently H or C1-C4 alkyl, R 6 is a C1-C4 alkyl optionally substituted with OH, R 7 is H, C1-C4 alkyl optionally substituted with OH, or 5- or 6-membered heteroaryl, E is phenyl or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1, p is an integer ranging from 1 to 12 is provided herein.

[0537] In some embodiments, the ligand-drug conjugate compound has the formula (Ia * ) or (Ia ** ):

[0538] [ka] or a salt thereof (wherein L is a ligand unit, Q is a linker unit as described above, p is an integer ranging from 1 to 12; The remaining variables are as described for the Drug-Linker moiety of Formula (Ia') or Formula (Ia'') above. It has.

[0539] In some embodiments, the ligand-drug conjugate compound has the formula (Ib * ) or (Ib ** ):

[0540] [ka] or a salt thereof (wherein L is a ligand unit, Q is a linker unit as described above, p is an integer ranging from 1 to 12; The remaining variables are as described for the Drug-Linker moiety of Formula (Ib') or Formula (Ib'') above. It has.

[0541] In some embodiments, the ligand-drug conjugate compound has the formula (Ic * ) or (Ic ** ):

[0542] [ka] or a salt thereof (wherein L is a ligand unit, Q is a linker unit as described above, p is an integer ranging from 1 to 12; The remaining variables are as described for the Drug-Linker moiety of Formula (Ic') or Formula (Ic'') above. It has.

[0543] In some embodiments, the ligand-drug conjugate compound has the formula (Id * ) or (Id ** ):

[0544] [ka] or a salt thereof (wherein L is a ligand unit, Q is a linker unit as described above, p is an integer ranging from 1 to 12; The remaining variables are as described for the Drug-Linker moiety of Formula (Id') or Formula (Id'') above. It has.

[0545] In some embodiments, the ligand-drug conjugate compound has the formula (Ie * ) or (Ie ** ):

[0546] [ka] or a salt thereof (wherein L is a ligand unit, Q is a linker unit as described above, p is an integer ranging from 1 to 12; The remaining variables are as described for the Drug-Linker moiety of Formula (Ie') or Formula (Ie'') above. It has.

[0547] In some embodiments, the ligand-drug conjugate compound has the formula (If * ) or (If ** ):

[0548] [ka] or a salt thereof (wherein L is a ligand unit, Q is a linker unit as described above, p is an integer ranging from 1 to 12; The remaining variables are as described for the Drug-Linker moiety of Formula (If') or Formula (If'') above. It has.

[0549] In the context of ligand-drug conjugate compounds, the assembly is best described in terms of its constituent parts. While some procedures for the preparation of ligand-drug conjugate compounds are described herein, the order of assembly and general conditions for preparing the compounds will be well understood by those skilled in the art. The constituent parts of the described ligand-drug conjugate compounds are often designated A, B, S, *, R, W, Y, and D are the same as the building blocks for the Drug-Linker Compounds described above. It should be understood that embodiments are contemplated in which the Drug unit D of the Ligand-Drug Conjugates described herein conforms to the description of Formula (I') or any subformula thereof. Other building blocks are described below.

[0550] Stretcher unit Z An exemplary stretcher unit for such an embodiment includes:

[0551] [ka] (In the formula, R 17 The wavy line adjacent to represents the connection to a parallel connector unit (B) or connector unit (A) when B is absent, or to a splitting agent (S * ), the other wavy line indicates covalent attachment to the sulfur atom of the ligand unit, R 17 is -CH2CH2(OCH2CH2) k -, -C1~C 10 Alkylene, C1-C 10 Heteroalkylene-, -C3-C8 carbocyclo-, -O-(C1-C8 alkylene)-, -arylene-, -C1-C 10 Alkylene-arylene-, -arylene-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-, -C3-C8 heterocyclo-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-, -C1~C 10 Alkylene-C(=O)-, C1-C 10 Heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C 10Alkylene-arylene-C(=O)-, -arylene-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-(C3-C8 carbocyclo)-C(=O)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-C(=O)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-NH-, -C1~C 10 Heteroalkylene-NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C 10 Alkylene-arylene-NH-, -arylene-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-NH-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-S-, C1-C 10 Heteroalkylene-S-, -C3-C8 carbocyclo-S-, -O-(C1-C8 alkylene)-S-, -arylene-S-, -C1-C 10 Alkylene-arylene-S-, -arylene-C1-C 10 Alkylene-S-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-S-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-S- or -(C3-C8 heterocyclo)-C1-C 10 alkylene-S-, and the subscript k is an integer ranging from 1 to 36. This includes those having the following structure.

[0552] In some embodiments, R 17 The group may be a basic unit (BU), such as an aminoalkyl moiety, e.g., -(CH) x NH2, -(CH2) x NHR a , and -(CH2) x NR a 2 (wherein the subscript x is an integer from 1 to 4, and each R a independently, C 1~6 Alkyl and C 1~6 haloalkyl, or two R a The groups may be substituted with aryl groups, which, in combination with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, or piperidinyl group.

[0553] Exemplary Stretcher units are of the formula Za or Za-BU, where R 17 is -CH2CH2(OCH2CH2) k -, -C1~C 10 Alkylene -C(=O)-, -C1 to C 10 Heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C 10 Alkylene-arylene-C(=O)-, -arylene-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-(C3-C8 carbocyclo)-C(=O)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-C(=O)-, or -(C3-C8 heterocyclo)-C1-C 10 alkylene-C(═O), where the subscript k is an integer ranging from 1 to 36):

[0554] [ka] (wherein the wavy line adjacent to the carbonyl carbon atom represents the L P , B, A, or S * The other wavy line indicates the covalent bond of the succinimide ring carbon atom to the sulfur atom of the Ligand unit. In some embodiments, the basic amino functionality of the Basic Unit (BU) is protected by a protecting group during synthesis.

[0555] In some embodiments, the Stretcher units of formula Za and Za-BU are as follows:

[0556] [ka]

[0557] [ka] (wherein the wavy line adjacent to the carbonyl carbon atom represents B, A, or S in the above formula, depending on the presence or absence of A and / or B. * (The other wavy line indicates the covalent bond of the succinimide ring carbon atom to the sulfur atom of the Ligand unit).

[0558] It will be understood that the Ligand unit-substituted succinimides may exist in hydrolyzed forms, which are exemplified below for the hydrolysis of Za or Za-BU, where structures representing the positional isomers from that hydrolysis have the formulae Zb and Zc, or Zb-BU and Zc-BU.

[0559] Thus, in some embodiments, the stretcher unit (Z) is:

[0560] [ka] (In the formula, R 17and the wavy line adjacent to the carbonyl carbon atom bonded to the succinic acid-amide moiety are as defined for Za or Za-BU, depending on the presence or absence of A and / or B, and R 17 is -C1-C5 alkylene-, and in Zb-BU and Zc-BU, the alkylene is replaced by a basic unit (BU), and BU is -(CH2) x NH2, -(CH2) x NHR a , or -(CH2) x N(R a ) 2 (wherein the subscript x is an integer from 1 to 4, and each R a independently, C 1~6 Alkyl and C 1~6 or both R are selected from the group consisting of haloalkyl a The groups, together with the nitrogen to which they are attached, define an azetidinyl, pyrrolidinyl, or piperidinyl group.

[0561] In some embodiments, -ZA- comprises a moiety derived from a maleimido-alkanoic acid moiety or an mDPR moiety. See, e.g., WO 2013 / 173337. In one group of embodiments, ZA- is derived from a maleimido-propionyl moiety.

[0562] In some embodiments, the Stretcher unit (Z) has the formula Zb', Zc', (R / S)-Zb'-BU, (S)-Zb'-BU, (R / S)-Zc'-BU or (S)-Zc'-BU, as follows:

[0563] [ka] where the wavy line is as defined for Za or Za-BU. It contains a succinic acid-amide moiety represented by the structure:

[0564] In some embodiments, the stretcher unit (Z) is

[0565] [ka] which may be made from a maleimido-amino-propionyl (mDPR) analog (a 3-amino-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid derivative); or

[0566] [ka] It contains a succinic acid-amide moiety represented by the structure:

[0567] Exemplary Stretcher units (wherein Za, Zb, or Zc) linked to Connector units (A) comprising Za', Zb', or Zc' 17 - is -CH2- or -CH2CH2-, or includes Za'-BU, Zb'-BU or Zc'-BU, and -R of Za'-BU, Zb'-BU or Zc'-BU 17 (BU)- is -CH(CHNH)-) has the following structure:

[0568] [ka] where the wavy line is as defined for Za or Za-BU.

[0569] The other Stretcher units attached to the Ligand unit (L) and the Connector unit (A) have the above structures, wherein A in any one of the above -Za'-A-, -Za'(BU)-A-, -Za'-A-, -Za'(BU)-A-, -Za'(BU)-A-, -Zb'-A-, -Zb'(BU)-A-, -Zb'-A-, -Zb'(BU)-, -Zc'-A- and Zc'(BU)-A- structures is

[0570] [ka] where the subscript m ranges from 1 to 6, n ranges from 8 to 24, and R PEG is a PEG capping unit, preferably H, -CH, or -CHCHCOH, and an asterisk ( * ) indicates covalent attachment to a Stretcher unit whose structure corresponds to formula Za, Za', Zb', or Zc', and the wavy line indicates covalent attachment to a Releasable Linker (RL).

[0571] In another embodiment, the Stretcher unit is attached to the Ligand unit via a disulfide bond between a sulfur atom of the Ligand unit and a sulfur atom of the Stretcher unit. An exemplary Stretcher unit of this embodiment has the formula Zb:

[0572] [ka] (wherein the wavy line indicates the connection to a parallel connector unit (B) or connector unit (A) when B is absent, or to a resolving agent (S * ) indicates adhesion to R 17 is -CH2CH2(OCH2CH2) k -, -C1~C 10 Alkylene, C1-C 10 Heteroalkylene-, -C3-C8 carbocyclo-, -O-(C1-C8 alkylene)-, -arylene-, -C1-C 10 Alkylene-arylene-, -arylene-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-, -C3-C8 heterocyclo-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-, -C1~C 10 Alkylene-C(=O)-, C1-C 10Heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C 10 Alkylene-arylene-C(=O)-, -arylene-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-(C3-C8 carbocyclo)-C(=O)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-C(=O)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-NH-, C1-C 10 Heteroalkylene-NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C 10 Alkylene-arylene-NH-, -arylene-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-NH-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-S-, C1-C 10 Heteroalkylene-S-, -C3-C8 carbocyclo-S-, -O-(C1-C8 alkylene)-S-, -arylene-S-, -C1-C 10 Alkylene-arylene-S-, -arylene-C1-C 10 Alkylene-S-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-S-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C 10Alkylene-(C3-C8 heterocyclo)-S- or -(C3-C8 heterocyclo)-C1-C 10 alkylene-S-, where the subscript k is an integer ranging from 1 to 36).

[0573] In yet another embodiment, the reactive group of the Stretcher unit precursor contains a reactive moiety capable of forming a bond with a primary or secondary amino group of a Ligand unit. Examples of these reactive moieties include, but are not limited to, activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates. Exemplary Stretcher units of this embodiment have the formulas Zci, Zcii, and Zciii:

[0574] [ka] (wherein the wavy line indicates the connection to a parallel connector unit (B) or connector unit (A) when B is absent, or to a resolving agent (S * ) indicates adhesion to R 17 is -CH2CH2(OCH2CH2) k -, -C1~C 10 Alkylene, C1-C 10 Heteroalkylene-, -C3-C8 carbocyclo-, -O-(C1-C8 alkylene)-, -arylene-, -C1-C 10 Alkylene-arylene-, -arylene-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-, -C3-C8 heterocyclo-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-, -C1~C 10 Alkylene-C(=O)-, C1-C10 Heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C 10 Alkylene-arylene-C(=O)-, -arylene-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-(C3-C8 carbocyclo)-C(=O)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-C(=O)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-NH-, C1-C 10 Heteroalkylene-NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C 10 Alkylene-arylene-NH-, -arylene-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-NH-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-S-, C1-C 10 Heteroalkylene-S-, -C3-C8 carbocyclo-S-, -O-(C1-C8 alkylene)-S-, -arylene-S-, -C1-C 10 Alkylene-arylene-S-, -arylene-C1-C 10 Alkylene-S-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-S-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C 10Alkylene-(C3-C8 heterocyclo)-S- or -(C3-C8 heterocyclo)-C1-C 10 alkylene-S-, where the subscript k is an integer ranging from 1 to 36).

[0575] In yet other embodiments, the reactive group of the Stretcher unit precursor contains a reactive nucleophile that can react with an electrophile present on or introduced into the Ligand unit. For example, in some aspects, the carbohydrate moiety on the targeting Ligand is mildly oxidized using a reagent such as sodium periodate, and the resulting electrophilic functional group (-CHO) of the oxidized carbohydrate is condensed with a Stretcher unit precursor containing a reactive nucleophile, such as a hydrazide, oxime, primary or secondary amine, hydrazine, thiosemicarbazone, hydrazine carboxylate, or arylhydrazide, such as those described in Kaneko, T. et al. (1991) Bioconjugate Chem. 2:133-41. Exemplary Stretcher units of this embodiment are represented by the formulas Zdi, Zdii, and Zdiii:

[0576] [ka] is expressed in square brackets.

[0577] where the wavy line indicates the splitting agent (S * ) indicates adhesion to R 17 is -CH2CH2(OCH2CH2) k -, -C1~C 10 Alkylene, C1-C 10 Heteroalkylene-, -C3-C8 carbocyclo-, -O-(C1-C8 alkylene)-, -arylene-, -C1-C 10 Alkylene-arylene-, -arylene-C1-C 10 Alkylene-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 Alkylene-, -C3-C8 heterocyclo-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-, -C1~C 10 Alkylene-C(=O)-, C1-C 10 Heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C 10 Alkylene-arylene-C(=O)-, -arylene-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-(C3-C8 carbocyclo)-C(=O)-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-C(=O)-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene -C(=O)-, -C1 to C 10 Alkylene-NH-, C1-C 10 Heteroalkylene-NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C 10 Alkylene-arylene-NH-, -arylene-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-NH-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C 10 Alkylene-NH-, -C1~C 10 Alkylene-S-, C1-C 10 Heteroalkylene-S-, -C3-C8 carbocyclo-S-, -O-(C1-C8 alkylene)-S-, -arylene-S-, -C1-C 10Alkylene-arylene-S-, -arylene-C1-C 10 Alkylene-S-, -C1~C 10 Alkylene-(C3-C8 carbocyclo)-S-, -(C3-C8 carbocyclo)-C1-C 10 Alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-S- or -(C3-C8 heterocyclo)-C1-C 10 alkylene-S-, where the subscript k is an integer ranging from 1 to 36.

[0578] In some embodiments, provided herein are ligand-drug conjugate compounds of Table 3, or pharmaceutically acceptable salts thereof. Ligand-drug conjugate compounds corresponding to the compounds of Table 3 but having a succinic acid-amide moiety in place of the succinimide moiety are contemplated.

[0579] [Table 8-1]

[0580] [Table 8-2]

[0581] [Table 8-3]

[0582] [Table 8-4]

[0583] [Table 8-5]

[0584] Subscript p The subscript p represents the number of drug linker moieties on the Ligand unit of an individual Ligand-Drug conjugate compound and is an integer ranging from 1 to 16, 1 to 12, 1 to 10, or 1 to 8. In any of the embodiments herein, there are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 drug linker moieties conjugated to the Ligand unit of an individual Ligand-Drug conjugate compound.

[0585] In some embodiments, any of the structures and descriptions described herein represent a population of individual Ligand-Drug conjugate compounds (i.e., Ligand-Drug conjugate compositions) that are substantially identical except for the number of Drug-Linker moieties attached to each Ligand unit, such that the subscript p represents the average number of Drug-Linker moieties attached to the Ligand units of the Ligand-Drug conjugate compositions. In this group of embodiments, the subscript p is a number ranging from 1 to about 16, 1 to about 12, 1 to about 10, or 1 to about 8, 2 to about 16, 2 to about 12, 2 to about 10, or 2 to about 8. In some embodiments, p is about 2. In some embodiments, p is about 4. In some embodiments, p is about 8. In some embodiments, p is about 16. In some embodiments, p is 2. In some embodiments, p is 4. In some embodiments, p is 8. In some embodiments, p is 16. In some embodiments, the value of the subscript p refers to the average drug loading and the drug loading of the predominant ligand-drug conjugate compound in the composition.

[0586] In some embodiments, conjugation is via a reduced interchain disulfide and there are 1 to about 8 Drug-Linker Compound molecules conjugated to the targeting agent resulting in a Ligand unit. In some embodiments, conjugation is via an introduced cysteine residue and a reduced interchain disulfide and there are 1 to 10, or 1 to 12, or 1 to 14, or 1 to 16 Drug-Linker Compound moieties conjugated to the Ligand unit. In some embodiments, conjugation is via an introduced cysteine residue and there are 2 or 4 Drug-Linker Compound molecules conjugated to the Ligand unit.

[0587] Ligand unit L In some embodiments of the present invention, a Ligand unit is present. The Ligand unit (L-) is a targeting agent that specifically binds to the targeting moiety. In one group of embodiments, the Ligand unit specifically and selectively binds to a cellular component (cell-binding agent) or another target molecule of interest. The Ligand unit targets the Drug unit (such as one of Formula (I) or any subformula thereof) and acts to present the Ligand unit to a specific target cell population with which it interacts due to the presence of its targeting component or molecule, allowing for subsequent release of free drug within the target cell (i.e., intracellularly) or within the vicinity of the target cell (i.e., extracellularly). Ligand units L include, but are not limited to, proteins, polypeptides, and peptides. Suitable Ligand units include, for example, antibodies, e.g., full-length antibodies and antigen-binding fragments thereof, interferons, lymphokines, hormones, growth factors and colony-stimulating factors, vitamins, nutrient-transporting molecules (such as, but not limited to, transferrin), or any other cell-binding molecule or substance. In some embodiments, the Ligand unit (L) is derived from an antibody or non-antibody protein targeting agent.

[0588] In one group of embodiments, the Ligand unit is linked to Q (a Linker unit) which comprises a glucuronide-releasable linker. As noted above, in some aspects, other linking components provide additional space between the Drug unit compound and the Ligand unit (e.g., a Stretcher unit and optionally a Connector unit A), or provide properties to the composition to increase solubility (e.g., a Resolving Agent S * ) are present in the conjugates described herein to serve this purpose. In some of these embodiments, the Ligand unit is attached to Z of the Linker unit via a heteroatom on the Ligand unit. Heteroatoms that may be present on the Ligand unit for such attachment include sulfur (in one embodiment, from a sulfhydryl group on the targeting ligand), oxygen (in one embodiment, from a carbonyl or hydroxyl group on the targeting ligand), and optionally substituted nitrogen (in one embodiment, from a primary or secondary amine functional group on the targeting ligand, or in another embodiment, from an optionally substituted amide nitrogen). These heteroatoms may be present on the targeting ligand in the native state of the ligand, e.g., in a naturally occurring antibody, or may be introduced into the targeting ligand via chemical modification or biological manipulation.

[0589] In some embodiments, the Ligand unit is an antibody.

[0590] Useful polyclonal antibodies are heterogeneous populations of antibody molecules derived from the serum of immunized animals. Useful monoclonal antibodies are homogeneous populations of antibodies against a particular antigenic determinant (e.g., cancer or immune cell antigen, protein, peptide, carbohydrate, chemical, nucleic acid, or fragment thereof). Monoclonal antibodies (mAbs) against an antigen of interest can be prepared by using any technique known in the art that provides for the production of antibody molecules by continuous cell line culture.

[0591] Useful monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or chimeric human-mouse (or other species) monoclonal antibodies. Antibodies include full-length antibodies and antigen-binding fragments thereof. Human monoclonal antibodies can be produced by any of a number of techniques known in the art (e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. USA. 80:7308-7312; Kozbor et al., 1983, Immunology Today 4:72-79; and Olsson et al., 1982, Meth. Enzymol. 92:3-16).

[0592] In some embodiments, antibodies include functionally active fragments, derivatives, or analogs of antibodies that specifically bind to target cells (e.g., cancer cell antigens) or other antibodies that bind to cancer cells or matrix. In this context, "functionally active" means that the fragment, derivative, or analog is capable of specifically binding to a target cell. To determine which CDR sequences bind to an antigen, synthetic peptides containing the CDR sequences are typically used in binding assays with the antigen (e.g., Biacore assays) by any binding assay method known in the art (see, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed., National Institute of Health, Bethesda, Md; Kabat E et al., 1980, J. Immunology 125(3):961-969).

[0593] In addition, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, which typically contain both human and non-human portions, are useful antibodies, typically obtained using standard recombinant DNA techniques. Chimeric antibodies are molecules in which different portions are derived from different animal species, such as those with a variable region derived from a mouse monoclonal and a constant region derived from a human immunoglobulin. See, for example, U.S. Patent Nos. 4,816,567 and 4,816,397, which are incorporated herein by reference in their entirety. Humanized antibodies are antibody molecules derived from non-human species that have one or more CDRs derived from a non-human species and a framework region derived from a human immunoglobulin molecule. See, for example, U.S. Patent No. 5,585,089, which is incorporated herein by reference in its entirety.Such chimeric and humanized monoclonal antibodies are described, for example, in International Publication No. WO 87 / 02671; European Patent Publication No. 0184187; European Patent Publication No. 0171496; European Patent Publication No. 0173494; International Publication No. WO 86 / 01533; U.S. Patent No. 4,816,567; European Patent Publication No. 012023; Berter et al., 1988, Science 240:1041-1043; Liu et al., 1987, Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al., 1987, Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al., 1987, Cancer. Res. 47:999-1005; Wood et al., 1985, Nature 314:446-449; and Shaw et al., 1988, J. Natl. Cancer Inst. 80:1553-1559; Morrison, 1985, Science 229:1202-1207; Oi et al., 1986, BioTechniques 4:214; U.S. Patent No. 5,225,539; Jones et al., 1986, Nature 321:522-525; Verhoeyan et al., 1988, Science 239:1534; and Beidler et al., 1988, J. Immunol. 141:4053-4060, each of which is incorporated herein by reference in its entirety.

[0594] In some embodiments, the antibody is fully human. In some embodiments, the antibody is produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chain genes, but which can express human heavy and light chain genes.

[0595] In some embodiments, the antibody is an intact or fully reduced antibody. The term "fully reduced" is meant to refer to an antibody in which all four interchain disulfide linkages have been reduced to provide eight thiols that can be attached to a linker (L).

[0596] Attachment to the antibody can be via a thioether linkage from native and / or engineered cysteine residues, or from amino acid residues engineered to participate in a cycloaddition reaction (e.g., a click reaction) with a corresponding linker intermediate. See, e.g., Maerle et al., PLOS One 2019:14(1), e0209860. In some embodiments, the antibody is an intact or fully reduced antibody, or an antibody with an engineered cysteine group that has been modified with a functional group capable of participating in click chemistry or other cycloaddition reactions (e.g., a Diels-Alder reaction or other [3+2] or [4+2] cycloaddition) for attachment of other components of the ADCs described herein. See, for example, Agard et al., J. Am. Chem. Soc. Vol. 126, pp. 15046-15047 (2004); Laughlin et al., Science, Vol. 320, pp. 664-667 (2008); Beatty et al., ChemBioChem, Vol. 11, pp. 2092-2095 (2010); and Van Geel et al., Bioconjug. Chem. Vol. 26, pp. 2233-2242 (2015).

[0597] Antibodies that specifically bind to cancer or immune cell antigens are commercially available or produced by any method known to those skilled in the art, such as, for example, chemical synthesis or recombinant expression techniques. Nucleotide sequences encoding antibodies that specifically bind to cancer or immune cell antigens can be obtained, for example, from the GenBank database or a similar database, literature publications, or by routine cloning and sequencing.

[0598] In some embodiments, the antibody can be used for the treatment of cancer (e.g., an antibody approved by the FDA and / or EMA).Antibodies that specifically bind to cancer or immune cell antigens are commercially available or produced by any method known to those skilled in the art, such as, for example, recombinant expression techniques.The nucleotide sequence encoding an antibody that specifically binds to cancer or immune cell antigens can be obtained, for example, from the GenBank database or a similar database, literature publications, or by routine cloning and sequencing.

[0599] In some cases, the antibody has a mutation or post-translational modification that affects non-Fab-mediated uptake. Peripheral immune cells that are highly responsive to TLR7 / 8 agonists can promote a strong systemic response when activated through non-antigen-specific Fc-mediated uptake of TLR7 / 8 antibody-drug conjugates, which may be harmful or otherwise undesirable. In such cases, the antibody can have a mutation that reduces effector function, such as L234A / L235A, D265A / N297A, D270A, K322A, P329A, P329G, or a combination thereof, which reduces non-immune uptake (e.g., FcgR-mediated uptake).

[0600] In some embodiments, the antibody can be configured to bind to a surface antigen of a cell. The antibody, or a complex comprising the antibody, can be configured to be internalized into the cell upon binding to the surface antigen. For example, the antibody or an ADC comprising the antibody can be configured to undergo endocytosis upon binding to a surface antigen of a cell. In some embodiments, the antibody (or an ADC comprising the antibody) is configured to be internalized into a cancer cell. In some embodiments, the antibody (or an ADC comprising the antibody) is configured to be internalized into an immune cell. In some embodiments, the immune cell is a tumor-associated macrophage. In some embodiments, the surface antigen is a receptor or receptor complex (e.g., expressed on a lymphocyte). In some embodiments, the receptor or receptor complex comprises an immunoglobulin gene superfamily member, a TNF receptor superfamily member, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein or other immune cell-expressed surface receptor.

[0601] In some embodiments, the antibody is configured to specifically bind to a cancer cell antigen. In some embodiments, the antibody is configured to specifically bind to an immune cell antigen. In some embodiments, the immune cell antigen is a tumor-associated macrophage antigen. In some embodiments, the antibody is configured to specifically bind to EphA2. The antibody component in an ADC is an antibody in the residue form, and thus, it will be understood that "Ab" in the ADC structures described herein incorporates the structure of an antibody.

[0602] Non-limiting examples of antibodies that can be used to treat cancer and antibodies that specifically bind to tumor-associated antigens are disclosed in Franke, AE, Sievers, EL, and Scheinberg, DA, "Cell surface receptor-targeted therapy of acute myeloid leukemia: a review," Cancer Biother Radiopharm. 2000, 15, 459-76; Murray, JL, "Monoclonal antibody treatment of solid tumors: a coming of age," Semin Oncol. 2000, 27, 64-70; Breitling, F., and Dubel, S., Recombinant Antibodies, John Wiley and Sons, New York, 1998, each of which is incorporated herein by reference in its entirety.

[0603] Non-limiting examples of antigens that the antibodies of the present disclosure can target include ADAM12 (e.g., catalog number 14139-1-AP), ADAM9 (e.g., IMGC936), AFP (e.g., ThermoFisher catalog number PA5-25959), AGR2 (e.g., ThermoFisher catalog number PA5-34517), AKAP-4 (e.g., catalog number PA5-52230), ALK (e.g., DLX521), ALPP (e.g., catalog number MA5-15652), ALPPL2 (e.g., catalog number PA5-22336), AM HR2 (e.g., ThermoFisher catalog number PA5-13902), androgen receptor (e.g., ThermoFisher catalog number MA5-13426), ANTXR1 (e.g., catalog number MA1-91702), ANXA1 (e.g., catalog number 71-3400), ARTN (e.g., ThermoFisher catalog number PA5-47063), ASCT2 (e.g., inductamab), Axl (e.g., BA3011, tilvestamab), B7-DC (e.g., catalog number PA5-20344), B7-H3 (e.g., enobrituzumab, omburtamab, MGD009, MGC018, DS-7300), B7-H4 (e.g., catalog number 14-5949-82), B7-H6 (e.g., catalog number 12-6526-42), B7-H7, BAFF-R (e.g., catalog number 14-9117-82), BCMA, BCR-ABL, BMPR2, BORIS, C4.4a, CanAg, C5 complement (e.g., BCD-148, CAN106), CA-125, CA19-9 (e.g., AbGn-7, MVT-5873), CA9 (e.g., girentuximab), CALC R (see, e.g., International Publication No. WO2015077826), CAMPATH-1 (e.g., alemtuzumab, ALLO-647, ANT1034), carcinoembryonic antigen (e.g., arcitumomab, sergituzumab, amnaleukin, labetuzumab), CCNB1, CD112 (see, e.g., U.S. Publication No. 20100008928), CD115 (e.g., axatilimab, cabilalizumab, emactuzumab), CD123 (e.g., BAY-943, CSL360), CD137 (e.g., ADG106, CTX-471), CD138,CD142, CD166, CD147 (e.g., gavilimomab, metuzumab), CD155 (e.g., U.S. Publication No. 2018 / 0251548), CD19 (e.g., ALLO-501), CD20 (e.g., divodilimab, ibritumomab tiuxetan), CD24 (see, e.g., U.S. Patent No. 8,614,301), CD244 (e.g., R&D AF1039), CD247 (e.g., AFM15), CD27 (e.g., varlilumab), CD274 (e.g., adebulimab, atezolizumab, galibrimab), CD3 (e.g., otelixizumab, visilizumab), CD30 (e.g., iratumumab), CD33 (e.g., lintuzumab, BI 836858, AMG 673), CD288, CD352 (e.g., SGN-CD352A), CD37 (e.g., rilotomab, GEN3009), CD38 (e.g., felzalutamab, AMG 424), CD3D, CD3E (e.g., foralumab, teplizumab), CD3G, CD45 (e.g., apamistamab), CD47 (e.g., retaprimab, magrolimab), CD48 (e.g., SGN-CD48A), CD5 (e.g., MAT 304, zolimomab alitox), CD56, CD59, CD70 (e.g., cusatuzumab), CD74 (e.g., milatuzumab), CD79A (see, e.g., International Publication No. WO2020252110), CD79b, CD96, CD97, CD-262 (e.g., tigatuzumab), CDCP1 (e.g., RG7287), CDH17 (see, e.g., International Publication No. WO2018115231), CDH3 (e.g., PCA062), CDH6 (e.g., HKT288), CEACAM1, CEACA M5, CEACAM6, CLDN1 (e.g., INSERM anti-claudin-1), CLDN16, CLDN18.1 (e.g., zolbetuximab), CLDN18.2 (e.g., zolbetuximab), CLDN19, CLDN2 (see, e.g., International Publication No. WO2018123949), CLEC12A (e.g., tepositamab), CS1, CLPTM1L, CSPG4 (e.g., U.S. Pat. No. 10,822,427), CXCR4 (e.g., urocuprumab), CYP1B1, c-Met, DCLK1 (e.g.,See International Publication No. WO2018222675), DDR1, de2-7 EGFR (e.g., MAb 806), DLL-3, DPEP1, DPEP3, DPP4, DR4 (e.g., mapatuzumab), DSG2 (see, e.g., U.S. Pat. No. 10,836,823), EGF, EGFR, endosialin (e.g., ontuxizumab), ENPP1, EPCAM (e.g., adecatumumab), EPHA receptor, EPHA2, ERBB2 (e.g., trastuzumab), ERBB3, ERVMER34_1, ETV6-AML (e.g., catalog number PA5-81865), FAS, FasL, Fas-associated antigen 1, FBP, FGFR1 (e.g., RG7992), FGFR2 (e.g., apruzumab), FGFR3 (e.g., vofatamab), FGFR4 (e.g., MM-161), FLT3 (e.g., 4G8SDIEM), FN, FN1, FOLR1 (e.g., farletuzumab), FRa, FSHR, FucGM1 (e.g., BMS-986012), FZD5, FZD8, G250, GAGE, GCC, GD2 (e.g., dinutuximab), GD3 (e.g., mitsumomab), GITR (e.g., ragifilimab), GloboH, GM2 (e.g., B IW-8962), GM3 (e.g., racotumomab), gp100, GPA33 (e.g., KRN330), GPC3 (e.g., codrituzumab), gpNMB (e.g., glembatumumab), GPR87, GUCY2C (e.g., indasatumab), HAS3, HAVCR2, HLA-E, HLA-F, HLA-G (e.g., TTX-080), HPV E6 E7, hTERT, ICAM1, IDO1, IFNAR1 (e.g., faralimomab), IFNAR2, IL13Ra2, IL1RAP (e.g., nidanilimab), IL-21R (e.g., PF-05230900), IL-5R (e.g., benralizumab), ITGAV (e.g., abituzumab), ITGB6, ITGB8, KISS1R, L1CAM (e.g., JCAR023), LAG-3 (e.g., enselimab), LAMP1, LCK, legumain, LMP2, LY6G6D (e.g., PA5-23303), LY9 (e.g., PA5-95601), LYPD1 (e.g., ThermoFisher catalog number PA5-26749), MAD-CT-1, MAD-CT-2,MAGEA1 (e.g., catalog no. MA5-11338), MAGEA3 (e.g., ThermoFisher catalog no. 60054-1-IG), MAGEA4 (e.g., catalog no. MA5-26117), MAGEC2 (e.g., ThermoFisher catalog no. PA5-64010), MELTF (e.g., ThermoFisher catalog no. H00004241-M04A), MerTk (e.g., DS5MMER, catalog no. 12-5751-82), metalloproteinases, MFSD13A, MICA (e.g., 1E2C8, catalog no. 66384 -1-IG), MICB (e.g., catalog no. MA5-29422), Mincle (e.g., OTI2A8, catalog no. TA505101), MLANA (e.g., catalog no. MA5-15237), ML-IAP (e.g., 88C570, ThermoFisher catalog no. 40958), MSLN (e.g., 5B2, catalog no. MA5-11918), MUC1 (e.g., MH1(CT2), ThermoFisher catalog no. MA5-11202), MUC5AC (e.g., 45M1, catalog no. MA5-12178), MYCN (e.g., NCM-II 100, ThermoFisher Catalog No. MA1-170), NA17, NCAM1 (e.g., ThermoFisher Catalog No. MA5-11563), Nectin-4 (e.g., Enfortumab), NOX1 (e.g., Catalog No. PA5-103220), NT5E (e.g., 7G2, ThermoFisher Catalog No. 41-0200), NY-BR-1 (e.g., NY-BR-1 No. 2, Catalog No. MA5-12645), NY-ESO-1 (e.g., E978m, Catalog No. 35-6200), OX40 (e.g., ABM193), OY-TES1, p53, p53 mutants, PAP, PAX3 (e.g., GT1210, ThermoFisher Catalog No. MA5-31583), PAX5, PDGFR-B (e.g., linucumab), PDPN (e.g., ThermoFisher Catalog No. 14-5381-82), PLAVl, PMSA, polysialic acid (see, e.g., Watzlawik et al. J Nat Sci. 2015, 1(8):e141), PR1, PROM1 (e.g.,Catalog number 14-1331-82), PSA (e.g., ThermoFisher Catalog number PA1-38514; Daniels-Wells et al. BMC Cancer 2013, 13:195), PSCA (e.g., AGS-1C4D4), PSMA (e.g., BAY 2315497), PTK7 (e.g., cofetuzumab), PVRIG, Ras mutants (e.g., Shin et al. Sci Adv. 2020, 6(3):eaay2174), RET (e.g., WO2020210551), RGS5 (e.g., TF-TA503075), RhoC (e.g., ThermoFisher catalog PA5-77866), ROR1 (e.g., cirumutuzumab), ROR2 (e.g., BA3021), ROS1 (e.g., WO2019107671), sarcoma translocation breakpoints, SART3 (e.g., TF 18025-1-AP), sialyl-Thomsen-nouveau antigen (e.g., Eavarone et al. PLoS One. 2018, 13(7):e0201314), Siglecs 1 to 16 (e.g., Angata et al. Trends Pharmacol Sci. 2015, 36(10):645-660), SIRPa (e.g., catalog number 17-1729-42), SIRPg (e.g., PA5-104381), SIT1 (e.g., PA5-53825), SLAMF7 (e.g., elotuzumab), SLC10A2 (e.g., ThermoFisher catalog number PA5-18990), SLC12A2 (e.g., ThermoFisher catalog number 13884-1-AP), SLC17A2 (e.g., ThermoFisher catalog number PA5-106752), SLC38A1 (e.g., ThermoFisher catalog number 12039-1-AP), SLC39A5 (e.g., ThermoFisher catalog number MA5-27260), SLC39A6 (e.g., radilatuzumab), SLC44A4 (e.g., ASG-5ME), SLC6A15 (e.g., ThermoFisher catalog number PA5-52586), SLC6A6 (e.g., ThermoFisher catalog number PA5-53431), SLC7A11 (e.g., ThermoFisher catalog number PA1-16893), SLC7A5, sLe, SLITRK6 (e.g.,siltratumab), sperm protein 17 (e.g., BS-5754R), SSX2 (e.g., ThermoFisher catalog number MA5-24971), survivin (e.g., PA1-16836), TACSTD2 (e.g., PA5-47074), TAG-72 (e.g., MA1-25956), tenascin, TF (e.g., Tiso, Tn, TNFRSF12 (e.g., BAY-356), TRAIL (e.g., catalog number 12-9927-42), TRAIL1, TRP-2 (e.g., PA5-52736), ULBP1 / 2 / 3 / 4 / 5 / 6 (e.g., PA5-82302), uPAR (e.g., ATN-658), UPK1B (e.g., Examples include VEGF (e.g., GNR-011), VEGFR2 (e.g., gentuximab), VSIR (e.g., ThermoFisher catalog no. PA5-52493), WT1 (e.g., ThermoFisher catalog no. MA5-32215), and XAGE1 (e.g., ThermoFisher catalog no. PA5-46413).

[0604] Non-limiting examples of target antigens include Axl (e.g., BA3011, tilvesta- mab), B7-1 (e.g., galiximab), B7-2 (e.g., catalog no. 12-0862-82), B7-DC (e.g., catalog no. PA5-20344), B7-H3 (e.g., enobrituzumab, omburtamab, MGD009, MGC018, DS-7300), B7-H4 (e.g., catalog no. 14-5949-82), B7-H6 (e.g., catalog no. 12-6526-42), B7-H7, BAFF-R (e.g., catalog no. 14-9117- 82), BCMA, C5 complement (e.g., BCD-148, CAN106), CCR4 (e.g., AT008, mogamulizumab-kpkc), CCR8 (e.g., JTX-1811), CD112 (see, e.g., U.S. Publication No. 20100008928), CD115 (e.g., axatilimab, cabilalizumab, emactuzumab), CD123 (e.g., BAY-943, CSL360), CD137 (e.g., ADG106, CTX-471), CD155 (e.g., U.S. Publication No. 2018 / 0251548), CD163 (e.g., TBI 304H), CD19 (e.g., ALLO-501), CD2 (e.g., BTI-322, siplizumab), CD20 (e.g., divodilimab, ibritumomab), CD24 (see, e.g., U.S. Pat. No. 8,614,301), CD244 (e.g., R&D AF1039), CD247 (e.g., AFM15), CD25 (e.g., basiliximab), CD27 (e.g., varlilumab), CD274 (e.g., adeburelimab, atezolizumab, galibrimab), CD278 (e.g., ferazilimab, vopratelimab), CD28 (e.g., REGN5668), CD3 (e.g., otelixizumab, visilizumab), CD30 (e.g., iratumumab), CD30L (see, e.g., U.S. Pat. No. 9,926,373), CD32 (e.g., mAb 2B6), CD33 (e.g., lintuzumab, BI 836858, AMG 673), CD352 (e.g., SGN-CD352A), CD37 (e.g., rilotomab, GEN3009), CD38 (e.g., felzalutamab, AMG424), CD3D, CD3E (e.g., foralumab, teplizumab), CD3G, CD40 (e.g., dacetuzumab, lucatumumab), CD44 (e.g., RG7356), CD45 (e.g., apamistamab), CD47 (e.g., retaplimab, magrolimab), CD48 (e.g., SGN-CD48A), CD5 (e.g., MAT304, zolimomab alitox), CD51, CD70 (e.g., cusatuzumab), CD74 (e.g., milatuzumab), CD79A (see, e.g., International Publication No. WO2020252110), CD83 (e.g., CBT004), CD97, CD262 (e.g., tigatuzumab), CLEC12A (e.g., tepositamab), CTLA4 (e.g., ipilimumab), CXCR4 (e.g., urocuprumab), DCIR, DCSIGN (see, e.g., International Publication No. WO2018134389) , Dectin 1 (see, e.g., U.S. Pat. No. 9,045,542), Dectin 2 (e.g., ThermoFisher Catalog No. MA5-16250), DR4 (e.g., mapatuzumab), endosialin (e.g., ontuxizumab), FasL, FLT3 (e.g., 4G8SDIEM), GITR (e.g., ragifilimab), HAVCR2, HER2, HER3, HLA-DR, HLA-E, HLA-F, HLA-G (e.g., TTX-080), ICAM1, IDO1, IFNAR1 (e.g., FasL, FLT3 ... larimomab), IFNAR2, IGF-1R, IL1RAP (e.g., nidanilimab), IL-21R (e.g., PF-05230900), IL-5R (e.g., benralizumab), integrin αvβ6, LAG-3 (e.g., enselimab), LAMP1, LAYN, LCK, LILRB2, LILRB4, MerTk (e.g., DS5MMER, catalog number 12-5751-82), mesothelin, MICA (e.g., 1E2C8, catalog number 66384-1-IG), MICB (e.g., catalog number MA 5-29422), MICA, Mincle (e.g., OTI2A8, Catalog No. TA505101), MRC1 (e.g., ThermoFisher Catalog No. 12-2061-82), MUC1, Muc16, NcaPi2B, Nectin-4, OX40 (e.g., ABM193), PD-1 (e.g., balstilimab, budigalimab, geptanolimab), PD-L1, prolactin receptor, PTK7, PVRIG, ROR-1, sialyl-Thomsen-nouveau antigen (e.g., Eavarone et al. PLoS One, 2018, 13(7):e0201314), Siglecs1-16 (e.g., Angata et al. TrendsPharmacol Sci. 2015, 36(10):645-660), SIRPa (e.g., catalog number 17-1729-42), SIRPg (e.g., PA5-104381), SIT1 (e.g., PA5-53825), SLAMF7 (e.g., elotuzumab), SLTRK6, STEAP1, TIGIT (e.g., etigilimab), TLR2 / 4 / 1 (e.g., tomalalimab), Trem2 (e.g., PY314), TROP2, Tyrol, ULBP1 / 2 / 3 / 4 / 5 / 6 (e.g., PA5-82302), uPAR (e.g., ATN-658), VSIR (e.g., ThermoFisher catalog number PA5-52493), ZIP6 (anti-integrin αvβ6).

[0605] (i) Heavy and light chain variable regions In some cases, the antibody target is selected from the group consisting of ADAM9, ASCT2, Axl, B7-H3, B7H4, BCMA, C4.4a, CanAg, CD123, CD138, CD142, CD166, CD19, CD20, CD228, CD25, CD30, CD33, CD352, CD38, CD48, CD56, CD59, CD70, CD74, CD79b, CDCP1, CEACAM5, claudin-18.2, c-Met, gpNMB, CS1, DLL3, DPEP-3, E Selected from the group consisting of GFR, EpCAM, EphA2, FGFR2, FRa, GCC, gpA33, GPC3, integrin αvβ6, h2A2, H2G12 / STn, HER2, HER3, ZIP6, IGF-1R, IL1Rap, ITGav / CD51, mesothelin, MICA, MUC-1, Muc16, NaPi2B, nectin-4, PD-L1, prolactin receptor, PTK7, ROR-1, SLAMF7, SLTRK6, STEAP1, TIGIT, and TROP2.

[0606] In some cases, an antibody of the disclosure comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; or the first sequence is SEQ ID NO: 44 and the second sequence is SEQ ID NO: 45; or the first sequence is SEQ ID NO: 55 and the second sequence is SEQ ID NO: 56; or the first sequence is SEQ ID NO: 69 and the second sequence is SEQ ID NO: 70; or the first sequence is whether the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; whether the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; whether the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; whether the first sequence is SEQ ID NO: 113 and the second sequence is SEQ ID NO: 114; whether the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; whether the first sequence is SEQ ID NO: 129 and the second sequence is SEQ ID NO: 130; whether the first sequence is SEQ ID NO: 137 and the second sequence is SEQ ID NO: 138 or the first sequence is SEQ ID NO: 153 and the second sequence is SEQ ID NO: 154; or the first sequence is SEQ ID NO: 161 and the second sequence is SEQ ID NO: 162; or the first sequence is SEQ ID NO: 169 and the second sequence is SEQ ID NO: 170; or the first sequence is SEQ ID NO: 177 and the second sequence is SEQ ID NO: 178; or the first sequence is SEQ ID NO: 185 and the second sequence is SEQ ID NO: 186; or the first sequence is SEQ ID NO: 193 and the second sequence is SEQ ID NO: 194; or the first sequence is SEQ ID NO: 201. or the first sequence is SEQ ID NO:209 and the second sequence is SEQ ID NO:210; or the first sequence is SEQ ID NO:217 and the second sequence is SEQ ID NO:218; or the first sequence is SEQ ID NO:225 and the second sequence is SEQ ID NO:226; or the first sequence is SEQ ID NO:233 and the second sequence is SEQ ID NO:234; or the first sequence is SEQ ID NO:241 and the second sequence is SEQ ID NO:242; or the first sequence is SEQ ID NO:249 and the second sequence is SEQ ID NO:250;whether the first sequence is SEQ ID NO: 297 and the second sequence is SEQ ID NO: 298; whether the first sequence is SEQ ID NO: 307 and the second sequence is SEQ ID NO: 308; whether the first sequence is SEQ ID NO: 315 and the second sequence is SEQ ID NO: 316; whether the first sequence is SEQ ID NO: 323 and the second sequence is SEQ ID NO: 324; whether the first sequence is SEQ ID NO: 331 and the second sequence is SEQ ID NO: 332; whether the first sequence is SEQ ID NO: 339 and the second sequence is SEQ ID NO: 340; whether the first sequence is SEQ ID NO: 347 and the second sequence is SEQ ID NO: the first sequence is SEQ ID NO:355 and the second sequence is SEQ ID NO:356; the first sequence is SEQ ID NO:363 and the second sequence is SEQ ID NO:364; the first sequence is SEQ ID NO:371 and the second sequence is SEQ ID NO:372; the first sequence is SEQ ID NO:379 and the second sequence is SEQ ID NO:380; the first sequence is SEQ ID NO:387 and the second sequence is SEQ ID NO:388; the first sequence is SEQ ID NO:395 and the second sequence is SEQ ID NO:396; the first sequence is SEQ ID NO:403, whether the second sequence is SEQ ID NO:404; whether the first sequence is SEQ ID NO:411 and the second sequence is SEQ ID NO:412; whether the first sequence is SEQ ID NO:419 and the second sequence is SEQ ID NO:420; whether the first sequence is SEQ ID NO:427 and the second sequence is SEQ ID NO:428; whether the first sequence is SEQ ID NO:435 and the second sequence is SEQ ID NO:436; whether the first sequence is SEQ ID NO:443 and the second sequence is SEQ ID NO:444; whether the first sequence is SEQ ID NO:451 and the second sequence is SEQ ID NO:452; whether the first sequence is SEQ ID NO:459 and the second sequence is SEQ ID NO:460; whether the first sequence is SEQ ID NO:467 and the second sequence is SEQ ID NO:468; whether the first sequence is SEQ ID NO:475 and the second sequence is SEQ ID NO:476; whether the first sequence is SEQ ID NO:483 and the second sequence is SEQ ID NO:484; whether the first sequence is SEQ ID NO:491 and the second sequence is SEQ ID NO:492; whether the first sequence is SEQ ID NO:501 and the second sequence is SEQ ID NO:502; whether the first sequence is SEQ ID NO:509 and the second sequence is SEQ ID NO:510;whether the first sequence is SEQ ID NO:517 and the second sequence is SEQ ID NO:518; whether the first sequence is SEQ ID NO:525 and the second sequence is SEQ ID NO:526; whether the first sequence is SEQ ID NO:533 and the second sequence is SEQ ID NO:534; whether the first sequence is SEQ ID NO:541 and the second sequence is SEQ ID NO:542; whether the first sequence is SEQ ID NO:549 and the second sequence is SEQ ID NO:550; whether the first sequence is SEQ ID NO:557 and the second sequence is SEQ ID NO:558; whether the first sequence is SEQ ID NO:565 and the second sequence is SEQ ID NO:569 whether the first sequence is SEQ ID NO:574 and the second sequence is SEQ ID NO:574; whether the first sequence is SEQ ID NO:581 and the second sequence is SEQ ID NO:582; whether the first sequence is SEQ ID NO:589 and the second sequence is SEQ ID NO:590; whether the first sequence is SEQ ID NO:597 and the second sequence is SEQ ID NO:598; whether the first sequence is SEQ ID NO:605 and the second sequence is SEQ ID NO:606; whether the first sequence is SEQ ID NO:613 and the second sequence is SEQ ID NO:614; whether the first sequence is SEQ ID NO:621, whether the second sequence is SEQ ID NO:622; whether the first sequence is SEQ ID NO:629 and the second sequence is SEQ ID NO:630; whether the first sequence is SEQ ID NO:637 and the second sequence is SEQ ID NO:638; whether the first sequence is SEQ ID NO:645 and the second sequence is SEQ ID NO:646; whether the first sequence is SEQ ID NO:653 and the second sequence is SEQ ID NO:654; whether the first sequence is SEQ ID NO:661 and the second sequence is SEQ ID NO:662; whether the first sequence is SEQ ID NO:669 and the second sequence is SEQ ID NO:670; whether the first sequence is SEQ ID NO: 677 and the second sequence is SEQ ID NO: 678; whether the first sequence is SEQ ID NO: 685 and the second sequence is SEQ ID NO: 686; whether the first sequence is SEQ ID NO: 693 and the second sequence is SEQ ID NO: 694; whether the first sequence is SEQ ID NO: 701 and the second sequence is SEQ ID NO: 702; whether the first sequence is SEQ ID NO: 703 and the second sequence is SEQ ID NO: 704; whether the first sequence is SEQ ID NO: 711 and the second sequence is SEQ ID NO: 712; whether the first sequence is SEQ ID NO: 713 and the second sequence is SEQ ID NO: 714;whether the first sequence is SEQ ID NO:715 and the second sequence is SEQ ID NO:716; whether the first sequence is SEQ ID NO:731 and the second sequence is SEQ ID NO:732; whether the first sequence is SEQ ID NO:739 and the second sequence is SEQ ID NO:740; whether the first sequence is SEQ ID NO:747 and the second sequence is SEQ ID NO:748; whether the first sequence is SEQ ID NO:755 and the second sequence is SEQ ID NO:756; whether the first sequence is SEQ ID NO:765 and the second sequence is SEQ ID NO:766; whether the first sequence is SEQ ID NO:773 and the second sequence is SEQ ID NO: or the first sequence is SEQ ID NO: 774; or the first sequence is SEQ ID NO: 781 and the second sequence is SEQ ID NO: 782; or the first sequence is SEQ ID NO: 789 and the second sequence is SEQ ID NO: 790; or the first sequence is SEQ ID NO: 797 and the second sequence is SEQ ID NO: 798; or the first sequence is SEQ ID NO: 805 and the second sequence is SEQ ID NO: 806; or the first sequence is SEQ ID NO: 813 and the second sequence is SEQ ID NO: 814; or the first sequence is SEQ ID NO: 821 and the second sequence is SEQ ID NO: 822; or the first sequence is SEQ ID NO: 829, whether the second sequence is SEQ ID NO:830; whether the first sequence is SEQ ID NO:837 and the second sequence is SEQ ID NO:838; whether the first sequence is SEQ ID NO:845 and the second sequence is SEQ ID NO:846; whether the first sequence is SEQ ID NO:853 and the second sequence is SEQ ID NO:854; whether the first sequence is SEQ ID NO:861 and the second sequence is SEQ ID NO:862; whether the first sequence is SEQ ID NO:869 and the second sequence is SEQ ID NO:870; whether the first sequence is SEQ ID NO:877 and the second sequence is SEQ ID NO:878; whether the first sequence is SEQ ID NO: 885 and the second sequence is SEQ ID NO: 886; whether the first sequence is SEQ ID NO: 893 and the second sequence is SEQ ID NO: 894; whether the first sequence is SEQ ID NO: 900 and the second sequence is SEQ ID NO: 901; whether the first sequence is SEQ ID NO: 909 and the second sequence is SEQ ID NO: 910; whether the first sequence is SEQ ID NO: 917 and the second sequence is SEQ ID NO: 918; whether the first sequence is SEQ ID NO: 925 and the second sequence is SEQ ID NO: 926; whether the first sequence is SEQ ID NO: 933 and the second sequence is SEQ ID NO: 934;whether the first sequence is SEQ ID NO:941 and the second sequence is SEQ ID NO:942; whether the first sequence is SEQ ID NO:943 and the second sequence is SEQ ID NO:944; whether the first sequence is SEQ ID NO:951 and the second sequence is SEQ ID NO:952; whether the first sequence is SEQ ID NO:959 and the second sequence is SEQ ID NO:960; whether the first sequence is SEQ ID NO:967 and the second sequence is SEQ ID NO:968; whether the first sequence is SEQ ID NO:975 and the second sequence is SEQ ID NO:976; whether the first sequence is SEQ ID NO:983 and the second sequence is SEQ ID NO:984; whether the first sequence is SEQ ID NO:991 and the second sequence is SEQ ID NO:992 the first sequence is SEQ ID NO:993 and the second sequence is SEQ ID NO:994; the first sequence is SEQ ID NO:995 and the second sequence is SEQ ID NO:996; the first sequence is SEQ ID NO:1003 and the second sequence is SEQ ID NO:1004; the first sequence is SEQ ID NO:1011 and the second sequence is SEQ ID NO:1012; the first sequence is SEQ ID NO:1019 and the second sequence is SEQ ID NO:1020; the first sequence is SEQ ID NO:1027 and the second sequence is SEQ ID NO:1028; the first sequence is SEQ ID NO:1035 and 1036; or the first sequence is SEQ ID NO:1043 and the second sequence is SEQ ID NO:1044.

[0607] In some cases, the antibody of the present disclosure targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT. For example, in some cases, the antibody comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is whether the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO:114; whether the first sequence is SEQ ID NO:121 and the second sequence is SEQ ID NO:122; whether the first sequence is SEQ ID NO:129 and the second sequence is SEQ ID NO:130; whether the first sequence is SEQ ID NO:137 and the second sequence is SEQ ID NO:138; whether the first sequence is SEQ ID NO:153 and the second sequence is SEQ ID NO:154; whether the first sequence is SEQ ID NO:161 and the second sequence is SEQ ID NO: 162; the first sequence is SEQ ID NO:169 and the second sequence is SEQ ID NO:170; the first sequence is SEQ ID NO:177 and the second sequence is SEQ ID NO:178; the first sequence is SEQ ID NO:185 and the second sequence is SEQ ID NO:186; the first sequence is SEQ ID NO:193 and the second sequence is SEQ ID NO:194; the first sequence is SEQ ID NO:201 and the second sequence is SEQ ID NO:202; the first sequence is SEQ ID NO:209 and the second sequence is SEQ ID NO:210. whether the first sequence is SEQ ID NO:217 and the second sequence is SEQ ID NO:218; whether the first sequence is SEQ ID NO:225 and the second sequence is SEQ ID NO:226; whether the first sequence is SEQ ID NO:233 and the second sequence is SEQ ID NO:234; whether the first sequence is SEQ ID NO:241 and the second sequence is SEQ ID NO:242; whether the first sequence is SEQ ID NO:249 and the second sequence is SEQ ID NO:250; whether the first sequence is SEQ ID NO:629 and the second sequence is SEQ ID NO:630;whether the first sequence is SEQ ID NO:637 and the second sequence is SEQ ID NO:638; whether the first sequence is SEQ ID NO:645 and the second sequence is SEQ ID NO:646; whether the first sequence is SEQ ID NO:653 and the second sequence is SEQ ID NO:654; whether the first sequence is SEQ ID NO:661 and the second sequence is SEQ ID NO:662; whether the first sequence is SEQ ID NO:669 and the second sequence is SEQ ID NO:670; whether the first sequence is SEQ ID NO:677 and the second sequence is SEQ ID NO:678; whether the first sequence is SEQ ID NO:685 and the second sequence is SEQ ID NO:686; the first sequence is SEQ ID NO: 693 and the second sequence is SEQ ID NO: 694; the first sequence is SEQ ID NO: 701 and the second sequence is SEQ ID NO: 702; the first sequence is SEQ ID NO: 703 and the second sequence is SEQ ID NO: 704; the first sequence is SEQ ID NO: 711 and the second sequence is SEQ ID NO: 712; the first sequence is SEQ ID NO: 713 and the second sequence is SEQ ID NO: 714; the first sequence is SEQ ID NO: 715 and the second sequence is SEQ ID NO: 716; or the first sequence is SEQ ID NO: 1027 and the second sequence is SEQ ID NO: 1028.

[0608] In some cases, an antibody of the disclosure comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 109. whether the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO:114; whether the first sequence is SEQ ID NO:121 and the second sequence is SEQ ID NO:122; whether the first sequence is SEQ ID NO:129 and the second sequence is SEQ ID NO:130; whether the first sequence is SEQ ID NO:137 and the second sequence is SEQ ID NO:138; whether the first sequence is SEQ ID NO:153 and the second sequence is SEQ ID NO:154; whether the first sequence is SEQ ID NO:161 and the second sequence is SEQ ID NO:16 2; the first sequence is SEQ ID NO:169 and the second sequence is SEQ ID NO:170; the first sequence is SEQ ID NO:177 and the second sequence is SEQ ID NO:178; the first sequence is SEQ ID NO:185 and the second sequence is SEQ ID NO:186; the first sequence is SEQ ID NO:193 and the second sequence is SEQ ID NO:194; the first sequence is SEQ ID NO:201 and the second sequence is SEQ ID NO:202; the first sequence is SEQ ID NO:209 and the second sequence is SEQ ID NO:210 the first sequence is SEQ ID NO:217 and the second sequence is SEQ ID NO:218; the first sequence is SEQ ID NO:225 and the second sequence is SEQ ID NO:226; the first sequence is SEQ ID NO:233 and the second sequence is SEQ ID NO:234; the first sequence is SEQ ID NO:241 and the second sequence is SEQ ID NO:242; the first sequence is SEQ ID NO:249 and the second sequence is SEQ ID NO:250; or the first sequence is SEQ ID NO:1027 and the second sequence is SEQ ID NO:1028. In some cases, the first sequence is SEQ ID NO:19 and the second sequence is SEQ ID NO:20.

[0609] In some cases, the heavy chain variable region has at least 85% sequence identity to the first sequence, and the light chain variable region has at least 85% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 90% sequence identity to the first sequence, and the light chain variable region has at least 90% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 95% sequence identity to the first sequence, and the light chain variable region has at least 95% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 98% sequence identity to the first sequence, and the light chain variable region has at least 98% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 99% sequence identity to the first sequence, and the light chain variable region has at least 99% sequence identity to the second sequence. In some cases, the heavy chain variable region comprises a first sequence and the light chain variable region comprises a second sequence.

[0610] (ii) Heavy and Light Chains In some cases, an antibody of the disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO:1 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:2 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:3 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:4 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:6 and the second sequence is SEQ ID NO:10. or the first sequence is SEQ ID NO:7 and the second sequence is SEQ ID NO:10; or the first sequence is SEQ ID NO:8 and the second sequence is SEQ ID NO:10; or the first sequence is SEQ ID NO:9 and the second sequence is SEQ ID NO:10; or the first sequence is SEQ ID NO:46 and the second sequence is SEQ ID NO:48; or the first sequence is SEQ ID NO:47 and the second sequence is SEQ ID NO:48; or the first sequence is SEQ ID NO:57 and the second sequence is SEQ ID NO:59; or the first sequence is SEQ ID NO:58 and the second sequence is SEQ ID NO:59; whether one sequence is SEQ ID NO:60 and the second sequence is SEQ ID NO:62; whether the first sequence is SEQ ID NO:61 and the second sequence is SEQ ID NO:62; whether the first sequence is SEQ ID NO:71 and the second sequence is SEQ ID NO:73; whether the first sequence is SEQ ID NO:72 and the second sequence is SEQ ID NO:73; whether the first sequence is SEQ ID NO:74 and the second sequence is SEQ ID NO:76; whether the first sequence is SEQ ID NO:75 and the second sequence is SEQ ID NO:76; whether the first sequence is SEQ ID NO:85 and the second sequence is SEQ ID NO:87; whether the sequence is SEQ ID NO:86 and the second sequence is SEQ ID NO:87; whether the first sequence is SEQ ID NO:88 and the second sequence is SEQ ID NO:90; whether the first sequence is SEQ ID NO:89 and the second sequence is SEQ ID NO:90; whether the first sequence is SEQ ID NO:251 and the second sequence is SEQ ID NO:252; whether the first sequence is SEQ ID NO:253 and the second sequence is SEQ ID NO:254; whether the first sequence is SEQ ID NO:255 and the second sequence is SEQ ID NO:256; whether the first sequence is SEQ ID NO:257 and the second sequence is SEQ ID NO:258;whether the first sequence is SEQ ID NO:259 and the second sequence is SEQ ID NO:260; whether the first sequence is SEQ ID NO:261 and the second sequence is SEQ ID NO:262; whether the first sequence is SEQ ID NO:263 and the second sequence is SEQ ID NO:264; whether the first sequence is SEQ ID NO:265 and the second sequence is SEQ ID NO:266; whether the first sequence is SEQ ID NO:267 and the second sequence is SEQ ID NO:268; whether the first sequence is SEQ ID NO:269 and the second sequence is SEQ ID NO: or the first sequence is SEQ ID NO:270; or the first sequence is SEQ ID NO:271 and the second sequence is SEQ ID NO:272; or the first sequence is SEQ ID NO:273 and the second sequence is SEQ ID NO:274; or the first sequence is SEQ ID NO:275 and the second sequence is SEQ ID NO:276; or the first sequence is SEQ ID NO:277 and the second sequence is SEQ ID NO:278; or the first sequence is SEQ ID NO:279 and the second sequence is SEQ ID NO:280; or the first sequence is SEQ ID NO:281 and the second sequence is SEQ ID NO:282. whether the first sequence is SEQ ID NO:283 and the second sequence is SEQ ID NO:284; whether the first sequence is SEQ ID NO:285 and the second sequence is SEQ ID NO:286; whether the first sequence is SEQ ID NO:287 and the second sequence is SEQ ID NO:288; whether the first sequence is SEQ ID NO:289 and the second sequence is SEQ ID NO:290; whether the first sequence is SEQ ID NO:299 and the second sequence is SEQ ID NO:300; whether the first sequence is SEQ ID NO: the first sequence is SEQ ID NO: 493 and the second sequence is SEQ ID NO: 494; the first sequence is SEQ ID NO: 717 and the second sequence is SEQ ID NO: 718; the first sequence is SEQ ID NO: 719 and the second sequence is SEQ ID NO: 720; the first sequence is SEQ ID NO: 721 and the second sequence is SEQ ID NO: 722; the first sequence is SEQ ID NO: 723 and the second sequence is SEQ ID NO: 724; or the first sequence is SEQ ID NO: 757 and the second sequence is SEQ ID NO: 758.

[0611] In some cases, an antibody of the disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 7. whether the first sequence is SEQ ID NO:7 and the second sequence is SEQ ID NO:10; whether the first sequence is SEQ ID NO:8 and the second sequence is SEQ ID NO:10; whether the first sequence is SEQ ID NO:9 and the second sequence is SEQ ID NO:10; whether the first sequence is SEQ ID NO:85 and the second sequence is SEQ ID NO:87; whether the first sequence is SEQ ID NO:86 and the second sequence is SEQ ID NO:87; whether the first sequence is SEQ ID NO:88 and the second sequence is SEQ ID NO:90; whether the first sequence is SEQ ID NO:89 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO:251 and the second sequence is SEQ ID NO:252; the first sequence is SEQ ID NO:253 and the second sequence is SEQ ID NO:254; the first sequence is SEQ ID NO:255 and the second sequence is SEQ ID NO:256; the first sequence is SEQ ID NO:257 and the second sequence is SEQ ID NO:258; the first sequence is SEQ ID NO:259 and the second sequence is SEQ ID NO:260; the first sequence is SEQ ID NO:261 and the second sequence is SEQ ID NO:262; the first sequence is SEQ ID NO:263 or the first sequence is SEQ ID NO:265 and the second sequence is SEQ ID NO:266; or the first sequence is SEQ ID NO:267 and the second sequence is SEQ ID NO:268; or the first sequence is SEQ ID NO:269 and the second sequence is SEQ ID NO:270; or the first sequence is SEQ ID NO:271 and the second sequence is SEQ ID NO:272; or the first sequence is SEQ ID NO:273 and the second sequence is SEQ ID NO:274; or the first sequence is SEQ ID NO:275 and the second sequence is SEQ ID NO:276;The first sequence is SEQ ID NO:277 and the second sequence is SEQ ID NO:278; the first sequence is SEQ ID NO:279 and the second sequence is SEQ ID NO:280; the first sequence is SEQ ID NO:281 and the second sequence is SEQ ID NO:282; the first sequence is SEQ ID NO:283 and the second sequence is SEQ ID NO:284; the first sequence is SEQ ID NO:285 and the second sequence is SEQ ID NO:286; the first sequence is SEQ ID NO:287 and the second sequence is SEQ ID NO:288. the first sequence is SEQ ID NO: 289 and the second sequence is SEQ ID NO: 290; the first sequence is SEQ ID NO: 717 and the second sequence is SEQ ID NO: 718; the first sequence is SEQ ID NO: 719 and the second sequence is SEQ ID NO: 720; the first sequence is SEQ ID NO: 721 and the second sequence is SEQ ID NO: 722; or the first sequence is SEQ ID NO: 723 and the second sequence is SEQ ID NO: 724.

[0612] In some cases, an antibody of the disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 7. whether the first sequence is SEQ ID NO:7 and the second sequence is SEQ ID NO:10; whether the first sequence is SEQ ID NO:8 and the second sequence is SEQ ID NO:10; whether the first sequence is SEQ ID NO:9 and the second sequence is SEQ ID NO:10; whether the first sequence is SEQ ID NO:85 and the second sequence is SEQ ID NO:87; whether the first sequence is SEQ ID NO:86 and the second sequence is SEQ ID NO:87; whether the first sequence is SEQ ID NO:88 and the second sequence is SEQ ID NO:90; whether the first sequence is SEQ ID NO:89 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO:251 and the second sequence is SEQ ID NO:252; the first sequence is SEQ ID NO:253 and the second sequence is SEQ ID NO:254; the first sequence is SEQ ID NO:255 and the second sequence is SEQ ID NO:256; the first sequence is SEQ ID NO:257 and the second sequence is SEQ ID NO:258; the first sequence is SEQ ID NO:259 and the second sequence is SEQ ID NO:260; the first sequence is SEQ ID NO:261 and the second sequence is SEQ ID NO:262; the first sequence is SEQ ID NO:263 or the first sequence is SEQ ID NO:265 and the second sequence is SEQ ID NO:266; or the first sequence is SEQ ID NO:267 and the second sequence is SEQ ID NO:268; or the first sequence is SEQ ID NO:269 and the second sequence is SEQ ID NO:270; or the first sequence is SEQ ID NO:271 and the second sequence is SEQ ID NO:272; or the first sequence is SEQ ID NO:273 and the second sequence is SEQ ID NO:274; or the first sequence is SEQ ID NO:275 and the second sequence is SEQ ID NO:276;the first sequence is SEQ ID NO:277 and the second sequence is SEQ ID NO:278; the first sequence is SEQ ID NO:279 and the second sequence is SEQ ID NO:280; the first sequence is SEQ ID NO:281 and the second sequence is SEQ ID NO:282; the first sequence is SEQ ID NO:283 and the second sequence is SEQ ID NO:284; the first sequence is SEQ ID NO:285 and the second sequence is SEQ ID NO:286; the first sequence is SEQ ID NO:287 and the second sequence is SEQ ID NO:288; or the first sequence is SEQ ID NO:289 and the second sequence is SEQ ID NO:290.

[0613] In some cases, an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO:1 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:2 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:3 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:4 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:6 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:7 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:8 and the second sequence is SEQ ID NO:10; or the first sequence is SEQ ID NO:9 and the second sequence is SEQ ID NO:10.

[0614] In some cases, an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, where the first sequence is SEQ ID NO:3 or SEQ ID NO:4, and the second sequence is SEQ ID NO:5.

[0615] In some cases, the heavy chain has at least 85% sequence identity to the first sequence, and the light chain has at least 85% sequence identity to the second sequence. In some cases, the heavy chain has at least 90% sequence identity to the first sequence, and the light chain has at least 90% sequence identity to the second sequence. In some cases, the heavy chain has at least 95% sequence identity to the first sequence, and the light chain has at least 95% sequence identity to the second sequence. In some cases, the heavy chain has at least 98% sequence identity to the first sequence, and the light chain has at least 98% sequence identity to the second sequence. In some cases, the heavy chain has at least 99% sequence identity to the first sequence, and the light chain has at least 99% sequence identity to the second sequence. In some cases, the heavy chain comprises the first sequence, and the light chain comprises the second sequence.

[0616] (iii) Complementarity-determining region In some cases, the antibodies of the disclosure have CDRs set forth in SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively (i.e., CDR-H1 has at least 80% sequence identity to SEQ ID NO: 13, CDR-H2 has at least 80% sequence identity to SEQ ID NO: 14, CDR-H3 has at least 80% sequence identity to SEQ ID NO: 15, CDR-L1 has at least 80% sequence identity to SEQ ID NO: 16, CDR-L2 has at least 80% sequence identity to SEQ ID NO: 17, and CDR-L3 has at least 80% sequence identity to SEQ ID NO: 18). SEQ ID NOs: 21, 22, 23, 24, 25, and 26, respectively; SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively; SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively; SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively; SEQ ID NOs: 77, 78, 79, 80, 81, and 82, respectively; SEQ ID NOs: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NOs: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NOs: SEQ ID NOs: 107, 108, 109, 110, 111, and 112; SEQ ID NOs: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NOs: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NOs: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NOs: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NOs: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NOs: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NOs: 163, 164, 165, 166, 167, and 168, respectively; SEQ ID NOs: 171, 172, 173, 174, 175, and 176, respectively; SEQ ID NOs: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NOs: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NOs: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NOs: 203, 204, 205, 206, 207, and 208, respectively; SEQ ID NOs: 211, 212, 213, 214, 215, and 216, respectively;SEQ ID NOs: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NOs: 227, 228, 229, 230, 231, and 232, respectively; SEQ ID NOs: 235, 236, 237, 238, 239, and 240, respectively; SEQ ID NOs: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively; SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively; and SEQ ID NOs: 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, and 240, respectively. SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively; SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively; SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively; SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively; SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively; SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively; SEQ ID NOs: 365, 366, 367, 368, 369, 370, 371, 372, 373, and 374, respectively. SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively; SEQ ID NOs: 381, 382, 383, 384, 385, and 386, respectively; SEQ ID NOs: 389, 390, 391, 392, 393, and 394, respectively; SEQ ID NOs: 397, 398, 399, 400, 401, and 402, respectively; SEQ ID NOs: 405, 406, 407, 408, 409, and 410, respectively; SEQ ID NOs: 413, 414, 415, 416, 417, and 418, respectively; SEQ ID NOs: SEQ ID NOs: 421, 422, 423, 424, 425, and 426; SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively; SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively; SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively; SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively; SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively; SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively;SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively; SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively; SEQ ID NOs: 495, 496, 497, 498, 499, and 500, respectively; SEQ ID NOs: 503, 504, 505, 506, 507, and 508, respectively; SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively; SEQ ID NOs: 519, 520, 521, 522, 523, and 524, respectively; and SEQ ID NOs: 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively; SEQ ID NOs: 543, 544, 545, 546, 547, and 548, respectively; SEQ ID NOs: 551, 552, 553, 554, 555, and 556, respectively; SEQ ID NOs: 559, 560, 561, 562, 563, and 564, respectively; SEQ ID NOs: 567, 568, 569, 570, 571, and 572, respectively; SEQ ID NOs: 575, 576, 577, 578, 579, and 580, respectively; SEQ ID NOs: 583, 584, 585, 586, 587, 588, 589, 590, 591, and 592, respectively. SEQ ID NOs: 591, 592, 593...

Claims

1. Compounds of formula (I): 【Chemical 1】 or a salt thereof (wherein X ｂ is -NR １ R ２ and X ａ teeth, 【Chemistry 2】 or X ａ and X ｂ together with the carbon atoms to which they are attached, 【Chemistry 3】 (wherein the asterisk represents X ａ and X ｂ represents a carbon atom of formula (I) bearing a group, R １ , R ２ , R ３ , R ４ , R ａ , R ｂ , R ５ , and R １０ are each independently H or C １ ~C ４ is alkyl, X is H, OH, or —C(O)NR ａ R ｂ , -S(O) ２ R ａ , -S(O)-R ａ , -S(O) ２ NR ａ R ｂ , -NHS(O) ２ R ａ or -NHC(O)R ａ and R ６ is C optionally substituted with OH １ ~C ４ is alkyl, R ７ is C optionally substituted with H, one or two OH moieties １ ~C ４ alkyl, or 5- to 6-membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R ８ , R ９ , and R １１ are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1; When X is H, R ７ , R ８ , R ９ , and R １１ at least two of which contain an OH moiety).

2. Compound of formula (II): 【Chemistry 4】 or a salt thereof (wherein R １ , R ３ , and R ４ are independently H or C １ ~C ４ is alkyl, R ６ is C optionally substituted with OH １ ~C ４ is alkyl, R ７ is C optionally substituted with H, one or two OH moieties １ ~C ４ alkyl, or 5- to 6-membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R ８ , R ９ , and R １１ are each independently H or OH, n is 0, 1, or 2; and q is 0 or 1.

3. 3. The compound of claim 1 or 2, wherein q is 0.

4. 3. The compound of claim 1 or 2, wherein q is 1.

5. 2. The compound of claim 1, or a salt thereof, wherein X is OH.

6. X is —C(O)NR ａ R ｂ , -S(O) ２ R ａ , -S(O)-R ａ , -S(O) ２ NR ａ R ｂ , -NHS(O) ２ R ａ or -NHC(O)R ａ 2. The compound of claim 1, wherein:

7. X ｂ But, -NR １ R ２ and X ａ but, 【Chemistry 5】 7. The compound according to claim 1, or any one of claims 3 to 6, wherein:

8. R ３ The compound according to any one of claims 1 to 7, or a salt thereof, wherein is H.

9. R ４ The compound according to any one of claims 1 to 8, or a salt thereof, wherein is H.

10. 10. The compound according to any one of claims 1 to 9, or a salt thereof, wherein n is 0 or 1.

11. X ａ and X ｂ together with the carbon atoms to which they are attached, 【Chemistry 6】 (wherein the asterisk represents X ａ and X ｂ 7. A compound according to claim 1 or any one of claims 3 to 6, or a salt thereof, which forms a group of formula (I) having a carbon atom of formula (I) bearing a group.

12. 12. The compound of any one of claims 1 or 3 to 11, wherein m is 1 or 2.

13. R １ 11. The compound according to claim 1, wherein is H, or a salt thereof.

14. R １ But C １ ~C ４ 11. The compound of claim 1, or a salt thereof, wherein:

15. R １ 15. The compound of any one of claims 1 to 10 or 14, or a salt thereof, wherein is methyl.

16. R ２ 16. The compound of any one of claims 1, 3 to 10, or 13 to 15, or a salt thereof, wherein is methyl.

17. R １０ 17. The compound of claim 1, wherein is H, or a salt thereof.

18. R １０ 17. The compound according to any one of claims 1 to 16, or a salt thereof, wherein is methyl.

19. R ６ But unsubstituted C １ ~C ４ 19. The compound of any one of claims 1 to 18, or a salt thereof, wherein:

20. R ６ 20. The compound of claim 1, or a salt thereof, wherein is isopropyl.

21. R ６ is substituted with OH １ ~C ４ 19. The compound of any one of claims 1 to 18, or a salt thereof, wherein:

22. R ７ is substituted with OH １ ~C ４ 22. The compound of any one of claims 1 to 21, or a salt thereof, which is alkyl.

23. R ７ But -CH ２ 23. The compound of any one of claims 1 to 22, or a salt thereof, wherein R is OH.

24. R ７ 22. The compound of any one of claims 1 to 21, or a salt thereof, wherein is H.

25. R ７ But unsubstituted C １ ~C ４ 22. The compound of any one of claims 1 to 21, or a salt thereof, which is alkyl.

26. R ７ 26. The compound of any one of claims 1 to 21 or 25, or a salt thereof, wherein is methyl.

27. R ７ The compound according to any one of claims 1 to 21, or a salt thereof, wherein is 5-6 membered heteroaryl.

28. R ８ 28. The compound of any one of claims 1 to 27, or a salt thereof, wherein is H.

29. R ８ 29. The compound of any one of claims 1 to 28, or a salt thereof, wherein is OH.

30. 30. The compound of any one of claims 1 to 29, or a salt thereof, wherein E is phenyl.

31. E-R ９ but, 【Chemistry 7】 and The wavy line indicates the point of attachment of E to the rest of the compound.

31. A compound according to any one of claims 1 to 30, or a salt thereof.

32. 30. The compound of any one of claims 1 to 29, or a salt thereof, wherein E is a 5- to 6-membered heteroaryl.

33. R ９ 33. The compound of any one of claims 1 to 32, or a salt thereof, wherein is H.

34. R ９ 34. The compound of any one of claims 1 to 33, or a salt thereof, wherein is OH.

35. X ａ but, 【Chemistry 8】 and X ｂ But, -NR １ R ２ and R １ is H or methyl, R ２ is methyl, X is OH, R ３ and R ４ is H, R ６ is isopropyl, R ７ But -CH ２ OH, R ８ is H, E is phenyl; R ９ is H, The compound of claim 1, or a salt thereof.

36. 【Chemical 9】 or a salt thereof.

37. Drug-linker compounds of the formula: Q-D or a salt thereof (wherein Q is, (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z’-A-S ＊ -RL-、 (iv) Z’-A-S ＊ -RL-Y-、 (v) Z’-A-B(S ＊ )-RL-、 (vi) Z’-A-B(S ＊ )-RL-Y-、 (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; is a linker unit selected from the group consisting of Z' is a Stretcher unit precursor; A is a bond or connector unit, B is a parallel connector unit, S ＊ is a resolving agent, RL is a releasable linker; W is an amino acid unit, Y is a spacer unit, D is a Drug unit of Formula (I'): 【Chemistry 10】 (In the formula, X ｂ is -NR ２ - ＃ Or -N ＋ R １ R ５ - ＃ where # represents the point of attachment to Q, and X ａ teeth, 【Chemistry 11】 or X ａ and X ｂ together with the carbon atoms to which they are attached, 【Chemistry 12】 (wherein the asterisk represents X ａ and X ｂ represents the carbon atom of formula (I) bearing a group, and # represents the point of attachment to Q, R １ and R ５ are independently １ ~C ４ is alkyl, X is H, OH, or —C(O)NR ａ R ｂ , -S(O) ２ R ａ , -S(O)-R ａ , -S(O) ２ NR ａ R ｂ , -NHS(O) ２ R ａ or -NHC(O)R ａ and R ２ , R ３ , R ４ , R １０ , R ａ , and R ｂ are each independently H or C １ ~C ４ is alkyl, R ６ is C optionally substituted with OH １ ~C ４ is alkyl, R ７ is C optionally substituted with H, one or two OH moieties １ ~C ４ alkyl, or 5- to 6-membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R ８ , R ９ , and R １１ are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1; When X is H, R ７ , R ８ , R ９ , and R １１ wherein at least two of the groups contain an OH moiety.

38. 38. The drug-linker compound of claim 37, or a salt thereof, wherein the linker unit Q is of formula (i), (ii), (iii), (iv), (x), or (xi).

39. 38. The drug-linker compound of claim 37, or a salt thereof, wherein the linker unit Q is of formula (v), (vi), (ix), or (xi).

40. 38. The drug-linker compound of claim 37, wherein the linker unit Q is of formula (viii), (ix), (x), or (xi), or a salt thereof.

41. The stretcher unit Z′ is 【Chemistry 13】 (In the formula, R １７ is -CH ２ CH ２ (OCH ２ CH ２ ) ｋ -, -C １ ~C １０ Alkylene-, C １ ~C １０ Heteroalkylene-, -C ３ ~C ８ Carbocyclo-, —O—(C １ ~C ８ alkylene)-, -arylene-, -C １ ~C １０ Alkylene-arylene-, -arylene-C １ ~C １０ Alkylene-, -C １ ~C １０ Alkylene-(C ３ ~C ８ Carbocyclo)-, -(C ３ ~C ８ Carbocyclo)-C １ ~C １０ Alkylene-, -C ３ ~C ８ Heterocyclo-, -C １ ~C １０ Alkylene-(C ３ ~C ８ heterocyclo)-, -(C ３ ~C ８ Heterocyclo)-C １ ~C １０ Alkylene-, -C １ ~C １０ Alkylene-C(=O)-, C １ ~C １０ Heteroalkylene -C(=O)-, -C ３ ~C ８ Carbocyclo-C(=O)-, -O-(C １ ~C ８ alkylene)-C(=O)-, -arylene-C(=O)-, -C １ ~C １０ Alkylene-arylene-C(═O)-, -arylene-C １ ~C １０ Alkylene -C(=O)-, -C １ ~C １０ Alkylene-(C ３ ~C ８ carbocyclo)-C(=O)-, -(C ３ ~C ８ Carbocyclo)-C １ ~C １０ Alkylene -C(=O)-, -C ３ ~C ８ Heterocyclo-C(=O)-, -C １ ~C １０ Alkylene-(C ３ ~C ８ heterocyclo)-C(=O)-, -(C ３ ~C ８ Heterocyclo)-C １ ~C １０ Alkylene -C(=O)-, -C １ ~C １０ Alkylene-NH-, C １ ~C １０ Heteroalkylene -NH-, -C ３ ~C ８ Carbocyclo-NH-, —O—(C １ ~C ８ alkylene)-NH-, -arylene-NH-, -C １ ~C １０ Alkylene-arylene-NH-, -arylene-C １ ~C １０ Alkylene -NH-, -C １ ~C １０ Alkylene-(C ３ ~C ８ carbocyclo)-NH-, -(C ３ ~C ８ Carbocyclo)-C １ ~C １０ Alkylene -NH-, -C ３ ~C ８ Heterocyclo-NH-, -C １ ~C １０ Alkylene-(C ３ ~C ８ heterocyclo)-NH-, -(C ３ ~C ８ Heterocyclo)-C １ ~C １０ Alkylene -NH-, -C １ ~C １０ Alkylene-S-, C １ ~C １０ Heteroalkylene -S-, -C ３ ~C ８ Carbocyclo-S-, —O—(C １ ~C ８ alkylene)-S-, -arylene-S-, -C １ ~C １０ Alkylene-arylene-S-, -arylene-C １ ~C １０ Alkylene -S-, -C １ ~C １０ Alkylene-(C ３ ~C ８ carbocyclo)-S-, -(C ３ ~C ８ Carbocyclo)-C １ ~C １０ Alkylene -S-, -C ３ ~C ８ Heterocyclo-S-, -C １ ~C １０ Alkylene-(C ３ ~C ８ heterocyclo)-S-, or -(C ３ ~C ８ Heterocyclo)-C １ ~C １０ alkylene-S-; the subscript k is an integer ranging from 1 to 36; R １７ is a basic unit (BU), such as an aminoalkyl moiety, e.g., —(CH ２ ) ｘ NH ２ , -(CH ２ ) ｘ NHR ａ , and -(CH ２ ) ｘ NR ａ ２ where x is an integer from 1 to 4, and each R ａ are independently １～６ Alkyl and C １～６ haloalkyl, or two R ａ groups combined with the nitrogen to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl group; The wavy line indicates the point of covalent attachment to the remainder of the drug-linker compound. That is, 41. The drug-linker compound of any one of claims 37 to 40, or a salt thereof.

42. The stretcher unit Z′ is 【Chemistry 14】 where the wavy line indicates the point of covalent attachment to the remainder of the Drug-Linker Compound.

42. The drug-linker of any one of claims 37 to 41, or a salt thereof,

43. Connector unit A is 【Chemistry 15】 (In the formula, Each R １００ are independently hydrogen or —C １ ~C ３ alkyl, R １１１ are independently hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, —CH ２ OH, -CH(OH)CH ３ , -CH ２ CH ２ SCH ３ , -CH ２ CONH ２ , -CH ２ COOH, -CH ２ CH ２ CONH ２ , -CH ２ CH ２ COOH, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ３ NH ２ , -(CH ２ ) ３ NHCOCH ３ , -(CH ２ ) ３ NHCHO, -(CH ２ ) ４ NHC (=NH)NH ２ , -(CH ２ ) ４ NH ２ , -(CH ２ ) ４ NHCOCH ３ , -(CH ２ ) ４ NHCHO, -(CH ２ ) ３ NHCONH ２ , -(CH ２ ) ４ NHCONH ２ , -CH ２ CH ２ CH(OH)CH ２ NH ２ , 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, 【Chemistry 16】 is selected from the group consisting of each subscript c is independently selected from an integer from 1 to 10; The wavy line indicates the attachment of the connector unit to the remainder of the drug-linker compound.

43. The drug-linker compound of any one of claims 37 to 42, or a salt thereof, wherein:

44. Connector unit A is 【Chemistry 17】 and c is an integer ranging from 1 to 6; The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof; 44. The drug-linker compound of any one of claims 37 to 43, or a salt thereof.

45. 43. The drug-linker compound of any one of claims 37 to 42, or a salt thereof, wherein A is a bond.

46. B, 【Chemistry 18】 and each AA is independently a proteinogenic or non-proteinogenic amino acid; The wavy line indicates the point of attachment to the remainder of the Drug-Linker Compound or salt thereof; 46. The drug-linker compound of claims 37 to 45, or a salt thereof.

47. 47. The drug-linker compound of any one of claims 37 to 46, or a salt thereof, wherein B is an amino acid.

48. B, 【Chemistry 19】 and The wavy line indicates the resolving agent S. ＊ indicates the attachment point to The asterisk indicates the point of attachment to the remainder of the drug-linker structure.

48. The drug-linker compound of any one of claims 37 to 47, or a salt thereof.

49. Splitting Agent S ＊ The drug-linker compound of any one of claims 37 to 48, or a salt thereof, wherein is a polyethylene glycol (PEG) unit, a cyclodextrin unit, a polyamide, a hydrophilic peptide, a polysaccharide, or a dendrimer.

50. Splitting Agent S ＊ However, 4 to 72 (CH ２ CH ２ 50. The drug-linker compound of any one of claims 37 to 49, or a salt thereof, wherein the PEG unit comprises a PEG-containing O) subunit.

51. The PEG unit is 【Chemistry 20】 and b is selected from the group consisting of 4 to 36; The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof; 51. The drug-linker of any one of claims 37 to 50, or a salt thereof.

52. The releasable linker RL is -(AA) １～１２ and each AA is independently a proteinogenic or non-proteinogenic amino acid; 52. The drug-linker compound of any one of claims 37 to 51, or a salt thereof.

53. The releasable linker RL is -AA １ -AA ２ -or-AA １ -AA ２ -AA ３ - (wherein, AA １ is attached to a stretcher unit Z′ or a connector unit A), 53. The drug-linker compound of any one of claims 37 to 52, or a salt thereof.

54. The releasable linker RL is 【Chemical 21】 and The wavy line adjacent to the -NH- group indicates attachment to Stretcher unit Z' or Connector unit A, and the wavy line adjacent to the -C(=O)- group indicates attachment to Spacer unit Y or Drug unit D.

54. The drug-linker compound of any one of claims 37 to 53, or a salt thereof.

55. 55. The drug-linker compound of any one of claims 37 to 54, or a salt thereof, wherein the releasable linker RL is a glycoside.

56. The releasable linker RL is 【Chemical 22】 where Su is a hexose derived from a monosaccharide, O' represents the oxygen atom of a glycosidic bond that can be cleaved by a glycosidase; A single asterisk ( ＊ ) indicates the site of covalent attachment to D, Double asterisk ( ＊＊ ) indicates the site of covalent attachment of Q to the rest of the 56. The drug-linker compound of any one of claims 37 to 55, or a salt thereof, wherein:

57. The releasable linker RL is 【Chemical 23】 and A single asterisk ( ＊ ) indicates the site of covalent attachment to D; Double asterisk ( ＊＊ ) indicates the site of covalent attachment of Q to the remainder of the 57. The drug-linker compound of any one of claims 37 to 56, or a salt thereof.

58. The spacer unit Y is 【Chemistry 24】 wherein EWG is an electron-withdrawing group; The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or its salt.

58. The drug-linker compound of any one of claims 37 to 39 or 41 to 57, or a salt thereof, wherein:

59. The spacer unit Y is 【Chemistry 25】 and The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof; 59. The drug-linker compound of any one of claims 37 to 39 or 41 to 58, or a salt thereof.

60. Z' is 【Chemical 26】 and R １７ But C １ ~C １０ is alkylene, A is a bond, RL is -AA １ -AA ２ - and A.A. １ and A.A. ２ are each independently a proteinogenic amino acid; Y is, 【Chemical 27】 and The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof; 60. The drug-linker compound of any one of claims 37, 41-42, 45-48, 52-54, or 58-59, or a salt thereof.

61. Z' is 【Chemical 28】 and A is a bond, RL is, 【Chemical Formula 29】 and Y is, 【Chemistry 30】 That is, 61. The drug-linker compound of any one of claims 37, 41-42, 45-48, 52-54, or 58-60, or a salt thereof.

62. Y-D, 【Chemical 31】 and The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof; 62. The drug-linker compound of any one of claims 37-38 or 41-61.

63. Y-D, 【Chemical 32】 and The wavy line indicates the site of attachment to the remainder of the Drug-Linker Compound or salt thereof; 62. The drug-linker compound of any one of claims 37-38 or 41-61. 【Request 64】 【Chemical 33】 63. The drug-linker compound of any one of claims 37, 41-42, 45-48, 52-54, 58-61, or 62, which is: or a salt thereof.

65. 【Catalog 34】 64. The drug-linker compound of any one of claims 37, 41-42, 45-48, 52-54, 58-61, or 63, which is: or a salt thereof.

66. Ligand-drug conjugate compounds of the formula: L-(Q-D) ｐ or a pharmaceutically acceptable salt thereof, L is a ligand unit; Q is, (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z’-A-S ＊ -RL-、 (iv) Z’-A-S ＊ -RL-Y-、 (v) Z’-A-B(S ＊ )-RL-、 (vi) Z’-A-B(S ＊ )-RL-Y-、 (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; is a linker unit selected from the group consisting of Z' is a stretcher unit; A is a bond or connector unit, B is a parallel connector unit, S ＊ is a resolving agent, RL is a releasable linker; W is an amino acid unit, Y is a spacer unit, D is a Drug unit of Formula (I'): 【Chemistry 35】 (In the formula, X ｂ is -NR ２ - ＃ Or -N ＋ R １ R ５ - ＃ where # represents the point of attachment to Q, and X ａ teeth, 【Chemical 36】 or X ａ and X ｂ together with the carbon atoms to which they are attached, 【Chemical 37】 (wherein the asterisk represents X ａ and X ｂ represents the carbon atom of formula (I) bearing a group, and # represents the point of attachment to Q, R １ and R ５ are independently １ ~C ４ is alkyl, X is H, OH, or —C(O)NR ａ R ｂ , -S(O) ２ R ａ , -S(O)-R ａ , -S(O) ２ NR ａ R ｂ , -NHS(O) ２ R ａ or -NHC(O)R ａ and R ２ , R ３ , R ４ , R １０ , R ａ , and R ｂ are each independently H or C １ ~C ４ is alkyl, R ６ is C optionally substituted with OH １ ~C ４ is alkyl, R ７ is C optionally substituted with H, one or two OH moieties １ ~C ４ alkyl, or 5- to 6-membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R ８ , R ９ , and R １１ are each independently H or OH, n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1; p is an integer ranging from 1 to 12; When X is H, R ７ , R ８ , R ９ , and R １１ wherein at least two of the groups contain an OH moiety.

67. 67. The ligand-drug conjugate compound of claim 66, wherein the linker unit Q is of formula (i), (ii), (iii), (iv), (x), or (xi), or a pharmaceutically acceptable salt thereof.

68. 67. The ligand-drug conjugate compound of claim 66, wherein the linker unit Q is of formula (v), (vi), (ix), or (xi), or a pharmaceutically acceptable salt thereof.

69. 67. The ligand-drug conjugate compound of claim 66, wherein the linker unit Q is of formula (viii), (ix), (x), or (xi), or a pharmaceutically acceptable salt thereof.

70. The Ligand unit L and Stretcher unit Z together form: 【Chemical Formula 38】 (In the formula, R １７ is -CH ２ CH ２ (OCH ２ CH ２ ) ｋ -, -C １ ~C １０ Alkylene-, C １ ~C １０ Heteroalkylene-, -C ３ ~C ８ Carbocyclo-, —O—(C １ ~C ８ alkylene)-, -arylene-, -C １ ~C １０ Alkylene-arylene-, -arylene-C １ ~C １０ Alkylene-, -C １ ~C １０ Alkylene-(C ３ ~C ８ Carbocyclo)-, -(C ３ ~C ８ Carbocyclo)-C １ ~C １０ Alkylene-, -C ３ ~C ８ Heterocyclo-, -C １ ~C １０ Alkylene-(C ３ ~C ８ heterocyclo)-, -(C ３ ~C ８ Heterocyclo)-C １ ~C １０ Alkylene-, -C １ ~C １０ Alkylene-C(=O)-, C １ ~C １０ Heteroalkylene -C(=O)-, -C ３ ~C ８ Carbocyclo-C(=O)-, -O-(C １ ~C ８ alkylene)-C(=O)-, -arylene-C(=O)-, -C １ ~C １０ Alkylene-arylene-C(═O)-, -arylene-C １ ~C １０ Alkylene -C(=O)-, -C １ ~C １０ Alkylene-(C ３ ~C ８ carbocyclo)-C(=O)-, -(C ３ ~C ８ Carbocyclo)-C １ ~C １０ Alkylene -C(=O)-, -C ３ ~C ８ Heterocyclo-C(=O)-, -C １ ~C １０ Alkylene-(C ３ ~C ８ heterocyclo)-C(=O)-, -(C ３ ~C ８ Heterocyclo)-C １ ~C １０ Alkylene -C(=O)-, -C １ ~C １０ Alkylene-NH-, C １ ~C １０ Heteroalkylene -NH-, -C ３ ~C ８ Carbocyclo-NH-, —O—(C １ ~C ８ alkylene)-NH-, -arylene-NH-, -C １ ~C １０ Alkylene-arylene-NH-, -arylene-C １ ~C １０ Alkylene -NH-, -C １ ~C １０ Alkylene-(C ３ ~C ８ carbocyclo)-NH-, -(C ３ ~C ８ Carbocyclo)-C １ ~C １０ Alkylene -NH-, -C ３ ~C ８ Heterocyclo-NH-, -C １ ~C １０ Alkylene-(C ３ ~C ８ heterocyclo)-NH-, -(C ３ ~C ８ Heterocyclo)-C １ ~C １０ Alkylene -NH-, -C １ ~C １０ Alkylene-S-, C １ ~C １０ Heteroalkylene -S-, -C ３ ~C ８ Carbocyclo-S-, —O—(C １ ~C ８ alkylene)-S-, -arylene-S-, -C １ ~C １０ Alkylene-arylene-S-, -arylene-C １ ~C １０ Alkylene -S-, -C １ ~C １０ Alkylene-(C ３ ~C ８ carbocyclo)-S-, -(C ３ ~C ８ Carbocyclo)-C １ ~C １０ Alkylene -S-, -C ３ ~C ８ Heterocyclo-S-, -C １ ~C １０ Alkylene-(C ３ ~C ８ heterocyclo)-S-, or -(C ３ ~C ８ Heterocyclo)-C １ ~C １０ alkylene-S-; the subscript k is an integer ranging from 1 to 36; R １７ is a basic unit (BU), such as an aminoalkyl moiety, e.g., —(CH ２ ) ｘ NH ２ , -(CH ２ ) ｘ NHR ａ , and -(CH ２ ) ｘ NR ａ ２ where x is an integer from 1 to 4, and each R ａ are independently １～６ Alkyl and C １～６ haloalkyl, or two R ａ groups combined with the nitrogen to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl group; The wavy line indicates the point of covalent attachment to the remainder of the ligand-drug conjugate compound.

70. The ligand-drug conjugate compound of any one of claims 66 to 69, which is: or a pharmaceutically acceptable salt thereof.

71. The Ligand unit L and Stretcher unit Z together form: 【Hua 39-1】 【Hua 39-2】 where the wavy line indicates the point of covalent attachment to the remainder of the ligand-drug conjugate compound.

71. The ligand-drug conjugate compound of any one of claims 66 to 70, which is: or a pharmaceutically acceptable salt thereof.

72. Connector unit A is 【Chemistry 40】 (In the formula, Each R １００ are independently hydrogen or —C １ ~C ３ alkyl, R １１１ are independently hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, —CH ２ OH, -CH(OH)CH ３ , -CH ２ CH ２ SCH ３ , -CH ２ CONH ２ , -CH ２ COOH, -CH ２ CH ２ CONH ２ , -CH ２ CH ２ COOH, -(CH ２ ) ３ NHC (=NH)NH ２ , -(CH ２ ) ３ NH ２ , -(CH ２ ) ３ NHCOCH ３ , -(CH ２ ) ３ NHCHO, -(CH ２ ) ４ NHC (=NH)NH ２ , -(CH ２ ) ４ NH ２ , -(CH ２ ) ４ NHCOCH ３ , -(CH ２ ) ４ NHCHO, -(CH ２ ) ３ NHCONH ２ , -(CH ２ ) ４ NHCONH ２ , -CH ２ CH ２ CH(OH)CH ２ NH ２ , 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, 【Chemistry 41】 is selected from the group consisting of each subscript c is independently selected from an integer from 1 to 10; The wavy line indicates the attachment of the connector unit to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

72. The ligand-drug conjugate compound of any one of claims 66 to 71, which is: or a pharmaceutically acceptable salt thereof.

73. Connector unit A is 【Chemistry 42】 and c is an integer ranging from 1 to 6; The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof; 73. The ligand-drug conjugate compound of any one of claims 66 to 72, or a pharmaceutically acceptable salt thereof.

74. 72. The ligand-drug conjugate compound of any one of claims 66 to 71, or a pharmaceutically acceptable salt thereof, wherein A is a bond.

75. B, 【Chemistry 43】 and each AA is independently a proteinogenic or non-proteinogenic amino acid; The wavy line indicates the point of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof; 75. The ligand-drug conjugate compound of claims 66 to 74, or a salt thereof.

76. 76. The ligand-drug conjugate compound of any one of claims 66 to 75, or a pharmaceutically acceptable salt thereof, wherein B is an amino acid.

77. B, 【Chemical Formula 44】 and The wavy line indicates the resolving agent S. ＊ indicates the attachment point to The asterisk indicates the point of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof; 77. The ligand-drug conjugate compound of any one of claims 66 to 76, or a pharmaceutically acceptable salt thereof.

78. Splitting Agent S ＊ is a polyethylene glycol (PEG) unit, a cyclodextrin unit, a polyamide, a hydrophilic peptide, a polysaccharide, or a dendrimer, or a pharmaceutically acceptable salt thereof.

79. Splitting Agent S ＊ However, 4 to 72 (CH ２ CH ２ 79. The Ligand-Drug Conjugate Compound of any one of claims 66 to 78, or a pharmaceutically acceptable salt thereof, wherein the PEG unit comprises a PEG-containing PEG-10 subunit.

80. The PEG unit is 【Chemistry 45】 and b is selected from the group consisting of 4 to 36; The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof; 80. The ligand-drug conjugate compound of any one of claims 66 to 79, or a pharmaceutically acceptable salt thereof.

81. The releasable linker RL is -(AA) １～１２ - and each AA is independently a proteinogenic or non-proteinogenic amino acid; 81. The ligand-drug conjugate compound of any one of claims 66 to 80, or a pharmaceutically acceptable salt thereof.

82. The releasable linker RL is -AA １ -AA ２ -or- AA １ -AA ２ -AA ３ - (wherein, AA １ is attached to the stretcher unit Z or the connector unit A), 82. The ligand-drug conjugate compound of any one of claims 66 to 81, or a pharmaceutically acceptable salt thereof.

83. The releasable linker RL is 【Chemistry 46】 and The wavy line adjacent to the -NH- group indicates attachment to a Stretcher unit Z or a Connector unit A, and the wavy line adjacent to the -C(=O)- group indicates attachment to a Spacer unit Y or a Drug unit D.

83. The ligand-drug conjugate compound of any one of claims 66 to 82, or a pharmaceutically acceptable salt thereof.

84. 84. The Ligand-Drug Conjugate compound of any one of claims 66 to 83, or a pharmaceutically acceptable salt thereof, wherein the releasable linker RL is a glycoside.

85. The releasable linker RL is 【Chemistry 47】 (In the formula, Su is a hexose derived from a monosaccharide, O' represents the oxygen atom of a glycosidic bond that can be cleaved by a glycosidase; A single asterisk ( ＊ ) indicates the site of covalent attachment to D, Double asterisk ( ＊＊ ) indicates the site of covalent attachment of Q to the rest of the 85. The ligand-drug conjugate compound of any one of claims 66 to 84, which is: or a pharmaceutically acceptable salt thereof.

86. The releasable linker RL is 【Chemistry 48】 and A single asterisk ( ＊ ) indicates the site of covalent attachment to D; Double asterisk ( ＊＊ ) indicates the site of covalent attachment of Q to the remainder of the 86. The ligand-drug conjugate compound of any one of claims 66 to 85, or a pharmaceutically acceptable salt thereof.

87. The spacer unit Y is 【Chemistry 49】 wherein EWG is an electron-withdrawing group; The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

87. The ligand-drug conjugate compound of any one of claims 66 to 68 or 70 to 86, which is: or a pharmaceutically acceptable salt thereof.

88. The spacer unit Y is 【Chemistry 50】 and The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof; 88. A ligand-drug conjugate compound according to any one of claims 66 to 68 or 70 to 87, or a pharmaceutically acceptable salt thereof.

89. R １７ But C １ ~C １０ is alkylene, A is a bond, RL is -AA １ -AA ２ - and A.A. １ and A.A. ２ are each independently a proteinogenic amino acid; Y is, 【Chemistry 51】 and The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof; 89. The ligand-drug conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, or 87-88, or a pharmaceutically acceptable salt thereof.

90. A is a bond, RL is, 【Chemistry 52】 and Y is, 【Chemistry 53】 That is, 90. The ligand-drug conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, or 87-89, or a pharmaceutically acceptable salt thereof.

91. Y-D, 【Chemical 54】 and The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof; 91. The ligand-drug conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, or 87-90, or a pharmaceutically acceptable salt thereof.

92. Y-D, 【Chemistry 55】 and The wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof; 91. The ligand-drug conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, or 87-90, or a pharmaceutically acceptable salt thereof.

93. 【Catalog 56】 92. The ligand-drug conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, or 87-91, which is: 【Request 94】 【Chemical 57-1】 【Chemistry 57-2】 93. The ligand-drug conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, 87-90, or 92, which is:

95. 95. The ligand-drug conjugate compound of any one of claims 66 to 94, wherein p is an integer ranging from 2 to 8.

96. 96. The ligand-drug conjugate compound of any one of claims 66 to 95, wherein p is 4.

97. 95. A pharmaceutical composition comprising a Ligand-Drug Conjugate compound according to any one of claims 66 to 94, and a pharmaceutically acceptable excipient.

98. 98. The pharmaceutical composition of claim 97, comprising a plurality of ligand-drug conjugate compounds having an average drug loading of 2 to 8.

99. 99. The pharmaceutical composition of claim 98, wherein the average drug loading is about 4.

100. 99. The pharmaceutical composition of claim 98, wherein the average drug loading is 3.5 to 4.

5.

101. 97. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a ligand-drug conjugate compound of any one of claims 66 to 96, or a pharmaceutically acceptable salt thereof.

102. 102. The method of claim 101, wherein the subject tolerates treatment from the Ligand Drug Conjugate Compound better than from a therapeutically effective dose of another Ligand Drug Conjugate Compound.

103. 103. The method of claim 102, wherein the other Ligand-Drug conjugate compound comprises a monomethyl auristatin E or monomethyl auristatin F Drug unit.

104. A compound selected from the group consisting of the compounds listed in Table 1 or a salt thereof.

105. A drug-linker compound selected from the group consisting of the compounds listed in Table 2 or salts thereof.

106. A ligand-drug conjugate compound selected from the group consisting of the compounds listed in Table 3 or salts thereof, wherein p is an integer ranging from 1 to 12.

107. 107. The ligand-drug conjugate compound of any one of claims 66 to 96 or 106, wherein L is an antibody.

108. 108. The ligand-drug conjugate compound of any one of claims 66-96 or 106-107, wherein L comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of any one of SEQ ID NOs: 1-1044.

109. 109. The ligand drug conjugate of any one of claims 66-96 or 106-108, wherein L comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 1-1044.

110. 110. The Ligand Drug Conjugate of any one of claims 66-96 or 106-109, wherein L comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 1-1044.

111. 111. The ligand drug conjugate of any one of claims 66-96 or 106-110, wherein L comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 1-1044.

112. 112. The ligand drug conjugate of any one of claims 66-96 or 106-111, wherein L comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of any one of SEQ ID NOs: 1-1044.

113. 113. The ligand drug conjugate of any one of claims 66-96 or 106-112, wherein L comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-1044.

114. 114. The ligand-drug conjugate compound of any one of claims 66-96 or 106-113, wherein L comprises the amino acid sequence of any one of SEQ ID NOs: 1-1044.

115. 115. The ligand-drug conjugate compound of any one of claims 66-96 or 106-114, wherein L consists of the amino acid sequence of any one of SEQ ID NOs: 1-1044.

116. 116. The ligand-drug conjugate of any one of claims 66-96 or 106-115, wherein p is 8.

117. 116. The ligand-drug conjugate of any one of claims 66-96 or 106-115, wherein p is an integer from 1 to 8.

118. A ligand-drug conjugate of the formula: 【Chemistry 58】 wherein L is an anti-gpNMB antibody; p is an integer from 1 to 14, or from 1 to 8, or is 8).

119. 119. The ligand-drug conjugate of claim 118, wherein the anti-gpNMB antibody comprises an amino acid sequence that is at least 80, 85, 90, 95, 98, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 935-944.

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