Antibody-drug conjugates

Abstract

Among other things, the present disclosure provides conjugates comprising target binding moieties, payload moieties and linkers. In some embodiments, tire present disclosure provides pharmaceutical compositions comprising provided conjugates. In some embodiments, the present disclosure provides methods for preventing or treating various conditions, disorders or diseases using provided conjugates and compositions thereof. In some embodiments, the present disclosure provides technologies for manufacturing provided conjugates and compositions thereof.

Description

ANTIBODY-DRUG CONJUGATES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application Nos.63 / 581,306, filed September 8, 2023, 63 / 591,078, filed June October 17, 2023, and 63 / 550,023, filed February 5, 2024, the entirety of each of which is incorporated herein by reference. BACKGROUND

[0002] Antibody-drug conjugates (ADCs) can provide an effective means of delivering a drug to a targeted site in a tissue or organism. Recognition of a target, such as a tumor, by the antibody minimizes exposure of non-target tissues to toxic chemotherapeutic agents and limits adverse effects associated with the toxicity of "free" drugs (i.e., unbound to a carrier such as an antibody). Therefore, a need exists for the development of new therapeutic modalities, such as ADCs, optimized to deliver a drug to a targeted site in a tissue or organism and minimize adverse effects. SUMMARY

[0003] Among other things, the present disclosure encompasses the recognition that conjugate designs, e.g., ADC designs, can impact their structures, properties, activities, etc. In some embodiments, the present disclosure provides conjugates that can provide various benefits and advantages, e.g., improved properties, improved activities, etc. For example, in some embodiments, provided conjugates have, among other things, improved solubility, reduced aggregation, improved activities, etc. In some embodiments, provided conjugates comprise moieties (e.g., carbohydrate moieties, PEG moieties, etc.) that can improve solubility and / or reduce aggregation. In some embodiments, provided conjugates comprise −(CH2CH2O)n− as described herein. In some embodiments, n is 1-24. In some embodiments, −(CH2CH2O)n− is in the chain of bonds from a target binding moiety to a payload moiety (compared to in a side chain off the chain of bonds from a target binding moiety to a payload moiety).

[0004] In some embodiments, the present disclosure provides conjugates comprising: i) a target binding moiety; ii) a payload moiety; and iii) a linker that connects the target binding moiety and the payload moiety; wherein: the linker comprises −(CH2CH2O)n− and LC; n is 0-24; LCis bonded to a payload moiety and is −LC1−LCO−; LC1is or comprises a cleavable unit; and LCOis a covalent bond, or a spacer moiety.

[0005] In some embodiments, the present disclosure provides conjugates comprising: i) a target binding moiety;Attorney Docket No.: 2013418-0163 ii) a payload moiety; and iii) a linker that connects the target binding moiety and the payload moiety; wherein: the linker comprises −(CH2CH2O)n− and LC; n is 0-24; LCis bonded to a payload moiety and is −LC1−LCO−; LC1is −Gly−Gly−Phe−Gly−, −Val−Ala−, −Val–Cit–, LC1S, −Gly−Gly−Phe−Gly−N(R’)−LC1S−, −Val−Ala−N(R’)−LC1S−, or −Val–Cit–N(R’)−LC1S−;, wherein the phenyl ring and the −CH2− is optionally substituted, and th d RLSis or comprises a sugar moiety;LCOis a covalent bond, or optionally substitut wherein the carbonyl is bonded to a payload moiety;each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10aliphatic, C1-10heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

[0006] In some embodiments, RLSis or comprises a sugar moiety so that LCis cleavable, e.g., by an enzyme. In some embodiments, RLSis or comprises a glucuronide moiety. In some embodiments, LCcan be cleaved by a β-glucuronidase. In some embodiments, RLSis or comprises a galactoside moiety. In some embodiments, LCcan be cleaved by a β-galactosidase. In some embodiments, RLSis or comprises a derivative thereof. In some embodiment . In someembodiments, RLSis or comprises r a derivative thereof. In some embodiments, RLSPage 2 of 555 12249041v1. In some embodiments, LC1is LC1Sas described herein. In some embodiments, nd. In some embodiments, LCis LC1as described herein. In some embodiments, LCisrein. In some embodiments, the phenyl ring the −CH2− in LC1Sis unsubstituted.

[0007] In some embodiments, n is 1-24.

[0008] In some embodiments, the present disclosure provides a conjugate, wherein the conjugate is a compound of formula A-1 or a salt thereof: ,wherein: each RAis independently a target binding moiety; s is 1-20; each LTis independently a covalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LTare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each LRXis independently a covalent bond, a moiety that results from a reaction between a group present on the unconjugated target binding moiety and a group present on an agent comprising LX’, or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LRXare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each of a and b is independently 1-10; each LX’is independently a covalent bond or an optionally substituted bivalent or polyvalent straight or branched C1-30aliphatic wherein 1-10 methylene units of LX’are optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each n is independently 0-24; each LZPis independently a covalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LZPare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each LCis independently −LC1−LCO−; each LC1is independentlle unit, or each LC1is independently −Gly−Gly−Phe−Gly−, −Val−Ala−, −Val–Cit–, LC1S, −Gly−Gly−Phe−Gly−N(R’)−LC1S−, −Val−Ala−N(R’)−LC1S−, or −Val–Cit– N(R’)−LC1S−;, wherein the phenyl ring and the −CH2− is optionally substituted, and the d RLSis or comprises a sugar moiety;p y ovalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LCOare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each RPis independently a payload moiety; t is 1-20; each –Cy– is independently an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

[0009] In some embodiments, a is 1 and b is 1.

[0010] In some embodiments, the present disclosure provides a conjugate (e.g., a conjugate of formula A-1), wherein the conjugate is a compound of formula A-2 or a salt thereof: ,wherein: RAis a target binding moiety; each LTis independently a covalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LTare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each LRXis independently a covalent bond, a moiety that results from a reaction between a group present on the unconjugated target binding moiety and a group present on an agent comprising −LX−(CH2CH2O)n−LZP−LC−RP, or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LRXare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−;each LXis independently a covalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LXare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each n is independently 0-24; each LZPis independently a covalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LZPare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each LCis independently −LC1−LCO−; each LC1is independently a cleavable unit, or each LC1is independently −Gly−Gly−Phe−Gly−, −Val−Ala−, −Val–Cit–, LC1S, −Gly−Gly−Phe−Gly−N(R’)−LC1S−, −Val−Ala−N(R’)−LC1S−, or −Val–Cit– N(R’)−LC1S−; , wherein the phenyl ring and the −CH2− is optionally substituted, and t nd RLSis or comprises a sugar moiety;each LCOis independently a covalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LCOare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each RPis independently a payload moiety; t is 1-20; each –Cy– is independently an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10aliphatic, C1-10heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

[0011] In some embodiments, each LC1is independently a cleavable unit. In some embodiments, each LC1is independently −Gly−Gly−Phe−Gly−, −Val−Ala−, −Val–Cit–, LC1S, −Gly−Gly−Phe−Gly−N(R’)−LC1S−, −Val−Ala−N(R’)−LC1S−, or −Val–Cit–N(R’)−LC1S−, wherein each variable is independently as described herein. In some embodiments, each LC1is independently −Gly−Gly−Phe−Gly−, −Val−Ala−, −Val–Cit–, or LC1S. In some embodiments, each LC1is independently −Val−Ala−, −Val–Cit–, or LC1S. In some embodiments, each LC1is independently −Val−Ala−, −Val– Cit–, or LC1S, wherein RLSis or comprises a glucuronide moiety. In some embodiments, each LC1isindependently −Val−Ala−, −Val–Cit–, or LC1S, wherei In some embodiments, each LC1is independently −Gly−Gly−P Cit–, orted , at Insome embodiments, each LC1is independently −Gly−Gly−Phe−Gly−, −Val−Ala−, –Val–Cit–, or ted currencey−, , each LCOis independently a covalent bond oroptionally substituted wherein the carbonyl is bonded to a payload moiety, and each occurrence of n n some embodiments, each LC1is independently −Val−Ala−. In some embodiments, each L is independently −Val−Ala− and each LCOis independently optionally substituted . In some embodiments, each LC1is independently −Val−Ala− andeach . In some embodiments, each LC1is independently −Val−Cit−. In som ependently −Val−Cit− and each LCOis independently optionallyand1 isd each LCOis a covalent bond. arget binding moiety binds to a polypeptide. For example, in someem o ments, a target n ng mo ety binds to HHLA2 or a fragment thereof.

[0013] In some embodiments, a target binding moiety is or comprises an antibody or an antigen- binding fragment thereof. For example, in some embodiments, a target binding moiety is or comprises an anti-HHLA2 antibody or an antigen-binding fragment thereof.

[0014] Those skilled in the art appreciate that various payload moieties, e.g., those reported for antibody-drug conjugates, can be utilized in accordance with the present disclosure. For example, in some embodiments, a payload moiety is or comprises camptothecin or a derivative or an analog thereof. In d is, . e, in some embodiments, provided linkers comprise PEG moieties. In some embodiments, provided linkers comprise −(CH2CH2O)n−, wherein n is 1-24. In some embodiments, provided linkers comprise cleavable units, e.g., GGFG, that directly bonded to payload moieties. In some embodiments, a cleavable unit can be cleaved by an enzyme, e.g., an enzyme present at a target site. In some embodiments, a cleavable unit is or comprises a polypeptide, e.g., GGFG, Val-Ala, Val-Cit, etc. In some embodiments, a polypeptide isbonded to a provided method at its C-terminus through −C(O)−. Among other things, the present disclosure provides antibody-drug conjugates in which there are no moieties (e.g., no spacer moieties) between cleavable units and payload moieties. In some embodiments, there are moieties, e.g., spacer moieties, between cleavable units and payload moieties. In some embodiments, a linker is or comprises −LZP−LC− wherein each variable is independently as described herein. In some embodiments, a linker is or comprises −(CH2CH2O)n−LZP−LC− wherein each variable is independently as described herein. In some embodiments, a linker is or comprises −LX−(CH2CH2O)n−LZP−LC− wherein each variable is independently as described herein.

[0016] In some embodiments, the present disclosure provides pharmaceutical compositions comprising provided conjugates and pharmaceutically acceptable carriers. Among other things, provided technologies, e.g., compounds, conjugates, agents, compositions, etc., are useful for preventing or treating various conditions, disorders or diseases. In some embodiments, when utilized as therapeutics, provided compounds, conjugates, agents, e.g., are provided in pharmaceutical compositions. Compounds, conjugates, agents, etc., may be various forms, e.g., salt forms. For example, in some embodiments, they may exist in various pharmaceutically acceptable salt forms. In some embodiments, in a composition a compound, conjugate, agent, etc., may exist in one or more forms, e.g., in one or more pharmaceutically acceptable salt forms.

[0017] In some embodiments, the present disclosure provides methods for preventing or treating various conditions, disorders or diseases. In some embodiments, the present disclosure provides a method for preventing a condition, disorder or disease, comprising administering or delivering to a subject susceptible thereto an effective amount of a provided compound, conjugate, agent or composition. In some embodiments, the present disclosure provides a method for treating a condition, disorder or disease, comprising administering or delivering to a subject suffering therefrom an effective amount of a provided compound, conjugate, agent or composition. In some embodiments, a condition, disorder or disease is cancer. In some embodiments, a subject has or is at risk of developing a cancer. In some embodiments, a subject has a solid tumor or a hematological cancer. In some embodiments, a solid tumor is or comprises one or more of: a renal cancer, a bone cancer, a skin cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a lung cancer, an ovarian cancer, a liver cancer, cholangiocarcinoma, or a thyroid cancer. In some embodiments, a hematological cancer comprises or is a leukemia or lymphoma. In some embodiments, a leukemia comprises or is acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic leukemia, or acute leukemia. In some embodiments, a lymphoma comprises or is Hodgkin lymphoma (HL), non-Hodgkin's lymphoma, lymphocytic lymphoma, or diffuse large B cell lymphoma (DLBCL). In some embodiments, a condition, disorder or disease is associated with aberrant expression of an agent that a target binding moiety can bind, e.g., HHLA2. In some embodiments, a conjugate is administered parenterally. In some embodiments, parenteral administration is or comprises subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion. In some embodiments, a conjugate is administered in

[0018] In some embodiments, the present disclosure provides technologies, e.g., methods, reagents, intermediates, etc., for manufacturing various compounds, e.g., conjugates described herein.

[0019] Various features, objects, and advantages of provided technologies are apparent in the detailed description that follows. It should be understood, however, that the detailed description, while indicating embodiments of provided technologies, is given by way of illustration only, not limitation. Various changes and modifications of provided technologies will become apparent to those skilled in the art from the present disclosure including the detailed description. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figures 1A, 1B and 1C. Provided conjugates can bind to targets. Figures 1A, 1B and 1C depict certain binding curves for anti-HHLA2 antibody drug conjugates binding to HHLA2+ A204 cells. Naked antibody, exatecan conjugates with DAR about 4 (Exatecan_DAR4), and exatecan conjugates with DAR about 8 (Exatecan_DAR8) for each of Hu2C4-H3L3 (1A), 65872 (1B), and 887-1DE (1C) were tested. Controls include human IgG1 isotype (IgG1 Control) and exatecan conjugates of human IgG1 isotype with DAR about 8 (IgG1-Exatecan_DAR8).

[0021] Figure 2. Provided conjugates can be internalized. Figure 2 depicts examples of induction of internalization in A204 cells by anti-HHLA2 antibodies: Hu2C4-H3L3, 65872, and 887-1DE.

[0022] Figures 3A and 3B. Provided conjugates can kill target cells. Figures 3A and 3B depict dose- response curves for data from example assessment of anti-HHLA2 antibody drug conjugates: Hu2C4- H3L3, 65872, and 887-1DE.3A: DAR is about 4.3B: DAR is about 8. Data for exatecan conjugates of human IgG1 isotype with DAR about 8 (IgG1-Exatecan_DAR8) and exatecan are also included.

[0023] Figure 4. Provided conjugates can bind to targets. Figure 4 depicts certain binding curves for anti-HHLA2 antibody drug conjugates binding to HEK cells overexpressing B7H7. Depicted are Hu2C4- H3L3 conjugates of LP-A, LP-B, and LP-C at DAR 8, and 65872 conjugates of LP-A, LP-B, and LP-C at DAR 8. Controls include Hu2C4-H3L3-PEG8-GGFG-Exatecan DAR8 and GGFG-Exatecan conjugates of human IgG1 isotype with DAR about 8. As demonstrated herein, provided conjugates can bind to targets.

[0024] Figure 5. Provided conjugates can kill target cells. Figure 5 depicts certain dose-response curves for data from example assessment of anti-HHLA2 antibody drug conjugates. Depicted are Hu2C4- H3L3 conjugates of LP-A, LP-B, and LP-C at DAR 8, and 65872 conjugates of LP-A, LP-B and LP-C at DAR 8. Controls include Hu2C4-H3L3-PEG8-GGFG-Exatecan DAR8 and GGFG-Exatecan conjugates of human IgG1 isotype with DAR about 8. As demonstrated herein, provided conjugates can effectively kill target cells. DEFINITIONS

[0025] In order for provided technologies to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications (e.g., patents, patent application publications, non-patent publications,etc.), websites and other reference materials referenced herein are each hereby incorporated by reference in its entirety; in the case of any conflict, the present disclosure will controlChemical Definitions

[0026] Compounds of the present disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry", Thomas Sorrell. University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”. 5th Ed., Ed.: Smith, M.B. and March, J.. John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0027] Aliphatic: As used herein, "aliphatic” means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or combinations thereof. In some embodiments, aliphatic groups contain 1-50 aliphatic carbon atoms In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms In oilier embodiments, aliphatic groups contain 1 -9 aliphatic carbon atoms In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-7 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1 -5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1 , 2, 3. or 4 aliphatic carbon atoms. Certain aliphatic groups include linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0028] Alkyl: As used herein, the term “alkyl” is given its ordinary meaning in the art and refers to an aliphatic group, e.g., a straight-chain alkyd group, a branched-chain alkyl group, a cycloalkyl (alicyclic) group, an alkyl substituted cycloalkyl group, a cycloalkyl substituted alkyl group, etc., which is saturated. In some embodiments, alkyl has 1-100 carbon atoms. In some embodiments, alkyl has about 1-30 (e.g., 1 , 2. 3, 4, 5, 6, 7. 8, 9, 10, 11, 12, 13. 14. 15. 16, 17, 18, 19. 20, 21, 22, 23, 24. 25, 26, 27, 28. 29, 30, 1-25. 1-20, 1-15, I -10, 3-30. etc.) carbon atoms. In some embodiments, alkyl has 1-20 (e g.. 1, 2, 3, 4, 5. 6, 7, 8. 9, 10. 11, 12, 13, 14, 15. 16, 17, 18, 19. 20, 1 -15, 1-10, etc.) carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 (e.g.. 1, 2. 3, 4, 5. 6. 7, 8, 9, 10, 11, 12. 13. 14. 15.16, 17, 18. 19. 20. 1-15, 1-10, etc.) carbon atoms in its backbone (e.g., Cj-Cao for straight cirain, C2-C20 for branched chain, etc.), and alternatively, about 1-10 (e.g.. 1, 2. 3, 4, 5. 6. 7. 8, 9, 10, 1 -5, 1-4. etc.) carbon atoms. In some embodiments, cycloalkyl rings have from about 3-10 (e.g., 3. 4, 5, 6. 7, 8. 9, 10, 3-8, 3-7. 3-6, 4-6. 5-6. 5-8, etc.) carbon atoms in their ring structure where such rings are monocyclic, bicyclic, or polycyclic, and alternatively about 5. 6 or 7 carbons in the ring structure. In some embodiments, an alkylgroup may be a lower alkyl group, wherein a lower alkyl group has 1-4 carbon atoms (e.g., C1-C4 for straight chain lower alkyls).

[0029] Aryl: The term “atyl”, as used herein, used alone or as part of a larger moiety as in “aralkyl,'’ “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclic or polycy clic ring systems having a total of, unless otherwise specified, 5-30 (e.g., 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 5-25, 5-20, 5-15, 5-14, 5-10, 5-9, etc.) ring members, wherein at least one ring in the system is aromatic, hi some embodiments, an aryl group is a monocyclic, bicyclic or polycyclic ring system having a total of five to fourteen (e.g., 5-10, 6-14, 6-10. 5, 6, 9, 10, 14, etc.) ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, each aromatic ring is independently 6-membered. In some embodiments, each aromatic ring atom is carbon. In some embodiments, each ring atom is carbon In some embodiments, an atyl group is a biaryl group. The term “aryl” may be used interchangeably with the term “aryl ring.” In some embodiments, “aryl” refers to an aromatic ring system which includes phenyl, biphenyl, naphthyl, binaphthyl, anthracyl and the like, w’hicb may bear one or more substituents. Also included within the scope of the term “aryl.” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phtbalitnidyl, naphthylmethyl, phenanthridinyl. or tetrabydronaphthyl, and the like.

[0030] Halogen: The term “halogen” means F, Cl. Br. or 1

[0031] Heteroatom: The term “heteroatom", as used herein means an atom that is not carbon or hydrogen. In some embodiments, a heteroatom is boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including oxidized forms of nitrogen, sulfur, phosphorus, or silicon; charged forms of nitrogen (e.g.. quaternized forms, forms as in iminium groups, etc.), phosphorus, sulfur, oxygen; etc.). In some embodiments, a hctcroatom is silicon, phosphorus, oxygen, sulfur or nitrogen. In some embodiments, a heteroatom is silicon, oxygen, sulfur or nitrogen. In some embodiments, a heteroatom is oxygen, sulfur or nitrogen.

[0032] Partially Unsaturated: As used herein, the term “partially unsaturated”, as used herein, refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated”, as used herein, is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties. as herein defined.

[0033] Unsaturated: The term '’unsaturated”, as used herein, means that a moiety has one or more units of unsaturation

[0034] Heteroaryl: The terms “heteroaryl” and “he teroar-”, as used herein, used alone or as part of a larger moiety , e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to monocyclic, bicyclic or polycyclic ring systems having a total of. unless otherwise specified. 5-30 (e.g., 5, 6, 7, 8, 9, 10. 11 , 12, 13, 14. 15, 16, 17, 18, 19, 20. 21, 22, 23, 24, 25. 26. 27. 28, 29. 30, 5-25, 5-20, 5-15. 5-14, 5-10, 5-9. etc.) ring members, wherein at least one ring in the system is aromatic and at least one aromatic ring atom is a heteroatom. In some embodiments, the number of ring heteroatoms in a heteroaryl group is about 1-10 (e.g.. 1, 2, 3, 4, 5. 6, 7, 8, 9, 10, 1-5, 1-4, 1-3, 1-2, etc.). In some embodiments, a heteroaryl group is a group having 5 to 10ring atoms, in some embodiments 5, 6, 9, or 10 ring atoms. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, each aromatic monocyclic ring unit is independently 5- or 6- membered. In some embodiments, a heteroaryl ring is monocyclic and is 5-membered. In some embodiments, a heteroaryl ring is monocyclic and is 6-membered. In some embodiments, a heteroaryl ring is bicyclic and is 9-membered. In some embodiments, a heteroaiyl ring is bicyclic and is 10- membcrcd. In some embodiments, a heteroaiyl group has 6, 10, or 14 JC electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five beteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. Heteroaiy l groups include, without limitation, thienyl, furanyl, pynolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyi, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyraziuyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. In some embodiments, a heteroaryl is a heterobiaryl group, such as bipyridyl and the like. The terms “heteroaryl" and “heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl. benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H--quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl. phenoxazinyl. tetrahydroquinolinyl. tetrabydroisoquinolinyl. and pyrido[2,3---b]---I,4--oxazm--3(4H)--one. A heteroaryl group may be monocyclic, bicyclic or polycyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring." ‘’heteroaiyl group." or “heteroaromatic.” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0035] Additionally, it will be appreciated that, when two groups cyclize to form an optionally substituted heteroaiyl ring having at least one nitrogen atom, the nitrogen atom in the ring can be, as valency permits, N or N-R . as defined herein.

[0036] Heterocycle: As used herein, the terms “heterocycle,” “heterocyclyl," “heterocyclic radical," and “heterocyclic ring", as used herein, are used interchangeably and refer to a monocyclic, bicyclic or polycyclic ring moiety (unless otherwise specified, 3-30 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. 13, 14, 15, 16, 17, 18, 19, 20, 25, 3-2.5, 3-2.0, 3-15. 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered) that is saturated or partially unsaturated and has one or more (e.g., 1-10, 1-5, 1, 2, 3, 4, 5, 6, 7, 8, 9. 10, etc.) heteroatom ring atoms. In some embodiments, the number of ring heteroatoms in a heterocyclyl group is about 1-10 (e.g., 1. 2, 3, 4, 5, 6, 7, 8, 9, 10. 1-5, 1-4, 1-3, 1-2. etc.). In some embodiments, a heterocyclyl group is a stable 3-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. In some embodiments, each monocyclic ring is independently 3-10 (e.g..3. 4, 5. 6, 7. 8. 9, 10. 3-8, 3-7, 3-6. 4-6, 5-6. 5-8. etc.) membered. In some embodiments, each monocyclic ring independently has 0-5 (e.g., 0. I, 2. 3. 4, 5, 1 -5. 1-4. 1-2, etc.) heteroatoms wherein at least one monocyclic ring independently has 1-5 (e.g.. 1, 2. 3. 4. 5, 1-5, 1-4, 1-2, etc.) heteroatoms. In someembodiments, each monocyclic ring is independently 3-7 membered. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring haring 0-3 heteroatoms selected from oxy gen, sulfur and nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as iu pyrrolidinyl), or *NR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any hctcroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydro thienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolmyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxany 1, dioxolanyl. diazepmyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,’’ “heterocyclic group." “heterocyclic moiety." and "heterocyclic radical." are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic, bicyclic or polycyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl. wherein the alkyl and heterocyclyl portions independently are optionally substituted.|0037] Additionally, it will be appreciated that, when two groups cyclize to form an optionally substituted heterocyclic ring having at least one nitrogen atom, the nitrogen atom in the ring can be. as valency' permits, N or N-RT, as defined infra.

[0038] Optionally Substituted: As described herein, compounds of the disclosure may contain optionally substituted, substituted and / or unsubstituted moieties. In general, the term “substituted,” means that one or more hydrogens of the designated moiety are independently replaced with a substituent.Unless otherwise indicated, an “optionally substituted” group may independently have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with two or more substituents, the substituents may be either the same or different at every position. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. Various substituents are described below.

[0039] Monovalent substituents are independently halogen; -(CH2)o-4R0: -(CH3)(,.,|ORn; -0(CH2)o.4R°. ”0“(CH2)o-4C(0)ORc'; “(CHzlv-iCHtOR0)?; ~(CH2)CMPII, which may be substituted with R°; “(CHjln-’OtCHri'i-i Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o 40(CH2)o -:”pyridyl which may be substituted with R°: -NO2: --CN; -N?; -(CT-I2)o-’N(R°)2; - (CH2)CMN(RO)C(O)R°; -N(R°)C(S)R°; -(CH2V 4N(RO)C(O)N(R°)2; -N(RO)C(S)N(R°)2: -(CH2)^4N(RO)C(O)OR°; -N(RQ)N(RO)C(O)R°: -N(RO)N(RO)C(O)N(R°)2; -N(RO)N(RO)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; -(CH2)O-4C(0)OR°; -(CH2)(MC(O)SR°; -(CH2)oX(0)OSi(R°)3; -(CH2)o-tOC(0)R°;OUttoaCH ; SR . -SC(S)SR°; tUt U; SCiGjR ; -(CH2)0 4C(O)N(R:')2; --U(S)N(R°)2; -C(S)SR°; -SC(S)SR°, - A ! I. • O( iOiXth ;. . -C(O)N(ORO)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°;−C(NORq)Rq; -(CH2)0–4SSRq; –(CH2)0–4S(O)2Rq; –(CH2)0–4S(O)2ORq; –(CH2)0–4OS(O)2Rq; −S(O)2N(Rq)2; -(CH2)0–4S(O)Rq; –N(Rq)S(O)2N(Rq)2; –N(Rq)S(O)2Rq; –N(ORq)Rq; −C(NH)N(Rq)2; – Si(Rq)3; –OSi(Rq)3; −P(Rq)2; −P(ORq)2; −OP(Rq)2; −OP(ORq)2; −N(Rq)P(Rq)2; −B(Rq)2; −OB(Rq)2; −P(O)(Rq)2; −OP(O)(Rq)2; −N(Rq)P(O)(Rq)2; –(C1-4straight or branched alkylene)O–N(Rq)2; or –(C1-4straight or branched alkylene)C(O)O–N(Rq)2; wherein each Rq may be independently substituted as defined below and is independently hydrogen, C1-10(e.g., C1-6, C1-5, C1-4, etc.) aliphatic, C1-10(e.g., C1-6, C1-5, C1-4, etc.) heteroaliphatic having 1-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, C6-10(e.g., C6, C10, etc.) aryl, 5-10 (e.g., 5- 9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 (e.g., 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur, −CH2−(C6-10(e.g., C6, C10, etc.) aryl), −O(CH2)0-1(C6-10(e.g., C6, C10, etc.) aryl), −CH2−(5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 (e.g., 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur), −O(CH2)0-1(5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 (e.g., 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur), a 3-10 (e.g., 3- 6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, or partially unsaturated ring having 0-5 (e.g., 0, 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, notwithstanding the definition above, two independent occurrences of Rq, taken together with their intervening atom(s), form a 3-10 (e.g., 3-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated or aromatic ring (for aromatic ring, 5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered) having, in addition to the intervening atom(s), 0-5 (e.g., 0, 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined below.

[0040] Monovalent substituents on Rq (or the ring formed by taking two independent occurrences of Rq together with their intervening atoms), are independently halogen, –(CH2)0–2Rz, –(haloRz), –(CH2)0–2OH, –(CH2)0–2ORz, –(CH2)0–2CH(ORz)2; –O(haloRz), –CN, –N3, –(CH2)0–2C(O)Rz, –(CH2)0–2C(O)OH, – (CH2)0–2C(O)ORz, –(CH2)0–2SRz, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHRz, –(CH2)0–2NRz2, –NO2, – SiRz3, –OSiRz3, -C(O)SRz, –(C1–4straight or branched alkylene)C(O)ORz, or –SSRzwherein each Rzis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)- membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. Divalent substituents on a saturated carbon atom of Rq are independently =O or =S.

[0041] Divalent substituents are independently the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, −O(C(R*2))2–3O−, or −S(C(R*2))2–3S−, wherein each independent occurrence of R*is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. Divalent substituentsthat are bound to vicinal substitutable carbons of an “optionally substituted” group are independently −O(CR*2)2–3O−, wherein each independent occurrence of R*is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)- membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0042] Substituents on the aliphatic group of R*are independently halogen, –Rz, -(haloRz), –OH, −ORz, –O(haloRz), –CN, –C(O)OH, –C(O)ORz, –NH2, –NHRz, –NRz2, or –NO2, wherein each Rzis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0043] Substituents on a substitutable nitrogen are independently –R†, −NR†2, −C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, –S(O)2R†, –S(O)2NR†2, −C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12 (e.g., 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0044] Substituents on the aliphatic group of R†are independently halogen, −Rz, -(haloRz), −OH, – ORz, –O(haloRz), –CN, –C(O)OH, –C(O)ORz, –NH2, –NHRz, –NRz2, or –NO2, wherein each Rzis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3, 4, 5, 6, 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 (e.g., 0, 1, 2, 3, 4, 1-4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0045] Pharmaceutically acceptable salt: As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinicacid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, campborsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, eihanesulfonate, formale, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyl-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonatc, mctbancsulfonatc, 2-naphtbalcncsulfonatc, nicotinate, nitrate, oleate, oxalate, palm itate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0046] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and [N(Cr -<iaiky 1)4]fsalts. Representative alkali or alkaline earth metal sails include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0047] Unless otherwise staled, structures depicted herein are meant to include all isomeric (e.g.. enantiomeric, diastereomeric. and geometric (or conformational)) forms of" the structures; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, etc Therefore, unless otherwise stated, single stereochemical isomers as well as enantiomeric, diastereomeric. and geometric (or conformational) mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric fonns are within the scope of the disclosure. As those skilled in the art appreciate, compounds and elements may exist in various isotopic forms. Unless otherwise stated, the present disclosure includes compounds that differ only in the presence of one or more isotopes at one or more positions, and compositions that are isotopically enriched at one or more positions of one or more compounds. For example, unless otherwise stated, in a compound H may be TT,2H orJH, and C may be1 ?C, “’C or1’"C. In some embodiments, compounds with certain isotopes, or compositions enriched for certain isotopes, are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure. In some embodiments, compounds of this disclosure comprise one or more deuterium atoms. In some embodiments, provided agent, compounds, conjugates, etc. are in salt forms, e.g.. pharmaceutically acceptable salt forms.

[0048] In some embodiments, combinations of substituents and variables envisioned by this disclosure are only those that result in the formation of stable compounds, wherein “stable’" refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).Other Definitions

[0049] About: As used herein, the term “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In some embodiments, the term “about” refers to arange of values that fall within 25%, 20%. 19%, 18%, 17%, 16%. 15%. 14%, 13%, 12%, 1 1%, 10%, 9%, 8%, 7%. 6%, 5%, 4%, 3%, 2%. I %, or less in either direction (greater than or less than) of the stated reference value rmless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0050] Affinity matured: As used herein, the term “affinity matured” refers to an antibody with one or more alterations in one or more CDRs thereof, which result in an improvement in affinity of an antibody for an antigen, compared to a parent antibody that does not possess those one or more alterations. In some embodiments, affinity matured antibodies will have nanomolar or even picomolar affinities for a target antigen. Affinity matured antibodies may be produced by any of a variety of procedures known in the art. Affinity maturation by VH and VL domain shuffling is described in Marks et al., BioTechnology 10:779-783 (1992). Random mutagenesis of CDR and / or framework residues is described in: Barbas et al. Proc Nat. Acad. Sci. U S A 91 :3809-3813 (1994); Schier et al.. Gene 169: 147- 155 ( 1995); Yellon et al., J. Immunol. 155: 1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins et al.. J Mol. Biol. 226:889-896 (1992).

[0051] Agent: As used herein, the term “agent” refers to a biological entity and / or compound including, for example, an antibody or antigen-binding fragment thereof, an organic molecule (e.g.. a small molecule), a peptide (e.g.. a fusion protein), an aptamer, a nucleic acid, a chimeric antigen receptor, a glycoprotein, a saccharide, a lipid, a growth factor, an enzyme, a synthetic molecule, a carbohydrate, a lipid, a hormone, a polymer, or a derivative, variation, complex, or any combination thereof. In appropriate circumstances, as will be clear from context to those skilled in the art, the term may be utilized to refer to an entity that is or comprises a cell or organism, or a fraction, extract, or component thereof Alternatively or additionally, as context will make clear, the term may be used to refer to a natural product. In some instances, again as will be clear from context, the term may be used to refer to one or more entities that is man-made in that it is designed, engineered, and / or produced through human action and / or is not found in nature. In some embodiments, an agent may be utilized in isolated or pure form. In some embodiments, an agent may be utilized in etude form. In some embodiments, agents are provided as collections or libraries, which may be screened to identify or characterize active agents within them. z\n agent may bind any cell moiety, such as a receptor, an antigenic determinant, or other binding site present on a target or target cell. Various agents are useful in the compositions and methods described herein.

[0052] Antibody: As used herein, the term “antibody" refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen. As is known in the art. intact antibodies as produced in nature are approximately 150 kD tetrameric agents comprising two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (about 25 kD each) that associate with each other into what is commonly referred to as a “Y- shaped” structure. Each heavy chain comprises at least four domains (each about 110 amino acids long) -- an amino-terminal variable (VH) domain (located at the tips of the ¥ structure), followed by three constant domains: CHI, CH2, and the carboxy-terminal CH3 (located at the base of the Y’s stem). Ashort region, known as the “switch,” connects the heavy chain variable and constant regions. The “hinge” connects CH2 and CH3 domains to the rest of the antibody Two disulfide bonds in this binge region connect the two heavy chain polypeptides to one another in an intact antibody Each light chain comprises two domains •- an amino-terminal variable ( VL) domain, followed by a carboxy -terminal constant (CI..) domain, separated from one another by another “switch”. Intact antibody tetramers comprise two heavy chain-light chain dimers in which the heavy and light chains arc linked to one another by a single disulfide bond; two other disulfide bonds connect the heavy chain hinge regions to one another so that the dimers are connected to one another and a tetramer is formed. Naturally -produced antibodies are also glycosylated, typically on the CH2 domain. Each domain in a natural antibody has a structure characterized by an ‘‘immunoglobulin fold” formed from two beta sheets (e.g., 3-, 4-, or 5-stranded sheets) packed against each other in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops known as ‘‘complementarity determining regions” (CDR1, CDR2, and CDR3) and four somewhat invariant “framework” regions (FR1, FR2, FR3, and FR4). When natural antibodies fold, the FR regions form the beta sheets that provide the structural framework for the domains, and the CDR loop regions from both the heavy and light chains are brought together in three-dimensional space so that they create a single hypervariable antigen binding site located at the tip of the Y structure. The Fc region of naturally -occurring antibodies binds to elements of the complement system, and also to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. Affinity and / or other binding attributes of Fc regions for Fc receptors can be modulated through glycosylation or other modification. In some embodiments, antibodies produced and / or utilized in accordance with the present disclosure include glycosylated Fc domains, such as Fc domains with modified or engineered glycosylation. In some embodiments, any polypeptide or complex of polypeptides that includes sufficient immunoglobulin domain sequences as found in natural antibodies can be referred to and / or used as an “antibody”, whether such polypeptide is naturally produced (e.g., generated by an organism reacting to an antigen) or produced by recombinant engineering, chemical synthesis, or other artificial system or methodology . In some embodiments, an antibody is polyclonal. In some embodiments, an antibody is monoclonal. In some embodiments, an antibody has constant region sequences characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, antibody sequence elements are humanized, primatized, or chimeric as is known in the art. Moreover, the term “antibody,” as used herein, can refer in appropriate embodiments (unless otherwise stated or clear from context) to any of tire art-known or developed constructs or formats for utilizing antibody structural and functional features in alternative presentation. For example, in some embodiments, an antibody utilized in accordance with provided technologies is in a format selected from, but not limited to, intact IgA, IgG, IgE or IgM antibodies; bispecific or multi- specific antibodies (e.g.. Zybodies'®, etc); and / or antibody fragments (preferably antibody fragments that exhibit desired antigen-binding activity). An antibody described herein can be an immunoglobulin, heavy chain antibody, light chain antibody. LRR-based antibody, or other protein scaffold with antibody -like properties, as well as any other immunological binding moiety' known in the art, e.g.. a Fab, Fab', Fab'2. Fab2. Fab3, F(ab’)2 , Fd, Fv, Feb, scFv, SMIP, antibody, diabody, triabody.tetrabody, minibody, maxibody, tandab. DVD, BiTe. TandAb, or any combmation thereof. The subunit structures and three-dimensional configurations of different classes of antibodies are known in the art. In some embodiments, an antibody may lack a covalent modification (e.g., attachment of a glycan) that it would have if produced naturally. In some embodiments, an antibody may contain a covalent modification (e.g., attachment of a glycan, a payload (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc), or other pendant group (e.g., poly -ethylene glycol, etc.).

[0053] Antibody agent: As used herein, the term "antibody agent’’ refers to an agent that specifically binds to a particular antigen. In some embodiments, the term encompasses any polypeptide or polypeptide complex that includes immunoglobulin structural elements sufficient to confer specific binding Exemplary' antibody agents include, but are not limited to monoclonal antibodies or polyclonal antibodies. In some embodiments, an antibody agent may include one or more constant region sequences that are characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, an antibody agent may include one or more sequence elements are humanized, primatized, or chimeric, as is known in the art. In many embodiments, the term "antibody agent” is used to refer to one or more of the art-known or developed constructs or formats for utilizing antibody structural and functional features in alternative presentation. For example, an antibody agent utilized in accordance with provided technologies is in a format including, but not limited to. intact IgA, IgG. IgE or IgM antibodies; bi- specific or multi-specific antibodies (e.g., Zybodies®, etc); antibody fragments such as Fab fragments. Fab' fragments. F(ab’)2 fragments. Fd' fragments. Fd fragments, and isolated CDRs or sets thereof; single chain Fvs; polypeptide-Fc fusions; single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); camelid antibodies: masked antibodies (e.g., Probodies®): Small Modular ImmunoPharmaceuticals (“SMIPs™ ); single chain or Tandem diabodies (TandAb®); VHHs;Anticalins®; Nanobodies® minibodies; BiTE®s; ankyrin repeat proteins or DARPINs®; Avimers®; DARTs; TCR-like antibodies;, Adnectins®; Affilins®; Trans-bodies®: Affibodies®; TritnerX®; MicroProteins; Fynomers®, Centyrins®; or KALBITOR®s. In some embodiments, an antibody lacks a covalent modification (e.g., attachment of a glycan) that it would have if produced naturally. In some embodiments, an antibody contains a covalent modification (e.g.. attachment of a glycan, a payload, e.g., a detectable moiety, a therapeutic moiety, or a catalytic moiety7), or other pendant group (e.g., poly- ethylene glycol) In many embodiments, an antibody agent is or comprises a polypeptide whose amino acid sequence includes one or more structural elements recognized by those skilled in the art as a complementarity determining region (CDR); in some embodiments an antibody agent is or comprises a polypeptide whose amino acid sequence includes at least one CDR (e.g., at least one heavy chain CDR and / or at least one light chain CDR) that is substantially identical to one found in a reference antibody. In some embodiments, an included CDR substantially identical to a reference CDR in that it is either identical in sequence or contains between 1-5 ammo acid substitutions as compared with the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR by at least 85%, 86%, 87%, 88%. 89%, 90%, 91%, 92%. 93%, 94%, 95%. 96%. 97%, 98%, 99%. or 100% sequence identity with the reference CDR. In some embodiments, an included CDR is substantially identical to areference CDR by at least 96%. 96%, 97%, 98%, 99%. or 100% sequence identity with the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that at least one amino acid within the included CDR is deleted, added, or substituted as compared with the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical with that of the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that 1-5 ammo acids within the included CDR arc deleted, added, or substituted as compared with the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in dial at least one amino acid within the included CDR is substituted as compared w ith the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical with that of the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that 1-5 amino acids within the included CDR are deleted, added, or substituted as compared with the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, an antibody agent is or comprises a polypeptide whose amino acid sequence includes structural elements recognized by those skilled in the art as an immunoglobulin variable domain. In some embodiments, an antibody agent is a polypeptide protein, having a binding domain that is homologous or largely homologous to an immunoglobulin-binding domain10054 j Antibody’ heavy chain: / ‘Vs used herein, the term "antibody heavy chain’" refers to the larger of the two types of polypeptide chains present in all antibodies in their naturally occurring conformations

[0055] Antibody light chain: As used herein, the term "antibody light chain” refers to the smaller of the two types of polypeptide chains present in all antibodies in their naturally occurring conformations

[0056] Antigen: As used herein, the term "antigen” or "Ag” refers to a molecule that is capable of provoking an immune response. This immune response may involve either antibody production, the activation of specific immunologically-competent cells, or both. A skilled artisan will understand that any macromolecule, including virtually ail proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. A skilled artisan will understand that any DN A that comprises a nucleotide sequence or a partial nucleotide sequence encoding a protein that elicits an immune response encodes an "antigen” as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full length nucleotide sequence of a gene. It is readily apparent that provided technologies include, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to elicit the desired immune response. Moreover, a skilled artisan will understand that an antigen need not be encoded by a "gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell, or a biological fluid.

[0057] Antigen-binding fragment: As used herein, the term "antigen-binding fragment” refers to a portion of an intact antibody that binds the antigen to which the intact antibody binds. An antigen-binding fragment of an antibody includes any naturally occurring, enzymatically obtainable, synthetic, orgenetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Exemplary 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. VHH, camelid, or VH or VL domains only); or multispecific antibodies formed from antibody' fragments. In some embodiments, the antigen-binding fragments of the antibodies described herein are scFvs. In some embodiments, the antigen-binding fragments of the antibodies described herein arc VHH domains only. As with full antibody molecules, antigen-binding fragments may be mono-specific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody may comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope of the same antigen. An antigen-binding fragment may be produced by any means. For example, in some embodiments, an antigen-binding fragment is enzymatically or chemically produced by fragmentation of an intact antibody or antibody agent. Alternatively, in some embodiments, an antigen-binding fragment is recombmantly produced. In some embodiments, an antigen-binding fragment is wholly or partially synthetically produced. In some embodiments, an antigen-binding fragment has a length of at least about 50, 60, 70, 80. 90, 100, 110, 120. 130. 140, 150, 160, 170, 180. 190, or 200 amino acids or more.

[0058] Antibody -Dependent Cellular Cytotoxicity: As used herein, the term “antibody-dependent cellular cytotoxicity" or "ADCC" refers to a phenomenon in which target cells bound by antibody are killed by immune effector cells. Without wishing to be bound by theory', ADCC is typically understood to involve Fc receptor (FcR)-bearing effector cells recognizing and subsequently killing antibody-coated target cells (e.g., cells that express on their surface specific antigens to which an antibody is bound) Effector cells that mediate ADCC include immune cells including, but not limited to, natural killer (NK) cells, macrophage, neutrophils, and eosinophils.|0059] Aptamer: As used herein, the term “aptamer" refers to a macromolecule composed of nucleic acid (e.g., RNA, DMA) that binds tightly to a specific molecular target (e.g., an umbrella topology glycan). A particular aptamer may be described by a linear nucleotide sequence and is typically about 15- 60 nucleotides in length. Without wishing to be bound by any theory, it is contemplated that the chain of nucleotides in an aptamer form intramolecular interactions that fold tire molecule into a complex three- dimensional shape, and this three-dimensional shape allows the aptamer to bind tightly to the surface of its target molecule. Given the extraordinary diversity of molecular shapes that exist within the universe of all possible nucleotide sequences, aptamers may be obtained for a wide array of molecular targets, including proteins and small molecules. In addition to high specificity , aptamers typically have very high affinities for their targets (e.g., affinities in the picomolar to low nanomolar range for proteins). In many embodiments, aptamers are chemically stable and can be boiled or frozen without loss of activity.Because they are synthetic molecules, aptamers are amenable to a variety of modifications, which can optimize their function for particular applications. For example, aptamers can be modified to dramatically reduce their sensitivity to degradation by enzymes in the blood for use in in vivo applications. In addition, aptamers can be modified to alter their biodistribution or plasma residence time.

[0060] Associated: Two events or entities are “associated” wife one another, as that semi is usedherein, if the presence, level, degree, type and / or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, or microbe) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and / or form correlates with incidence of and / or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they arc and / or remain in physical proximity with one another. In some embodiments, two or more entities physically associated with one another are covalently linked to one another. In some embodiments, two or more entities physically associated with one another are not covalently linked to one another but are non-covalently associated, for example, by means of hydrogen bonds, r an der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.[0061 j Binding: As used herein, the term “binding" refers to a non-covalent association between or among two or more entities. "Direct” binding involves physical contact between entities or inoieties. Indirect binding involves physical interaction by way of physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts -- including where interacting entities or moieties are studied in isolation or in the context of more complex systems (e.g., while covalently or otherwise associated with a carrier entity and / or in a biological system or cell)

[0062] Cancer: As used herein, the terms “cancer.” “malignancy,” “neoplasm,” “tumor,” and “carcinoma,” refer to cells that exhibit relatively abnormal, uncontrolled, and / or autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. In some embodiments, a tumor is or comprises cells that are precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and / or non-metastatic. In some embodiments, cancer is or comprises a solid tumor. In some embodiments cancer is or comprises a hematologic tumor. Examples of various cancers are described herein and include, but are not limited to, hematopoietic cancers including leukemias, lymphomas (Hodgkin’s and non-Hodgkin’s), myelomas and myeloproliferative disorders; sarcomas, melanomas, adenomas, carcinomas of solid tissue, squamous cell carcinomas of the mouth, throat, larynx, and lung, liver cancer, genitourinary cancers, such as prostate, cervical, bladder, uterine, and endometrial cancer and renal cell carcinomas, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, head and neck cancers, breast cancer, gastro-intestinal cancers, nervous system cancers, or benign lesions, such as papillomas, as well as several other types including those as described elsewhere herein.

[0063] Carrier: as used herein, “carrier” refers to a diluent, adjuvant, excipient, and / or vehicle with which a composition is administered. In some exemplary embodiments, carriers include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil. sesame oil and the like. In some embodiments, can ters are or include one or more solid components.|0064] CDR: As used herein, “CDR” refers to a complementarity determining region within an antibody variable region. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions. A “set of CDRs” or “CDR set” refers to a group of three or six CDRs that occur in either a single variable region capable of binding the antigen or the CDRs of cognate heavy and light chain v ariable regions capable of binding the antigen. The exact definitional CDR boundaries and lengths are subject to different classification and numbering systems. Certain systems have been established in the art for defining CDR boundaries (e.g.. Rabat, IMGT. Chothia, or a combination thereof). CDRs may therefore be referred to by Kabas, Chothia, IMGT. or any other boundary' definitions known in the art. Despite differing boundaries, each of these systems has some degree of overlap in what constitutes the “hypervariable regions" within die variable sequences. CDR definitions according to these systems may therefore differ in length and boundary areas with respect to the adjacent framework region (see. e.g., Rabat et al., in "Sequences of Proteins of Immunological Interest.” 5 th Edition, U.S. Department of Health and Human Services, 1992; Chothia et al, (1987) J. Mol. Biol. 196, 90k and MacCalhim et al., J. Mol. Biol. (1996) 262. 732, each of which is incorporated by reference in its entirety). Those skilled in the art appreciate the differences between and among these systems and are capable of understanding CDR boundaries to the extent required to understand and to practice the claims and disclosure herein.

[0065] Chemotherapeutic Agent: The term “chemotherapeutic agent,” as used herein has its art- understood meaning referring to one or more pro-apoptotic, cytostatic and / or cytotoxic agents, for example specifically including agents utilized and / or recommended for use in treating one or more diseases, disorders or conditions associated with undesirable cell proliferation. In many embodiments, chemotherapeutic agents are useful in the treatment of cancer. In some embodiments, a chemotherapeutic agent may be or comprise one or more alkylating agents, one or more anthracyclines, one or more cytoskdetal disruptors (e.g. microtubule targeting agents such as taxanes, maytansine and analogs thereof, of), one or more epothilones, one or more histone deacetylase inhibitors HDACs), one or more topoisomerase inhibitors (e.g., inhibitors of topoisomerase I and / or topoisomerase II), one or more kinase inhibitors, one or more nucleotide analogs or nucleotide precursor analogs, one or more peptide antibiotics, one or more platinum-based agents, one or more retinoids, one or more vinca alkaloids, and / or one or more analogs of one or more of the following (i.e , that share a relevant anti-proliferative activity). In some embodiments, a chemotherapeutic agent may be or comprise one or more of Actinomycin. All- bans retinoic acid, an Auiristatin, Azacitidine. Azathioprine, Bleomycin, Bonezomib, Carboplatm, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Curcumin. Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Epothilone. Etoposide, Fluorouracil. Gemcitabine, Hydroxyurea, Idarabicin, Imatinib. Irinotecan, Maytansine and / or analogs thereof (e.g. DMI) Mechlorethamine. Mercaptopurine. Methotrexate, Mitoxantrone, a Maytansinoid. Oxaliplatin, Paclitaxel, Pemetrexed. Teniposide. Tioguanine, Topotecan. Valrubicin. Vinblastine, Vincristine. Vindesine, Vinorelbine, or combinations thereof In some embodiments, a chemotherapeutic agent may be utilized in the context of an antibody -drug conjugate. In some embodiments, a chemotherapeutic agent is anantibody -drug conjugate comprising: hLLl -doxorubicin, hRS7-SN-38, hMN-14-SN-38, hLL2-SN-38, hA20-SN-38, hPAM4-SN-38, hLLl-SN-38. bRS7-Pro-2-P-Dox, hMN-14-Pro-2-P-Dox, hLL2-Pro-2-P- Dox, hA20-Pro-2-P-Dox, hPAM4-Pro-2-P-Dox. hLLl-Pro-2-P-Dox, P4 / D10-doxorubicm, gemtuzumab ozogamicin, brenluximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, glembatumomab vedotin, SAR3419, SAR566658, BIIB0L5, BT062. SGN-75, SGN-CD19A, AMG-172, AMG-595. BAY- 94-9343, ASG-5ME, ASG-22ME, ASG-16M8F, MDX-1203, MLN-0264, anti-PSMA ADC, RG-7450. RG-7458, RG-7593, RG-7596, RG-7598, RG-7599, RG-7600, RG-7636, ABT-414, IMGN-853, IMGN- 529, vorsetuzumab mafodotin, and / or lorvotuzumab mertansine.

[0066] Chimeric antibody : as used herein, refers to an antibody whose amino acid sequence includes VH and VL region sequences that are found in a first species and constant region sequences that are found in a second species, different from the first species. In many embodiments, a chimeric antibody has murine VH and VL regions linked to human constant regions. In some embodiments, an antibody with human VH and VL regions linked to non-human constant regions (e.g., a mouse constant region) is referred to as a "reverse chimeric antibody."'

[0067] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form - e g , gas, gel, liquid, or solid.[006§] Comprising: A composition or method described herein as “comprising” one or more named dements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method. To avoid prolixity, it is also understood that any composition or method described as "comprising” (or which “comprises”) one or more named elements or steps also describes the corresponding, more limited composition or method “consisting essentially of’ (or which "consists essentially of) tlie same named elements or steps, meaning that the composition or method includes the named essential dements or steps and may also include additional elements or steps that do not materially affec t the basic and novel charactenstic(s) of the composition or method. It is also understood that any composition or method described herein as “comprising” or “consisting essentially of’ one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method “consisting of’ (or “consists of’) the named elements or steps to the exclusion of any other unnamed element or step. In any composition or method disclosed herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step.

[0069] Conservative sequence modifications: As used herein, the term “conservative sequence modifications” refers to amino acid modifications that do not significantly affect or alter the binding characteristics of an antibody- or antigen-binding fragment thereof containing the amino acid sequence. Such conservative modifications include amino acid substitutions. additions, and deletions. Modifications can be introduced into an antibody compatible with various embodiments by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis Conservative ammo acid substitutions are ones in -which an amino acid residue is replaced with an amino acid residue having asimilar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g.. aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isolcucinc) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within the CDR regions of an antibody can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for the ability to bind antigens using the functional assays described herein.[0070 j Combination therapy: The term ‘'combination therapy", as used herein, refers to those situations in which two or more different therapeutic agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents. When used in combination therapy, too or more different therapeutic agents may be administered simultaneously or separately. This administration in combination can include simultaneous administration of the too or more therapeutic agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is. two or more therapeutic agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, too or more therapeutic agents can be simultaneously administered, wherein the agents are present in separate formulations. In another alternative, a first therapeutic agent can be administered followed by one or more additional therapeutic agents. In the separate administration protocol, two or more therapeutic agents may be administered a few minutes apart, or a few hours apart, a few days apart, or a few weeks apart. In some embodiments, two or more therapeutic agents may be administered within hours (e g.. less than about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours) apart.

[0071] Effective amount: As used herein, an “effective amount” refers to a dose that is adequate to prevent or treat at least one sign and / or symptom of a disease, disorder or condition (e.g., cancer) in an individual. Amounts effective for a therapeutic or prophylactic use will depend on, for example, the stage and severity of the disease, disorder or condition being treated, the age, weight, and general state of health of the patient, and the judgment of the prescribing physician. The size of the dose will also be determined by the active selected, method of administration, timing and frequency of administration, the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular active, and the desired physiological effect. It will be appreciated by one of skill in the art that various diseases or disorders could require prolonged treatment involving multiple administrations. For purposes of the disclosure, the amount or dose of a therapeutic agent (e.g., at least one HHLA2 binding agent described herein) administered should be sufficient to effect a therapeutic or prophylactic response in a subject over a reasonable time frame (e.g., reduction or other lessening of severity' or duration of at least one sign or symptom). For example, the dose should be sufficient to detect, treat, or prevent cancer in a period of from about 2 hours or longer, e.g.. about 12 to about 24 or more hours, from the time of administration. In some embodiments, the lime period is even longer. The dose will be determined by theefficacy of one or more particular therapeutic agents and condition of a subject (e.g.. a human) as well as body weight of a subject (e g , a human) to be treated.

[0072] Encoding: As used herein, tire term '‘encoding’’ refers to the inherent property of specific sequences of nucleotides in a poly nucleotide, such as a gene, a cDNA, or an niRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (e.g., rRNA, tRNA or niRNA) or a defined sequence of amino acids and biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRN A corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to lite mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.

[0073] Engineered: As used herein, the term "engineered ’ refers to the aspect of having been manipulated by the hand of man. For example, a polynucleotide is considered to be "engineered” when two or more sequences, that are not linked together in that order in nature, are manipulated by the hand of man to be directly linked to one another in the engineered polynucleotide. For example, in some embodiments, an engineered polynucleotide comprises or is a regulatory sequence that is found in nature in operative association with a first coding sequence but not in operative association with a second coding sequence, is linked by the hand of man so that it is operatively associated with the second coding sequence. Comparably, a cell or organism is considered to be "engineered” if it has been manipulated so that its genetic information is altered (e.g.. new genetic material not previously present has been introduced, for example by transformation, mating, somatic hybridization, transfection, transduction, or other mechanism, or previously present genetic material is altered or removed, for example by substitution or deletion mutation, or by mating protocols). In some embodiments, engineered antibodies or antigen- binding fragments thereof (e.g., engineered monoclonal antibodies or antigen-binding fragments thereof) include VH and / or VL region sequences from a reference antibody raised in a non-human species (e.g., a mouse) and modifications in those sequences relative to a reference antibody intended to render them more "human-like” or more similar to human gcrmline variable sequences.

[0074] As is common practice and is understood by those in the art, progeny of an engineered polynucleotide or cell are typically still referred to as "engineered” even though the actual manipulation was performed on a prior entity.

[0075] Epitope: As used herein, the term "epitope” refers to any moiety that is specifically recognized by an immunoglobulin (e.g., antibody or receptor) binding component. In some embodiments, an epitope is comprised of a plurality of chemical atoms or groups on an antigen. In some embodiments, such chemical atoms or groups are surface-exposed when the antigen adopts a relevant three-dimensional conformation. In some embodiments, such chemical atoms or groups are physically near to each other in space when the antigen adopts such a conformation. In some embodiments, at least some such chemical atoms are groups are physically' separated from one another when the antigen adopts an alternative conformation (e.g., is linearized).|0076] Expression: As used herein, the term ‘'expression” of a nucleic acid sequence refers to generation of any gene product from a nucleic acid sequence (e.g., a nucleic acid sequence encoding an anti-HHLA2 antibody or antigen-binding fragment thereof described herein). In some embodiments, a gene product can be a transcript. In some embodiments, a gene product can be a polypeptide. In some embodiments, expression of a nucleic acid sequence involves one or more of the following: (1) production of an RNzA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing. 5’ cap formation, and / or 3' end formation); (3) translation of an RNA into a polypeptide or protein; and / or (4) post-translational modification of a polypeptide or protein.

[0077] Fragment: As used herein, the term “fragment’’ refers to a structure that includes a discrete portion of the whole, but lacks one or more moieties found in the whole structure. In some embodiments, a fragment consists of such a discrete portion. In some embodiments, a fragment consists of or comprises a characteristic structural element or moiety found in the whole. In some embodiments, an antigen- binding fragment comprises or consists of at least 3. 4. 5, 6, 7, 8, 9. 10. Il, 12, 13. 14. 15, 16, 17, 18, 19. 20, 25, 30, 35, 40, 45, 50, 55. 60. 65. 70. 75. 80. 85, 90, 95, 100, 110. 120. 130, 140, 150. 160. 170, 180, 190. 200, 210. 220, 230, 240, 250. 275, 300, 325. 350. 375. 400, 425, 450, 475. 500, or more monomeric units (e.g.. amino acids) as found in a whole antibody. In some embodiments, an antigen-binding fragment comprises or consists of at least about 5%. 10%, 15%. 20%. 25%. 30%, 25%. 40%. 45%,, 50%>, 55%, 60%, 65%. 70%, 75%, 80%, 85%. 90%, 95%, 96%, 97%. 98%, 99%, or more of the monomeric units (e.g.. residues) found in a whole antibody In some embodiments, a nucleotide fragment comprises or consists of at least about 5%. 10%, 15%, 20%, 25% 30%, 25%, 40%, 45%. 50%. 55%, 60%, 65%, 70%., 75%, 80%. 85%, 90%, 95%, 96%. 97%, 98%, 99%, or more of the monomeric units (e.g., residues) found in the whole nucleotide.

[0078] Framework region: as used herein, the term “framework region” refers to the sequences of a variable region minus the CDRs. Because a CDR sequence can be determined by different systems, likewise a framework sequence is subject to correspondingly different interpretations. The six CDRs divide the framework regions on the heavy and light chains into four sub-regions (FR1, FR2, FR3, and FR4) on each chain, in which CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying the particular sub-regions as FR1, FR2. FR3 or FR4, a framework region, as referred by others, represents the combined FRs within the variable region of a single, naturally occurring immunoglobulin chain. As used herein, a FR represents one of the four sub- regions. FR 1 , for example, represents the first framework region closest to the am ino terminal end of the variable region and 5* with respect to CDR1, and FRs represents two or more of the sub-regions constituting a framework region.

[0079] Gene: As used herein, the term “gene” refers to a DNA sequence in a chromosome that codes for a product (e.g., an RNA product and / or a polypeptide product). In some embodiments, a gene inchides coding sequence (i e , sequence that encodes a particular product); in some embodiments, a gene includes non-coding sequence. In some embodiments, a gene may include both coding (e.g., exonic) and non- coding (e.g., mtronic) sequences. In some embodiments, a gene may include one or more regulatoryelements that, for example, may control or impact one or more aspects of gene expression (e.g., cell-type- specific expression and / or inducible expression).

[0080] Homology: As used herein, the term “homology” refers to the overall relatedness between polymeric molecules, e.g., between nucleic acids (e.g., DNA and / or RNA) and / or between polypeptides. In some embodiments, polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%. 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%. 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical, in sotne embodiments, polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%. 90%, 95%, or 99% similar (e.g., containing residues with related chemical properties at corresponding positions). As will be understood by those skilled in the art, a variety of algorithms are available that permit comparison of sequences in order to determine their degree of homology, including by permiting gaps of designated length in one sequence relative to another when considering which residues “correspond” to one another in different sequences. Calculation of the percent homology between two nucleic acid sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g.. gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-corresponding sequences can be disregarded for comparison purposes) In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%. at least 40%, at least 50?4 at least 60%. at least 70%. at least 80%. at least 90%, at least 95%, or substantially 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position: when a position in the first sequence is occupied by7a similar nucleotide as the corresponding position in the second sequence, then the molecules are similar at that position. The percent homology between the two sequences is a function of the number of identical and similar positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences.

[0081] Host cell: as used herein, the term “host cell” refers to a cell into which exogenous DNA (recombinant or otherw ise) has been introduced. Persons of skill upon reading this disclosure will understand that such terms refer not only to the particular subject cell, but also to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not. in fact, be identical to the parent cell, but are still included within the scope of the term host cell as used herein. In some embodiments, host cells include prokaryotic and eukaryotic cells selected from any of the Kingdoms of life that are suitable for expressing an exogenous DMA (e.g,, a recombinant nucleic acid sequence). Exemplary cells include those of prokaryotes and eukaryotes (single-cell or multiple-cell), bacterial cells (e.g., strains of E. coli. Bacillus spp., or Streptomyces spp.). mycobacteria cells, fungal cells, yeast cells (e.g., S. cerevisiae, S. pombe, P. pastoris, or P. methanolica). plant cells, insect cells (e g.. SF-9. SF-21. baculovirus-infected insect cells, or Trichoplusia ni.), non-htiman animal ceils, hitman cells, or cell fusions (e.g.. hybridomas or quadromas).In some embodiments, the cell comprises or is a human, monkey, ape, hamster, rat, or mouse cell. In some embodiments, the cell is a eukaryotic cell chosen from: CHO (e.g., CHO KI, DXB-1 1 CHO, Veggie- CHO), COS (e.g , COS-7), retinal celt Vero, CVI, kidney (e.g.. HEK293, 293 EBNA. MSR 293, MDCK, HaK, BHK), HeLa, HepG2, WI38, MRC 5, Colo205, HB 8065, HL -60. (e.g., BHK21), Jurkai, Daudi, A431 (epidermal), CV-1. U937, 3T3, L cell, C127 cell, SP2 / 0, NS-0, MMT 060562. Sertoli cell, BRL 3 A cell, HT1080 cell, myeloma cell, tumor cell, or a cell line derived from an aforementioned cell. In some embodiments, a cell comprises one or more viral genes.|0082] Human antibody: as used herein, the term “human antibody” refers to antibodies having variable and constant regions generated (or assembled) from human immunoglobulin sequences. Antibodies or antigen-binding fragments thereof may be considered “human” even though their amino acid sequences include residues or elements not encoded by human germline immunoglobulin sequences (e.g., sequence variations that may have been introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), such as in one or more CDRs and in particular CDR3.

[0083] Humanized: as used herein, the term “humanized” refers to antibodies or antigen-binding fragments thereof whose amino acid sequence includes VH and / or VL region sequences fiom a reference antibody raised in a non-human species (e.g., a mouse), but also includes modifications in those sequences relative to the reference antibody intended to render them more “human-like” or more similar to human germline variable sequences. In some embodiments, a humanized antibody or an tigen -binding fragment thereof is one that immuuospecifically binds to an antigen of interest and has a FR region with substantially the ammo acid sequence of a human antibody' and a CDR with substantially the amino acid sequence of a non-human antibody. A humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab; F(ab')2. FabC, Fv) in which all or substantially all of the CDR regions correspond to a non-human immunoglobulin (e.g., a donor immunoglobulin) and all or substantially all of the framework regions correspond to a human immunoglobulin consensus sequence. In some embodiments, a humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin constant region. In some embodiments, a humanized antibody contains both the light chain as well as at least the variable domain of a heavy chain. The antibody also may include a CHI, hinge, CH2, CH3, and, optionally, a CH4 region of a heavy chain constant region. In some embodiments, a humanized antibody only contains a humanized VL region. In some embodiments, a humanized antibody only contains a humanized VH region. In some certain embodiments, a humanized antibody contains humanized VH and VL regions.

[0084] Identity: As used herein, the term “identity” refers to the subunit sequence identity between two polymeric molecules, particularly between two ammo acid molecules, such as between two polypeptide molecules. When two amino acid sequences have the same residues at the same positions; e.g., if a position in each of two polypeptide molecules is occupied by an Arginine, then they are identical at that position. The identity or extent to which two amino acid sequences have the same residues at the same positions in an alignment is often expressed as a percentage. The identity between two amino acid sequences is a direct function of the number of matching or identical positions; e.g., if half of the positions(e.g., five positions in a polymer of 10 amino acids in length) in two sequences are identical, the two sequences are 50% identical; if 90% of the positions (e.g., nine positions in a polymer of 10 amino acids in length) are identical, the two amino acids sequences are 90% identical

[0085] Immune cell: As used herein, the term “immune cell." refers to a cell that is involved in an immune response, e.g., promotion of an immune response. Examples of immune cells include, but are not limited to. T cells, natural killer (NK) cells, macrophages, monocytes, dendritic cells, neutrophils, eosinophils, mast cells, platelets, large granular lymphocytes, Langerhans' cells, or B-lymphocytes.

[0086] Immune checkpoint: As used herein, the term “immune checkpoint" refers to a group of molecules on the cell surface of CD4+ and / or CD8+ T cells as well as NK cells that fine-tune immune responses by down-modulating or inhibiting an anti-tumor immune response. Immune checkpoint proteins are well-known in the art and include, without limitation, HHLA2, KIR family receptors, CTLA-4. PD-1. VISTA. B7-H2, B7-H3. PD-L1. B7-H4, B7-H6. 1COS, HVEM, PD-L2, CD 160, gp49B. PIR-B, TIM-1. TIM-3. TIM-4. LAG-3, GITR. 4-IBB. OX-40, BTLA. SIRPa, CD47. CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT. CD226. CD155, CD112. butyrophilins. and A2aR. In some embodiments, NK cells comprise TIGIT. CD226. and / or CD96. The term further encompasses biologically active protein fragment, as well as nucleic acids encoding full-length immune checkpoint proteins and biologically active protein fragments thereof In some embodiment, the term further encompasses any fragment according to homology descriptions provided herein.

[0087] Immune response: As used herein the term “immune response" refers to a cellular and / or systemic response to an antigen that occurs when lymphocytes identify antigenic molecules as foreign and induce the formation of antibodies and / or acti vate lymphocytes to remove the antigen. In some embodiments, an immune cell response can include proliferation of an immune effector cell (e.g., a T cell), cy tokine production by an immune effector cell (e.g.. a T cell), and / or release of cytotoxic granules comprising perforin and / or granzymes by an immune effector cell (e.g., a T cell).

[0088] Immunoglobulin: As used herein, the term “immunoglobulin’’ or “Ig," refers to a class of proteins that function as antibodies. Antibodies expressed by B cells are sometimes referred to as a BCR (B cell receptor) or antigen receptor. The five members included in this class of proteins are IgA. IgG, IgM, IgD. and IgE. IgA is the primary antibody that is present in body secretions, such as saliva, tears, breast milk, gastrointestinal secretions and mucus secretions of the respiratory and genitourinary tracts. IgG is the most common circulating antibody. IgM is the main immunoglobulin produced in the primary immune response in most subjects. It is the most efficient immunoglobulin in agglutination, complement fixation, and other antibody responses, and is important in defense against bacteria and viruses. IgD is an immunoglobulin that has no known antibody function, but may serve as an antigen receptor. IgE is an immunoglobulin that mediates immediate hypersensitivity by causing release of mediators from mast cells and basophils upon exposure to allergen.

[0089] “Improve, ” “increase", “inhibit" or “reduce": As used herein, the terms “improve,”“increase," “inhibit," “reduce,” or grammatical equivalents thereof, indicate values that are relative to a baseline or other reference measurement. In some embodiments, an appropriate reference measurement isor comprises a measurement in a particular system (e.g., in a single individual) under otherwise comparable conditions absent presence of (e.g., prior to and / or after) a particular agent or treatment, or in presence of an appropriate comparable reference agent In some embodiments, an appropriate reference measurement is or comprises a measurement in comparable system known or expected to respond m a particular way, in presence of the relevant agent or treatment.

[0090] Isolated: As used herein, the term “isolated" refers to something altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not “isolated," but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated." An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell.

[0091] KD: as used herein, the term “KD” refers to the dissociation constant of a binding agent (e.g., an antibody or anti gen -binding fragment thereof) from a complex with its partner (e.g., the epitope to which the antibody or antigen-binding fragment thereof binds). The term "KD.” as used herein, equals Koff divided by K„n.|0092] Koff as used herein, the term “Kof / ’ refers to the off rate constant for dissociation of a binding agent (e.g., an antibody or antigen-binding fragment thereof) from a complex with its partner (e.g., the epitope to which the antibody or anti gen -binding fragment thereof binds).

[0093] KOI1:as used herein, the term “K;,n” refers to the on rate constant for association of a binding agent (e.g., an antibody or antigen-binding fragment thereof) with its partner (e.g.. the epitope to which the antibody or antigen-binding fragment thereof binds).

[0094] Modulating: As used herein the term "modulating,” refers to mediating a detectable increase or decrease in a level of a response and / or change in nature of a response in a subject compared with a level and / or nature of a response in a subject without a treatment or an untreated subject. The term encompasses perturbing and / or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, preferably, a human.

[0095] Monoclonal Antibody: A “monoclonal antibody” or "mAb” refers to an antibody obtained from a population of substantially homogeneous antibodies, such that individual antibodies of the population are identical and / or bind the same epitope, except for possible variant antibodies (e.g., containing naturally occurring mutations or arising during production of a monoclonal), such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which ty pically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.

[0096] Operably linked: As used herein, the term “operably linked” refers to functional linkage between, for example, a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter For example, a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DN Asequences are contiguous and, where necessary to join two protein coding regions, in the same reading frame

[0097] Pharmaceutically acceptable: As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / I isk ratio.

[0098] Pharmaceutically acceptable earner: As used herein, the term “pharmaceutically acceptable carrier" means a pharmaceutically -acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically acceptable carriers include sugars, such as lactose, glucose and sucrose: starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethvl cellulose, ethyl cellulose and cellulose acetate: powdered tragacanth; malt; gelatin: talc; excipients, such as cocoa butter and suppository waxes: oils, such as peanut oil, cottonseed oil, safflower oil. sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide: alginic acid; pyrogen-free water; isotonic saline;Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0099] Polynucleotide: As used herein, the term “polynucleotide” refers to a chain of nucleotides. Furthermore, nucleic acids are polymers of nucleotides. Thus, nucleic acids and polynucleotides as used herein are interchangeable. One skilled in the art has the general knowledge that nucleic acids are polynucleotides, which can be hydrolyzed into the monomeric “nucleotides.” The monomeric nucleotides can be hydrolyzed into nucleosides. As used herein polynucleotides include, but are not limited to, all nucleic acid sequences which are obtained by any means available in the art, including, without limitation, recombinant means, i.e,, the cloning of nucleic acid sequences from a recombinant library or a cell genome, using ordinary cloning technology and PCR™, and the like, and by synthetic means.

[0100] Poly peptide: As used herein, the terms “polypeptide” or "protein,” as used interchangeably herein, refer to any polymeric chain of residues (e.g.. amino acids) that are typically linked bv peptide bonds. In some embodiments, a polypeptide has an amino acid sequence that occurs in nature. In some embodiments, a polypeptide has an amino acid sequence that does not occur in nature. In some embodiments, a polypeptide has an amino acid sequence that is engineered in that it is designed and / or produced through action of the band of man. A polypeptide may comprise or consist of natural amino acids, non-natural amino acids, or both A polypeptide may comprise or consist of only natural amino acids or only non-natural amino acids. A polypeptide may comprise D-atnino acids. I, -amino acids, orboth. A polypeptide may include one or more pendant groups or other modifications, e.g., modifying or attached to one or more amino acid side chains at the N-terminus, at the C -terminus, or both In some embodiments, such pendant groups or modifications are chosen from acetylation, amidation, lipidation, methylation, or pegylation. including combinations thereof. A polypeptide may be cyclic and / or may comprise a cyclic portion. In some embodiments, a polypeptide is not cyclic and / or does not comprise any cyclic portion. In some embodiments, a polypeptide is linear. A polypeptide may be or comprise a stapled poly peptide. The term “polypeptide” may be appended to a name of a reference polypeptide, activity', or structure; in such instances, it is used herein to refer to polypeptides that share the relevant activity or structure and thus can be considered members of the same class or family of polypeptides. For each such class, the present specification provides and / or those skilled in the art will be aware of exemplary' polypeptides within the class whose amino acid sequences and / or functions are known; in some embodiments, such exemplary polypeptides are reference polypeptides for the polypeptide class or family. In some embodiments, a member of a polypeptide class or family shows significant sequence homology or identity with, shares a common sequence motif (e.g., a characteristic sequence element) with, and / or shares a common activity (in some embodiments at a comparable level or within a designated range) with a reference polypeptide of the class. For example, a member polypeptide may have an overall degree of sequence homology or identity with a reference poly peptide that is at least about 30-40% and is often about 50%. 60%. 70%. 80%, 90%, 91%, 92%. 93%. 94%, 95%. 96%. 97%, 98%, 99% or more and / or includes at least one region (e.g.. a conserved region that may be or comprise a characteristic sequence element) that shows very high sequence identity’, often greater than 90% or even 95%, 96%. 97%, 98%. or 99%. Such a conserved region usually encompasses at least 3-4 and often up to 20 or more amino acids; in some embodiments, a conserved region encompasses at least one stretch of at least 2. 3. 4. 5, 6. 7, 8, 9, 10, 11. 12. 13, 14, 15 or more contiguous amino acids. A useful polypeptide may comprise or consist of a fragment of a parent polypeptide. A useful polypeptide may comprise or consist of a plurality of fragments, each of which is found in the same parent polypeptide in a different spatial arrangement relative io one another than is found in the polypeptide of interest (e.g.. fragments that are directly linked in the parent may be spatially separated in the polypeptide of interest or vice versa, and / or fragments may be present in a different order in the polypeptide of interest than in the parent) so that the polypeptide of interest is a derivative of its parent polypeptide.

[0101] Single chain antibodies: As used herein, the term “single chain antibodies'’ refers to antibodies formed by recombinant DNA techniques in which immunoglobulin heavy and light chain fragments are linked to the Fv region via an engineered span of ammo acids. Various methods of generating single chain antibodies are known, including those described in U.S. Pat. No. 4,694,778; Bird (1988) Science 242:423-442: Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; Ward et al. (1989) Nature 334:54454; and Skerra et al. (1988) Science 242: 1038-1041.

[0102] Recombinant: as used herein, is intended to refer to polypeptides that are designed, engineered, prepared, expressed, created, manufactured, and / or or isolated by recombinant means, such as polypeptides expressed using a recombinant expression vector transfected into a host cell, polypeptidesisolated from a recombinant, combinatorial human polypeptide libraiy (see, e.g, Hoogenboom, TIB Tech 15 :62, 1997; Azzazy Clin. Biochem , 35:425, 2002; Gavilondo BioTechniques 29: 128, 2002;Hoogenboom Immunology' Today 21 :371, 2000), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor Nuc. Acids Res. 20:6287. 1992: Little Immunology Today 12:364, 2000; KeHermann Curr. Opin. Biotechno] 13:593, 2002; Murphy Proc. Natl Acad Sci USA 111 :5153, 2104) or polypeptides prepared, expressed, created or isolated by any other means that involves splicing selected sequence elements to one another. In some embodiments, one or more of such selected sequence dements is found in nature. In some embodiments, one or more of such selected sequence elements is designed in silico. In some embodiments, one or more such selected sequence elements results from mutagenesis (e.g., in vivo or in vitro) of a known sequence element, e.g, from a natural or synthetic source. For example, in some embodiments, a recombinant antibody polypeptide is comprised of sequences found in the germline of a source organism of interest (e.g, human, mouse, etc.). In some embodiments, a recombinant antibody has an amino acid sequence that resulted from mutagenesis (e.g, in vitro or in vivo, for example in a transgenic animal), so that the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while originating from and related to germlme VH and VL sequences, do not naturally exist within the germline antibody repertoire in vivo|0103] Subject: As used herein, the term '‘subject” refers to an organism, for example, a mammal (e.g, a human, a non-human mammal, a non-buman primate, a primate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, a cat, or a dog). In some embodiments, a human subject is an adult, adolescent, or pediatric subject In some embodiments, a subject is suffering from a disease, disorder or condition, e.g, a disease, disorder, or condition that can be treated as provided herein, e.g, a cancer or a tumor listed herein. In some embodiments, a subject is susceptible to a disease, disorder, or condition. In some embodiments, a susceptible subject is predisposed to and / or shows an increased risk (as compared to the average risk observed in a reference subject or population) of developing a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms of a disease, disorder, or condition. In some embodiments, a subject does not display’ a particular symptom (e.g, clinical manifestation of disease) or characteristic of a disease, disorder, or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition In some embod iments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[0104] Substantial identity: As used herein, the term “substantial identity” refers to a comparison between amino acid or nucleic acid sequences. As will be appreciated by those of ordinary skill in the art, two sequences are generally considered to be substantially identical if they contain identical residues in corresponding positions. As is well known in this art, amino acid or nucleic acid sequences may be compared using any of a variety of algorithms, including those available in commercial computer programs such as BLASTN for nucleotide sequences and BLASTP, gapped BLAST, and PS1-BLAST for amino acid sequences. In some embodiments, two sequences are considered to be substantially identicalif at least 50%, 55%, 60%, 65%, 70%, 75%. 80%, 85%, 90%, 91%. 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more of their corresponding residues are identical over a relevant stretch of residues. Tn some embodiments, the relevant stretch is a complete sequence. In some embodiments, the relevant stretch is at least 10, 15, 20, 25. 30, 35, 40, 45. 50. 55, 60, 65, 70, 75, 80, 85, 90. 95, 100, 125, 150. 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more residues. Tn the context of a CDR, reference to “substantial identity” ty pically refers to a CDR having an amino acid sequence at least 80%, preferably at least 85%, at least 90%, at least 95%, at least 98% or at least 99% identical to that of a reference CDR.

[0105] Substantially: As used herein, the term 'substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term "substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0106] Suffering from: An individual who is “suffering from” a disease, disorder, and / or condition has been diagnosed with and / or displays one or more symptoms of a disease, disorder, and / or condition.

[0107] Target: As used herein, the term “target” refers to an agent, cell, tissue, organ, or site within die body that is the subject of provided methods, systems, compounds, and / or compositions, for example, a cell, tissue, organ or site within a body that is in need of treatment or is preferentially bound by, for example, a HHLA2 binding agent described herein.

[0108] Therapeutic: As used herein, the term “therapeutic" refers to a treatment and / or prophylaxis. A therapeutic effect is obtained, for example, by suppression, remission, or eradication of a disease state.

[0109] Therapeutic agent: As used herein, the phrase “therapeutic agent" refers to any agent that, when administered to a subject, has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect. In some embodiments, a therapeutic agent can be an agent that, when administered to a subject, can prevent an tindesired side effect. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of. reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. A therapeutic agent includes, but is not limited to, at least one HHLA2 binding agent as described herein.

[0110] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art. the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, and / or the target cell or tissue.For example, the effective amount of compound in a fonnulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of. reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose. In some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0111] Treat: As used herein, the terms “treat,” “■treatment,’' or “treating" refer to partial or complete alleviation, amelioration, delay of onset of, inhibition, prevention, relief, and / or reduction in incidence and / or severity of one or more symptoms or features of a disease, disorder, and / or condition. In some embodiments, treatment is administered to a subject who does not exhibit signs or features of a disease, disorder, and / or condition (e.g.. may be prophylactic). In some embodiments, treatment is administered to a subject who exhibits only early or mild signs or features of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of de veloping pathology associated with the disease, disorder, and / or condition. In some embodiments, treatment is administered to a subject who exhibits established, severe, and / or late-stage signs of the disease, disorder, or condition.

[0112] Tumor: As used herein, the term “ tumor” refers to an abnormal growth of ceils or tissue. A tumor may comprise cells that are precancerous (e.g.. benign), malignant, pre-metastatic, metastatic, and / or non-metastatic. In some embodiments, a tumor is associated with or is a manifestation of a cancer. In some embodiments, a tumor is a disperse tumor or a liquid tumor. In some embodiments, a tumor is a solid tumor.

[0113] Throughout this disclosure, various aspects of provided technologies can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of a provided technology’ . Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2. to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3. 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0114] As used herein in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” may be understood to mean "at least one”: (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising”, "comprise”, “including” (whether used with “not limited to” or not), and "include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iy) the term ‘'another” may be understood to mean at least an additional / second one or more: (v) the terms "about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are includedDETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0115] In some embodiments, the present disclosure provides conjugates. In some embodiments, a conjugate comprises a target binding moiety, a payload moiety, and a linker connecting a target binding moiety and a pay load moiety. In some embodiments, the present disclosure provides technologies for manufacturing conjugates. In some embodiments, the present disclosure provides technologies for assessing conjugates. In some embodiments, the present disclosure provides conjugates compositions, e.g., pharmaceutical compositions. In some embodiments, the present disclosure provides methods for using provided conjugates and compositions thereof In some embodiments, the present disclosure provides technologies for preventing or treating various conditions, disorders or diseases utilizing provided conjugates and compositions thereof.

[0116] Certain embodiments, including those for target binding moieties. payload moieties, linkers, conjugates, etc., are described below as examples.Target Binding Moieties

[0117] A target binding moiety binds to a target that can be or comprise a polypeptide, a small molecule, a carbohydrate, a lipid or a nucleic acid In some embodiments, a target is on a surface of a cell, e.g , a cancer cell.

[0118] In some embodiments, a target binding moiety is or comprises an antibody or an antigen - binding fragment thereof. In some embodiments, a target binding moiety is an antibody or an antigen- binding fragment thereof. In some embodiments, a target binding moiety7is an antibody. In some embodiments, a target binding moiety is a monoclonal antibod)’. In some embodiments, a target binding moiety is not trastuzumab. In some embodiments, a target binding moiety shares less than about 90%, 95%, or 99% sequence identity' to trastuzumab. In some embodiments described herein, a target binding moiety shares less than about 85%, 86%, 8 / %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% sequence identity to trastuzumab. In some embodiments, it is less than about 95%. In some embodiments, it is less than about 90%. In some embodiments, it is less than about 85%. In some embodiments, a target binding moiety is not an anti-HER2 antibody. In some embodiments, a target binding moiety is not an anti-HER2 antibody or an antigen-binding fragment thereof.|0119] In some embodiments, a target binding moiety is a moiety of an antibody that without conjugation comprises four Cys residues that form two inter-heavy- and light-chain disulfide bonds. In some embodiments, each of the four Cys residues is independently conjugated to a payload moiety. In some embodiments, the target binding moiety' is a moiety' of an antibody that without conjugation comprises eight residues that form inter-chain disulfide bonds. In some embodiments, each of the eight Cys residues is independently conjugated to a payload moiety.

[0120] Those skilled in the art appreciate that various antibodies (e.g., those approved by FDA, those that can bind to the same antigens or entities (e.g., polypeptides, cells, etc.) as such antibodies, etc.) and antigen-binding fragments thereof can be utilized as target binding moieties in accordance with the present disclosure. For example, in some embodiments, a target binding moiety is an anti-HHLA2 antibody or antigen -binding fragment thereof.|0121] In some embodiments, a target binding moiety is or comprises an antibody or an antigen- binding fragment thereof In some embodiments, a target binding moiety comprises an antibody. In some embodiments, a target binding moiety is an antibody. In some embodiments, a target binding moiety comprises an antigen-binding fragment of an antibody. In some embodiments, a target binding moiety is an antigen-binding fragment of an antibody In some embodiments, an antibody is a chimeric antibody. [0122 j In some embodiments, an antibody is a human antibody. In some embodiments, an antibody is a humanized antibody. In some embodiments, an antibody is a monospecific antibody. In some embodiments, an antibody is a bispecific antibody. In some embodiments, an antibody is a monoclonal antibody. In some embodiments, an antibody or an antigen-binding fragment thereof is or comprises a heavy chain constant region or a fragment thereof. In some embodiments, a heavy chain constant region is IgG I . In some embodiments, a heavy chain constant region is IgG2. In some embodiments, a heavy chain constant region is lgG3. In some embodiments, a heavy chain constant region is IgG4. Additionally or alternatively, an antibody or an antigen-binding fragment thereof is or comprises a light chain constant region. In some embodiments, a light chain constant region is a light chain constant regions of kappa. In some embodiments, a light chain constant region is a light chain constant regions of lambda.

[0123] In some embodiments, a target binding moiety is or comprises a chimeric antibody or an antigen-binding fragment thereof. In some embodiments, a target binding moiety independently is or comprises a human antibody or an antigen-binding fragment thereof. In some embodiments, a target binding moiety independently is or comprises a humanized antibody or an antigen -binding fragment thereof. In some embodiments, a target binding moiety independently is or comprises a monospecific antibody or an antigen-binding fragment thereof. In some embodiments, a target binding moiety independently is or comprises a bispecific antibody or an antigen-binding fragment thereof (e g., an HHL.A2 binding ami and at least one other non-HHLA2 binding arm). In sonic embodiments, a target binding moiety independently is or comprises an anti-EGFR x HER3 bi specific antibody or an antigen- binding fragment thereof. In some embodiments, a target binding moiety independently is or comprises a biparatopic antibody or an antigen -binding fragment thereof In some embodiments, a target binding moiety is an anti-HHLA2 antibody or an antigen-binding fragment thereof. In some embodiments, an ntibody or an antigen-binding fragment thereof is an anti-HER2 x HHLA2 bispecific antibody or an antigen-binding fragment thereof. In some embodiments, such an antibody or antigen-binding fragment thereof comprises CDR sequences of trastuzumab. In some embodiments, such an antibody or antigen- binding fragment thereof comprises antigen-binding sequences of trastuzumab.

[0124] For example, in some embodiments, a target binding moiety is or comprises an anti-HHLA2 antibody or an antigen-binding fragment thereof.

[0125] In some embodiments, an anti-HHLA2 antibody or an antigen-binding fragment thereof is or comprises:(a) a heavy chain variable region (VH) comprising one, two, or three VH CDR sequences each with at least about 90% identity to a VH CDR of Table I; and / or(b) a light chain variable region (VL) comprising one, two. or three VL CDR sequences each with at leastabout 90% identity' to a VL CDR of Table 1.

[0126] In some embodiments, an anti-HHLA2 an tibody or an antigen-binding fragment thereof is or comprises:(a) a VH comprising one, two, or three VH CDR sequences each with at least about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% identity to a VH CDR of Table 1 ; and / or(b) a VL comprising one, two, or three VL CDR sequences each with at least about 91%, 92%. 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% identity to a VL CDR of Table 1 .

[0127] In some embodiments, an anti~HHLA2 antibody or an antigen-binding fragment thereof is or comprises:(a) a VH comprising one, two, or three VH CDR sequences each comprising or consisting of a VH CDR of Table I; and / or(b) a VL comprising one, two, or three VL CDR sequences each comprising or consisting of a VL CDR of Table 1 .

[0128] In some embodiments, an anti-HHLA2. antibody or an antigen-binding fragment thereof is or comprises:(a) a VH with at least about 90% or more identity to a VH of Table 1 : and / or(b) a VL with at least about 90% or more identity’ to a VL of Table 1 .

[0129] In some embodiments, an anti-HHLA2 antibody or antigen -binding fragment thereof is or comprises:(a) a VH with at least about 95%, 96%, 97%, 98%, 99% or 99.5% identity’ to a VH of Tabic 1; and / or(b) a VL with at least about 95%, 96%, 97%, 98%. 99% or 99.5% identity to a VI.. of Table 1 ,

[0130] In some embodiments, an anti-HHLA2 or antigen -binding fragment thereof is or comprises:(a) a VH comprising or consisting of a VH of Table 1; and / or(b) a VL comprising or consisting of a VL of Table 1 .

[0131] In some embodiments, an anti-HHLA2 or antigen-binding fragment thereof is or comprises:(a) a heavy chain with at least about 90% or more identity to a heavy chain of Table 1 ; and / or(b) a light chain with at least about 90% or more identity to a light chain of Table I .

[0132] In some embodiments, an anti-HHLA2. or antigen-binding fragment thereof is or comprises:(a) a heavy chain with at least about 95%, 96%, 97%, 98%. 99% or 99.5% identity to a heavy chain of Table 1 ; and / or(b) a light chain with at least about 95%, 96%, 97%, 98%, 99% or 99.5% identity to a light chain of Table 1.

[0133] In some embodiments, an anti-HHLA2 or antigen-binding fragment thereof is or comprises:(a) a heavy chain comprising or consisting of a heavy chain of Table 1 ; and / or(b) a light chain comprising or consisting of a light chain of Table 1 ,

[0134] In some embodiments, a target binding moiety comprises each of the CDRs of 887-IDE in Table 1 . In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, 99%, or 99.5% identity to VH of 887-IDE inTable 1. In some embodiments, a target binding moiety is or comprises VH of 887-1 DE in Table 1. In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%. 98%, 99%, or 99.5% identity to VL of 887-IDE in Table 1. In some embodiments, a target binding moiety is or comprises VL of 887-IDE in Table 1. In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity to a heavy chain of 887- IDE in Tabic 1. In some embodiments, a target binding moiety is or comprises a heavy chain of 887-IDE in Table 1. In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%, 99%, or 99.5% identity to a light chain of 887-IDE in Table 1 . In some embodiments, a target binding moiety is or comprises a light chain of 887-IDE in Table 1. In some embodiments, a target binding moiety comprises 887-IDE in Table 1 or antigen-binding fragments thereof. In some embodiments, a target binding moiety is 887-IDE in Table 1 .

[0135] In some embodiments, a target binding moiety comprises each of the CDRs of 65889 in Table 1 . In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%, 91%. 92%, 93%. 94%, 95%, 96%. 97%. 98%. 99%, or 99.5% identity to VH of 65889 in Table 1. In some embodiments, a target binding moiety is or comprises VH of 65889 in Table 1. In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%. 91%, 92%, 93%. 94%. 95%, 96%, 97%. 98%. 99%, or 99.5% identity to VL of 65889 in Table 1. In some embodiments, a target binding moiety is or comprises VL, of 65889 in Table 1 In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%. 91%. 92%, 93%, 94%, 95%, 96%, 97%. 98%. 99%, or 99.5% identity to a heavy chain of 65889 in Table 1. In some embodiments, a target binding moiety is or comprises a heavy chain of 65889 in Table 1. In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%. 98%, 99%, or 99.5% identity to a light chain of 65889 in Table 1. In some embodiments, a target binding moiety is or comprises a light chain of 65889 in Table 1 . In some embodiments, a target binding moiety comprises 65889 in Table 1 or antigen-binding fragments thereof. In some embodiments, a target binding moiety is 65889 in Table 1.

[0136] In some embodiments, a target binding moiety comprises each of the CDRs of 65872 in Table 1 . In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity to VH of 65872 in Table 1. In some embodiments, a target binding moiety is or comprises VH of 65872 in Table I. In some embodiments, a target binding moiety- is or comprises a sequence with about or at least about 90%. 91%, 92%, 93%, 94%, 95%. 96%, 97%, 98%, 99%. or 99.5% identity to VL of 65872 in Table 1. In some embodiments, a target binding moiety is or comprises VL of 65872 in Table 1 , In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%, 91%. 92%, 93%, 94%, 95%, 96%, 97%, 98%. 99%, or 99.5% identity to a heavy chain of 65872 in Table 1 In some embodiments, a target binding moiety is or comprises a heavy chain of 65872 in Table 1. In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%, 91%.92%, 93%, 94%. 95%, 96%, 97%, 98%, 99%, or 99.5% identity to a light chain of 65872 in Table 1. In some embodiments, a target binding moiety is or comprises a light chain of 65872 in Table 1. In some embodiments, a target binding moiety comprises 65872 in Table 1 or antigen-binding fragments thereof. In some embodiments, a target binding moiety is 65872 in Table 1.

[0137] In some embodiments, a target binding moiety comprises each of the CDRs of Hu2C4-H3L3 m Table 1. In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%. 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%, 99%, or 99.5% identity to VH of Hu2C4- H3L3 in Table 1. In some embodiments, a target binding moiety is or comprises VH of Hu2C4-H3L3 in Table 1. In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%, 91%, 92%. 93%, 94%, 95%, 96%. 97%,, 98%, 99%, or 99.5% identity to VL of Hu2C4-H3L3 in Table 1. In some embodiments, a target binding moiety is or comprises VL of Hu2C4-H3L3 in Table 1. In some embodiments, a target binding moiety is or comprises a sequence with about or at least about 90%, 91%, 92%, 93%. 94%, 95%. 96%, 97%. 98%, 99%, or 99.5% identity to a heavy chain of Hu2C4- H3L3 in Table 1 . In some embodiments, a target binding moiety is or com prises a heavy chain of Hu2C4- H3L3 in Table 1. In some embodiments, a target binding moiety is or comprises a sequence with about or al least about 90%, 91%. 92%. 93%, 94%>, 95%. 96%. 97%, 98%. 99%. or 99.5% identity to a light chain of Hu2C4-H3L3 in Table 1 . In some embodiments, a target binding moiety is or comprises a light chain of Hu2C4-H3L3 in Table 1. In some embodiments, a target binding moiety comprises Hu2C4-H3L3 in Table I or antigen-binding fragments thereof. In some embodiments, a target binding moiety is Hu2.C4- H3L3 in Table I .

[0138] In some embodiments, conjugates or target binding moieties bind their targets, e.g., HHLA2, with a KZJ of about or no more than about 1. 5, 10, 15, 20, 30. 50, 100 or 500 pM, or about or no more than about 1, 5, 10, 15, 20, 30, 50, 100 or 500 nM. In some embodiments, conjugates or target binding moieties bind their targets, e.g., HHI..A2, with an affin ity of about or at least about 10, 20, 50, 100, 200, 300, 400, 500, 600, 700, 800. 900, or 1000-fold over background or a reference agent (e.g., absence of the conjugates, immunoglobulins that target different targets, conjugates that target different targets, etc.).

[0139] In some embodiments, a conjugate comprises two or more target binding moieties. In some embodiments, each target binding moiety of a provided conjugate targets the same agent. In some embodiments, each target binding moiety targets the same agent, wherein the agent is or comprises a polypeptide, a nucleic acid, or a lipid. In some embodiments, each target binding moiety targets the same agent, wherein the agent is a polypeptide. In some embodiments, each target binding moiety targets the same antigen. In some embodiments, each target binding moiety is independently an antibody or an antigen-binding fragment thereof, and each target binding moiety shares about or at least about 90%. 95%, 96%. 97%, 98% or 99% sequence identity. In some embodiments, each target binding moiety is independently an antibody or an anti gen -binding fragment thereof, and each target binding moiety shares the same amino acid sequence. In some embodiments, each target binding moiety is the same. In some embodiments, each target binding moiety is independently a target binding moiety described hereinPayload Moieties

[0140] Various pay load moieties including those reported for antibody -drug conjugates can be utilized in accordance with the present disclosure. In some embodiments, a payload moiety is moiety of a payload which is or comprises a cytotoxic agent.

[0141] In some embodiments, a payload is or comprises calicheamicm or a derivative or an analog thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a pay load is or comprises N-acetyl gamma calicheamicin.

[8142] In some embodiments, a payload is or comprises a topoisomerase inhibitor. In some embodiments, a payload is or comprises caraptothecin or a derivative or an analog thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a pay load is or comprises exatecan or a derivative or an analog thereof, or pharmaceutically acceptable salt thereof.

[0143] Exatecan ((l S.9S)-l-Amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-i,2,3,9,T2,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-Z>]quinoline-10, 13-dione) is a structural analog of campothecin. Exatecan comprises a chemical structure:

[0144] Among other things, the present disclosure provides various exatecan conjugates, e.g„ various conjugates in the Examples. As shown herein, in various embodiments, exatecan is conjugated through its -NH2to a target binding moiety, e.g., an antibody, via a linker.

[0145] A derivative of exatecan is used in trastuzumab dcruxtccan (sold under the trade name Enhertu), which is an antibody -drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to tire topoisomerase I inhibitor dcruxtccan (a derivative of exatecan). Trastuzumab binds to epidermal growth factor receptor 2 (HER2 / neu), and once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound dcruxtccan along with it. Trastuzumab deruxtecan has a chemical structure:

[0146] Without wishing to be bound to a particular theory, a conjugate binds to its target, e.g..HHLA2, and once bound, a conjugate can be internalized by the cell, carrying the bound payload (e.g., exatecan) along with it.

[0147] In some embodiments, a payload moiety ipharmaceutically acceptable salt thereof.

[0148] In some embodiments, a payload moiety iembodiments, a pay load moiety

[0149] In some embodiments, a topoisomerase inhibitor is or comprises SN-38 or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, a payload is or comprises a microtubule disrupting agent. In some embodiments, a payload is or comprises an anti-mitotic agent In some embodiments, a payload is orcomprises a microtubule inhibitor. For example, in some embodiments, a pay load is or comprises MMAE or a derivative or an analog thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a payload is or comprises MMAE or a pharmaceutically acceptable salt thereof. In some embodiments, a payload is or comprises MMAF or a derivative or an analog thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a payload is or comprises MMAF or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, a payload is or comprises an alkylating agent. In some embodiments, a pay load is or comprises a DNA alkylating agent. In some embodiments, a payload is or comprises pyrrolobenzodiazepine. In some embodiments, a payload is or comprises a pyrrolobenzodiazepine dimer. In some embodiments, a payload is or comprises SG3199 or a derivative or an analog thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a pay load is or comprises SG3199 or a pharmaceutically acceptable salt thereof.|G152| In some embodiments, a payload is or comprises a microtubule inhibitory agent, e.g., maytansine, or a derivative or an analog thereof (e.g., DM1, DM4. etc.), or a pharmaceutically acceptable salt thereof. In some embodiments, a payload is or comprises DM1 or a pharmaceutically acceptable salt thereof. In some embodiments, a payload is or comprises DM4 or a pharmaceutically acceptable salt thereof.^0153] In some embodiments, a payload is or comprises an auristatin, a maytansinoid. a duocarmycin, a hemiasterlin, an eribulin, a N -myristoyl transferase inhibitor, an amanitin or a derivative or an analog thereof. In some embodiments, a payload is or comprises an auristatin or a derivative or an analog thereof. In some embodiments, a payload is or comprises a maytansinoid or a derivative or an analog thereof In some embodiments, a payload is or comprises a duocarmycin or a derivative or an analog thereof. In some embodiments, a pay load is or comprises a hemiasterlin or a derivative or an analog thereof. In some embodiments, a pay load is or comprises ati eribulin or a derivative or an analog thereof. In some embodiments, a pay load is or comprises a N -myristoyl transferase inhibitor or a derivativ e or an analog thereof (see, e.g., WO 2022058745). In some embodiments, a pay load is or comprises an anthracy cline or a derivative or an analog thereof (see, e.g., US I I 833120). In some embodiments, a pay load is or comprises nemorubicin or a metabolite (e.g.. PNU-159682), or a derivative or an analog thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a pay load is or comprises PNU-159682, or a derivative or an analog thereof, or a pharmaceutically acceptable salt thereof. See, e.g., Holte D. et al. Evaluation of PNU-159682 antibody drug conjugates (ADCs). Bioorg Med Chem Lett. 2020 Dec 15;30(24): 127640. doi: I0.1016 / i.bmcl.2020.127640. Epub 2020 Oct 28. PMID: 33127540. In some embodiments, a payload is or comprises PNU-159682 or pharmaceutically acceptable salt thereof, hi some embodiments, a payload is or comprises an amanitin or a derivative or an analog thereof. For example, in some embodiments, a payload moiety is or comprises,, y y is orcomprises

[0154] In some embodiments, a payload is or comprises a chemotherapeutic agent.

[0155] Among other tilings, conjugates can deliver payloads (e.g., one or more payloads). In some embodiments, a conjugate delivers at least one cytotoxic agent (e g . 2, 3. 4. or more). In some embodiments, a conjugate delivers at least one chemotherapeutic agent (e.g., 2, 3. 4. or more). In some embodiments, a conjugate delivers a caraptotbecin. an auristatin. a maytansinoid, a duocarmycin. a hemiasterlin, an eribulin, or a N -myristoyl transferase inhibitor, or a derivative or an analog thereof, or a pharmaceutically acceptable salt thereof.

[0156] A payload can be conjugated at various positions, and often at a functional group such as amino, hydroxyl, etc. In some embodiments, a functional group is bonded to a secondary' or tertiary carbon. In some embodiments, a functional group is bonded to a ring atom In some embodiments, a functional group is bonded to a ring carbon atom. In some embodiments, a ring is a polycyclic ring system, e.g., those found in exatecan or derivates or analogs thereof. In some embodiments, provided technologies provide conjugates to functional groups, e.g., those bonded to secondary' or tertiary' carbon atoms or ring atoms (e.g., ring carbon atoms) without spacer moieties. In some embodiments, Lciis bonded to a functional group (e.g., an amino group) of a payload moiety' at its -C(O)-. In some embodiments, a payload is bonded to a linker at an amino group. In some embodiments, for a payload moiety, H-payload moiety is the corresponding payload. In some embodiments, a pay load moiety is Rpas described herein.

[0157] In some embodiments, a payload is a small molecule. For example, in some embodiments, its molecular weight is about or no more than about 5000. 4000, 3000. 2500. 2000. 1500, 1000, 900, 800, 700, 600 or 500 Da.

[0158] In some embodiments, in a conjugate one or more pay load moieties are (e.g., exatecan or a derivative or an analog thereof, or pharmaceutically acceptable salt thereof) covalently bound to a single target binding moiety, e.g., an anti-HERV-H LTR -Associating 2 (HHLA2) antibody or antigen -binding fragment thereof. In some embodiments, the payload moiety to target binding moiety ratio, which equals die number of payload moieties (e.g., exatecan or a derivative thereof, or pharmaceutically acceptable salt thereof) covalently bound to a single target binding moiety in various conjugates, is referred to as the drug to antibody ratio (DAR). In some embodiments, provided conjugates have a DAR of between about 1 and about 20. In some embodiments, provided conjugates have a DAR of between about 1 and about 16. In some embodiments, provided conjugates have a DAR of between about 1 and about 12. In someembodiments, provided conjugates have a DAR of between about 2 and about 15. In some embodiments, provided conjugates have a DAR of between about 2 and about 12. In some embodiments, provided conjugates have a DAR of between about 2 and about 10. In some embodiments, provided conjugates have a DAR of between about 2 and about 8. In some embodiments, provided conjugates have a DAR of between about 4 and about 8. In some embodiments, provided conjugates have a DAR of between about 7 and about 9. In some embodiments, provided conjugates have a DAR of between about 6 and about 10. In some embodiments, provided conjugates have a DAR of between about 4 and about 12. In some embodiments, provided conjugates have a DAR of about 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, provided conjugates have a DAR of about 2, 4, 6, or 8. In some embodiments, provided conjugates have a DAR of about 2 or more. In some embodiments, provided conjugates have a DAR of about 2. In some embodiments, provided conjugates have a DAR of about 4. In some embodiments, provided conjugates have a DAR of about 8. In some embodiments, the payload moieties are the same. Linkers

[0159] In some embodiments, a conjugate comprises one or more linkers that each connect a payload moiety, which may be in a pharmaceutically acceptable salt form thereof, to a target binding moiety, which may also be in a pharmaceutically acceptable salt form thereof. In some embodiments, a linker is bivalent, and connects a single payload moiety to a single target binding moiety. In some embodiments, a linker is polyvalent, and connects one or more payload moieties to one or more target binding moieties. In some embodiments, a linker is polyvalent, and connects one or more payload moieties to a single target binding moiety. In some embodiments, a linker is polyvalent, and connects a single target binding moiety to a single payload moiety.

[0160] In some embodiments, a linker comprises −(CH2CH2O)n− described herein. In some embodiments, a linker comprises LCas described herein. In some embodiments, a linker comprises −(CH2CH2O)n− and LCas described herein. In some embodiments, a linker comprises a PEG moiety. In some embodiments, a linker comprises −(CH2CH2O)n−, wherein n is at least 1. In some embodiments, a linker comprises −(CH2CH2O)n−, wherein n is 1-24. In some embodiments, n is 4. In some embodiments, n is 8.

[0161] In some embodiments, a linker comprises −(CH2CH2O)n−LZP−LC−, wherein each variable is independently as described herein.

[0162] In some embodiments, a linker comprises −LX−(CH2CH2O)n−LZP−LC−, wherein each variable is independently as described herein.

[0163] In some embodiments, a linker is comprises−LRX−LX−(CH2CH2O)n−LZP−LC−, wherein each variable is independently as described herein.

[0164] In some embodiments, a linker is comprises −LT−LRX−LX−(CH2CH2O)n−LZP−LC−, wherein each variable is independently as described herein.

[0165] In some embodiments, a linker is or compriseswherein each variable is independently as described herein. LZP

[0166] As described herein, in some embodiments, LZPconnects –(CH2CH2O)n− to LCwherein n is not 0. In some embodiments, LZPconnects LXwith LC. In some embodiments, LZPis absent (a covalent bond). Various moieties including many utilized in antibody-drug conjugates can be utilized as LZPin accordance with the present disclosure.

[0167] In some embodiments, LZPis a covalent bond. In some embodiments, LZPis an optionally substituted bivalent straight or branched C1-20(e.g., C1-6, C1-10, C1-15, C2-8, C5-10, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, etc.) aliphatic wherein 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, 1-3, 1-2, etc.) methylene units of LZPare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−. In some embodiments, LZPis an optionally substituted bivalent straight or branched C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic wherein 1-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) methylene units of LZPare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−. In some embodiments, LZPis optionally substituted bivalent C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic. In some embodiments, LZPcomprises −C(O)− which is bonded to LC. In some embodiments, LZPis −(CH2)Z−C(O)−, wherein z is 1-19, and each of the −CH2− is independently optionally substituted. In some embodiments, LZPis −(CH2)Z−C(O)−, wherein z is 1-19, each of the −CH2− is independently optionally substituted, and LC1is or comprises a peptide moiety (e.g., GGFG, Val-Ala, Val-Cit, etc.). In some embodiments, LZPis −(CH2)Z−C(O)−. In some embodiments, LZPis −(CH2)Z−N(R’)C(O)−, wherein z is 1-19, each of the −CH2− is independently optionally substituted, and R’ is as described herein. In some embodiments, LZPis −(CH2)Z−N(R’)C(O)−, wherein z is 1-19, each of the −CH2− is independently optionally substituted, R’ is as described herein, and LC1is LC1S(e.g., oGlu, mGlu, etc.). In some embodiments, LZPis −(CH2)Z−N(R’)C(O)−, wherein z is 1-19 and R’ is as described herein. In some embodiments, LZPis −(CH2)Z−NHC(O)−, wherein z is 1-19. In some embodiments, z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 1-15, 1-10, etc. In some embodiments, z is 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, 1-3, 1-2, etc.). In some embodiments, z is 1-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.). In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments LZPis −(CH2)2−C(O)−, wherein −C(O)− is bonded to the amino group of the first amino acid in LC. In some embodiments, LZPis −(CH2)2−C(O)−, wherein −C(O)− is bonded to the amino group of the first amino acid in LC, wherein LCis −LC1−LCO−. In some embodiments, LZPis −(CH2)2−N(R’)−C(O)−, wherein −C(O)− is bonded to LC1, each of the −CH2− is independently optionally substituted, R’ is as described herein, and LC1is LC1S. In some embodiments, LZPis −(CH2)2−N(R’)−C(O)−, wherein −C(O)− is bonded to LC, each of the −CH2− is independently optionally substituted, R’ is as described herein, and LC1is LC1S(e.g., oGlu, mGlu, etc.). In some embodiments, LZPis −(CH2)2−NH−C(O)−, wherein −C(O)− is bonded toLC1, and LC1is LC1S. In some embodiments, LZPis −(CH2)2−NH−C(O)−, wherein −C(O)− is bonded to LC, and LC1is LC1S(e.g., oGlu, mGlu, etc.). For example, as demonstrated in the Examples, in some embodiments, LZPis −(CH2)2−NH−C(O)−, and LCis mGlu; in some embodiments, LZPis −(CH2)2−NH−C(O)−, and LCis oGlu. In some embodiments, LZPis −(CH2)2−C(O)−N(R’)−, wherein −N(R’)− is bonded to LC1, each of the −CH2− is independently optionally substituted, R’ is as described herein, and LC1is LC1S. In some embodiments, LZPis −(CH2)2−C(O)−N(R’)−, wherein −N(R’)− is bonded to LC, each of the −CH2− is independently optionally substituted, R’ is as described herein, and LC1is LC1S(e.g., oGlu, mGlu, etc.). In some embodiments, LZPis −(CH2)2−C(O)−NH−, wherein −NH− is bonded to LC1, and LC1is LC1S. In some embodiments, LZPis −(CH2)2−C(O)−NH, wherein −NH− is bonded to LC, and LC1is LC1S(e.g., oGlu, mGlu, etc.). In some embodiments, LZPis −(CH2)2−C(O)−NH−, and LCis mGlu; in some embodiments, LZPis −(CH2)2−C(O)−NH−, and LCis oGlu. LC1In some embodiments, each LC1is independently a cleavable unit as described herein. Variable cleavable units can be utilized in accordance with the present disclosure. In some embodiments, certain cleavable units that when utilized as described herein can provide various advantages, e.g., improved property (e.g., solubility, stability, etc.), activity, etc. In some embodiments, LC1is or comprises a polypeptide. In some embodiments, each LC1is independently −Gly−Gly−Phe−Gly−, −Val−Ala−, −Val– Cit–, LC1S, −Gly−Gly−Phe−Gly−N(R’)−LC1S−, −Val−Ala−N(R’)−LC1S−, or −Val–Cit–N(R’)−LC1S− wherein each variable is independently as described herein. In some embodiments, LC1is In some–. In some embodiments, LC1is −Val-Ala. In some embodiments, LC1is LC1Sas described herein. In some embodiments, LC1is −Gly−Gly−Phe−Gly−N(R’)−LC1S−, −Val−Ala−N(R’)−LC1S−, or −Val–Cit– N(R’)−LC1S−. In some embodiments, LC1is −Gly−Gly−Phe−Gly−NH−LC1S−, −Val−Ala−NH−LC1S−, or −Val–Cit–NH−LC1S−. In some embodiments, LC. In some.L and R

[0168] , wherein the phenyl ring and the −CH2− is optionally s and RLSis or comprises a sugar moiety. Insome embodiments , wherein the carbonyl is bonded to LCO, and RLSis or comprises a sugar −CH − is unsubstiLS2tuted). In some embodiments, R is or comprises a sugar moiety so that LCis cleavable, e.g., by an enzyme. In some embodiments, RLSis or comprises a glucuronide moiety. In some embodiments, LCcan be cleaved by a β-glucuronidase. In some embodiments, RLSis or comprises a galactoside moiety. In some embodiments, LCcan be cleaved by a β- galactosidase. In some embodiments, RLSis or comprise r a derivative thereof. Insome embodiments In some embodiments, RLSis or comprisesderivative thereof. In some embodiments,In some embodiments, a sugar moiety is protected, e.g., in a compound useful for preparing a conjugate. In some embodiments, one or more or all -OH is protected, e.g., as -OC(O)R wherein R is as described herein. In some embodiments, R is -CH3. In some embodiments, -COOH is protected as -C(O)OR wherein R is as described herein and is not H. In some embodiments, R is optionally substituted Ci-s alkyl. In some embodiments, each -OH is protected as -OAc and -COOH is protected as -C(O)OMe. In some embodiments,|0169] For example, in some embodiments., wherein the phenyl ring and the -CH;- is optionally substituted, and the carbonyl is bonded io Lco. In some embodiments, Iwherein the carbonyl is bonded to L'J' or a payload moiety (“oGhi”) In some embodiments, L, wherein the phenyl ring and the -CH;- is optionally substituted, and the carbonyl is bonded to 10°. In some embodiments,wherein the carbonyl is bonded to 1?" or a payload moiety (“mGlu ”). In some embodiments, L' is such L'1f As those skilled in the art readily appreciate, various acidic and basic groups may exist in one or more forms. In some embodiments, a group, e.g., -COOH, is in its acidic form. In some embodiments, a group, e.g. -COOH. is in a salt form.In some embodiments, a group, e.g -COOH. is in a pharmaceutically acceptable salt form. In some embodiments, in a preparation or composition, a group, e.g. -COOH. may exist in multiple forms, e.g.. inits acid form and / or one or more pharmaceutically acceptable salt forms.

[0170] In some embodiments, LL1is Lu sas described herein. In some embodiments, IAUis a covalent bond. In some embodiments, Lcis LC1as described herein. In some embodiments, Lcis LC1Sas described herein.L{

[0171] In some embodiments, Lcois a covalent bond. In some embodiments, Lcois a spacer moiety as described herein. In some embodiments, Lcois a spacer. In some embodiments, Lc ois an optionally substituted bivalent straight or branched C1.20 (e.g.. Cw,, CM O, CMS. CAg, CMO, CI , C2. C?,, Ci, Cs, Co. C, Cs, CC. C10, C;i , Ci ?, CB. C14, Css, Ci6, Cn, C is, C)9, C20. etc.) aliphatic wherein 1-10 (e.g., 1. 2, 3. 4, 5, 6. 7. 8. 9, 10, 1-5, 1-4, 1-3, 1-2. etc.) methylene units of Lcoare optionally and independently replaced by a group selected from -O-, ~N(R’)--, -C(O)-, -S-. -S(O)-, -S(O>?-. -C(O)N(R’)-. -S(O)2(NR’)-, and “Cy-~. In some embodiments, L" " is an optionally substituted bivalent straight or branched C1.10 (e.g., Co 0, C2.8, Ci, C?„ C?„ Ci, Cs, Co, C?, Cs, C$>, C10. etc.) aliphatic wherein 1 -5 (e.g., 1. 2. 3, 4. 5, 1-5, 1-4. 1-2. etc.) methylene units ofare optionally and independently replaced by a group selected from -O-. -N(R’)-, -C(O)-, ~S~, ~S(O)~, ~S(O)2~. -C(O)N(R')~, ~S(O)2(NR')~ and -Cy-. For example, in some embodiments. Lcois optionally substitutedwherein the carbonyl is bonded to the payload moiety , and the ammo group is bonded to ~C(O)~ of I / ‘. In some embodiments.L.C'Jis(PABA). In some embodiments, LtOis a covalent bond, and the payload moiety is bonded to -C(O)~ of L' '. In some embodiments, LZ E' is optionally substituted bivalent Ct-to(e.g.. C1 6. Cz-s, Ci , C2, Cs, CK C5, Co, C7, Cs, Cs, Cis. etc.) aliphatic.

[0172] As described herein, Lcis bonded to a payload moiety and iswherein each of I..Ciand Lu’1is independently as described herein. In some embodiments, Lcis cleavable. In some embodiments, Lcis LC1. In some embodiments. Lcis LL1 SFor example, in some embodiments. Lcis oGlu. In some embodiments. Lcis mGhi. In some embodiments, LLis -LC1-L'“C- wherein LC 1is Val-Ala, and Lcois optionally substitutedIn some embodiments. LLis -L^'-L00-wherein LC1is Val-Cit, andis optionally substitutedTn some embodiments, Lcis -Val-Aia-NH-Luswherein Lvlais as described herein. In some embodiments. Lcis “Val-Ala-NH-L018wherein Lc,ais as described herein (e.g., mGln. oGlu, etc.). In some embodiments, LLis -Val-Ala-NH-LC1!>-mGlu-. In some embodiments. Lcis ~Val--Ala~NH”Lcls~oGlu~. In some embodiments, Lcis -Val--Cit--NH-Lci swherein LCI Sis as described herein (e.g., mGIu, oGlu, etc.). In some embodiments, LLis -Val-Cit-NH-I.cl b---mGlu--. In some embodiments, Lcis -Val-Cit-NH-Lc! s-oGlu~. In some embodiments, L(is -GGFG-NH-LC1 swherein Lc, sis as described herein (e g , mGIu, oGlu, etc.). In some embodiments, Lcis -GGFG- NH~LL 1 S~mGlu“. In some embodiments, Lcis -GGFG-NH-Lus-oGlu-

[0173] In some embodiments, L, wherein the carbonyl is bonded to a pay load moiety. In some embodiments, L' is, wherein the carbonyl is bonded to a pay load moiety . In some embodiments.. wherein the carbonyl is bonded to a payload moiety. In some embodiments, Lciswherein the carbonyl is bonded to a payloadwherein the carbonyl is bonded to a payload moiety . In some embodiments, Lcis, wherein the carbonyl is bonded to a payload moiety. Io some embodiments., wherein the carbonyl is bonded to a payload moiety. In some embodiments,wherein the carbonyl is bonded to a payload moiety, hi some embodiments, Lcis Val-Cit-PABA. wherein the carbonyl of PABA is bonded to a payload moiety. In some embodiments. LcisGGFG--PABA, wherein the carbonyl of PABA is bonded to a pay load moiety. In some embodiments, L' is Val-Ala-NH-oGlu. wherein the carbonyl of oGlu is bonded to a payload moiety’ In some embodiments. L’’ is Val-Cit-NH-oGlu, wherein the carbonyl of oGlu is bonded to a payload moiety. In some embodiments, L(is Val-Ala-NH-mGlu. wherein the carbonyl of mGlu is bonded to a payload moiety. In some embodiments, Lcis Val-Cit-NH-mGlu. wherein the carbonyl of mGlu is bonded to apayload moiety.

[0174] Unless otherwise specified, polypeptide sequences are from N to C.

[0175] In some embodiments, -Lzp-Lc~ is -(CH2)2C(O)-GGFG- In some embodiments, is -(Cri2)2C(O) -Vai-- Ala -. In some embodiments, L:1 . is (CH -;.Ci Os -Vai ~Cit~. In some embodiments, -L / r-L''- is -(CH?)2C(O)-GGFG~PABA- In some embodiments, -LZf~Ll- is -(CH2)2C(O) -Val-Ala-PABA-. In some embodiments, -L / P-Lc- is -(CH2)2C(O)-Val--Cit -PABA--. In some embodiments, -L^-L0- is -(CH2)2NHC(O)oGlc- In some embodiments, -LzP-Lc- is -(CH2)2NHC(O)-mGlc- In some embodiments, -LZB'-Ll- is -(CH2)2C(O)-(oGlc-a)-. In some embodiments, — Lzp— L*-’~ is ~-(CH2)2C(O)-(mGlc-a)~. -lA -L' - is ~(CH2)2NHC(O)-mGl«-. In some embodiments, -LzP-Lc- is -(CH2)2NHC(O)-oGlu- In some embodiments, -Lzp-Lc- is bonded to a pay load moiety at its -C(O)-. n

[0176] In some embodiments, the linker comprises -(CH2CH2O)B-. wherein n is 0-24. In some embodiments, n is 1 -24. In some embodiments, n is 6-24 In some embodiments, n is 7-20. In some embodiments, n is 8-15. In some embodiments, n is 5-10. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8,9. 10, 11, 12, 13. 14, 15, 16, 17. 18, 19 or 20. In some embodiments, n is 2. In some embodiments, n is 4 In some embodiments, n is 5, 6. 7, 8, 9, or 10. In some embodiments, n is 8. In some embodiments, n is10. In some embodiments, n is 0.

[0177] In sonic embodiments, n is 0 and L’ comprises a carbohydrate moiety. In some embodiments, n is 0 and 1.5 comprises a glucuronic acid moiety. In some embodiments, n is 0 and 1.5 comprises a galactose moiety. In some embodiments, n is 0, and 1A is oGlc, oGlc-a, mGlc, or mGlc-a. In some embodiments, n is 0 and L(is niGlu. In some embodiments, n is 0 and L5 is oGIu.

[0178] In some embodiments, -(CH2CH2O)n-LzP-Lc- is -(CH2CH2O)g-(CH2)2C(O)-GGFG-. In some embodiments, ~(CH2CH2O)n~Lzp--Lc“ is “(CH2CH2O)8~(CH2)2C(O)”Val“Ala--, In some embodiments, “(CH2CH2O)n-Lzp-LL“ is -(CH2CH2O)s-(CH2)2C(O)-Val-Cit--. In some embodiments. — (CH2CH2O)n— Lzr-Lc— is -(CH2CH2O)8-(CH2)2C(O)-GGFG-PABA-. In some embodiments, "(CH2CH2O)n“Lzp“LC“ is “(CH2CH2O)8“(CH2)2C(O)- Vai -Ala-PABA-, In some embodiments, -(CH2CH2O)n-Lzp-Lc- is -(CH2CH2O)8-(CH2)2C(O)-VaI-Cit-PABA-. In some embodiments. -(CH2CH2O)n--Lzp“Lc^ is -(CH2CH2O)8--(CH2)2NHC(O)-OG1C“-. In some embodiments. -(CH2CH2O)n-Lzp-Lc- is -(CH2CH2O)8-(CH2)2NHC(O)-mGlc-. In some embodiments, -(CH2CH2O)n-LZ1’-L' - is -(CH2CH2O)8-(CH2)2C(O)-(oGlc-a)-. In some embodiments.“(CH2CH2O)n-L / 'p“Lc-- is “(CH2CH2O)8-(CH2)2C(O)--(mGIc-a)--. In some embodiments, -(CH2CH2O)n-LZ1'-L''- is -(CH2CH2O)8-(CH2)2NHC(O)-L''1S-. In some embodiments. -(CH2CH2O)n-Lzp-Li-- is -(CH2CH2O)8 -(CH2)2NHC(O)-mGlu- . In some embodiments, -(CHiCHiOln-L'^ -1.5 ~ is -(CH2CH2O)8-(CH2)2NHC(O)-oGIu-. In some embodiments, -(CHeCH^in-L^-L0- is bonded to a payload moiety at its -C(O)-.zA

[0179] In some embodiments, Lxis a covalent bond. In some embodiments, Lxis an optionally substituted bivalent straight or branched C1.20 (e.g., Ci.g, CMO, CMS, C2.S, C5.10, Ci, C2, C3, C<, C5, Cs, C7, C8, Cy, C10, Cn , Ci2, CB, C14, C15, Ci6, Ci?, Cis, C19, C2u, etc.) aliphatic wherein 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, 1-3, 1-2, etc.) methylene units of Lxare optionally and independently replaced by a group selected from -O~, --N(R’)-. --C(O)--, -S- -S(O)- , ~S(O)2“ -C(O)N(R’)- , -S(O)2(NR') -, and -Cy- In some embodiments, Lxis an optionally substituted bivalent straight or branched Cmo (e.g., Ci-6, C2-s, Ci. C2, C3, C4, Cs. Cs, C?, Cs, Cy. Cio, etc.) aliphatic wherein 1-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2. etc.) methylene units of Lxare optionally and independently replaced by a group selected from 0 -N(R‘)~, — C(O)— , -S-, — S(O)~ . -S(O)2~, -C(O)N(R’)-, -S(O)2(NR’)-, and -Cy-. In some embodiments, Lxis -(CH2)x“C(O)“N(R')“. In some embodiments, Lxis -(CH2)x-C(O)~N(R')-, wherein x is 1-19, and -N(R')~ is bonded to -(CH2CH2O)n-. In some embodiments, Lxis -(CH2)x“'C(O) ~NH-. wherein x is 1- 19, and -NH- is bonded to -(CH2CH2O)n-. In some embodiments, Lxis -(CAI2)x-C(O)-N(R )- or -(CH2)X“C(O)“NH-, and x is 1-6, In some embodiments. Lxis -(CH2)5~C(O)“N(R’)-, wherein -N(R’)- is bonded to -(CH2CH2O)n-. In some embodiments, Lxis -(CH2)5-C(O)-NH-. wherein -NH- is bonded to --(CH2CH2O)n--. In some embodiments, LAis -(CH2)3“C(O)-N(R’)--. wherein -N(R') - is bonded to -(CH2CH2O)n- In some embodiments. Lxis -(CH2)2-C(O)--NH -, wherein -NH- is bonded to -(CH2CH2O)n-. In some embodiments, x is 1. 2, 3, 4. 5. 6, 7, 8, 9, 10. 1 1 , 12, 13. 14, 15, 16, 17. 18. 19, 1-15. 1 -10. etc. In some embodiments, x is I -10 (e.g., 1, 2, 3. 4. 5, 6. 7, 8, 9. 10. 1-5. 1 -4. 1 -3, 1-2, etc ) In some embodiments, x is 1-5 (e g , 1, 2, 3, 4, 5. 1-5, 1-4, 1 -2, etc ). In some embodiments, x is 1 . In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5.|01S0] In some embodiments, -Lx-(CH2CH2O)n-Lzp-Lc- is~(CH2)5C(O)NH-(CH;CH?.O)>J-(CH2)2C(O)- GGFG-. In some embodiments,— Lx-(CH2CH2O)n— Lzp-Lc— is -CCH2)5C(O)NH-(CH2CH2O)8-(CH2)2C(O)-Val-Ala-. In some embodiments, Lx(CH2CH2O)n LzpLc- is - (CdI2)5C(O)NH (CH2CH2O)8 (CH2)2C(O) Vai -Cit-. In some embodiments, -LA-(CH2CH2O)n-LzP-Lc- is---(CH2)5C(O)NI-I--(CH2CH2O)8---(CI-I2)2C(Oy- GGFG --P / \.BA-- . In some embodiments, -Lx-(CH2CH2O)n-Lzp-I,c- is --(CH2)5C(O)NH-(CH2CH2O)8-(CH2)2C(O)-Val-Ala-PABA-, In some embodiments, “Lx~(CH2CH2O)n“Lz ?~LC“ is-(CH2)5C(O)NI-I-(CH2CH2O)8-"(CI-I2!2C(O)- Val-Cit -PABzA-. In some embodiments, -Lx-(CH2CH2O)n-Lzp-Lc- is ~(CH2)5C(O)NH-(CH2CH2O)s~(CH2)2NHC(O)-oGlc-. In some embodiments, -Lx-(CH2CH2O)n-Lz p-Lc- is ~(CH2)5C(O)NH--(CH2CH2O)8--(CH2.)2NHC(O)~mGlc--.In some embodiments. --I,x---(CH2CH2O)n--L / P---L' -- is -(CH2)5C(O)NH-(CH2CH2O)8-(CH2)2C(O)-(oGic-a)-. In some embodiments, --Lx--(CH2CH2O)n---L,ZE--L' --- is ---(CH2)5C(O)NH--(CH2CH2O)8--(CH;)2C(O)---(mGIC"a)--. In some embodiments, “Lx~-(CH2CH2O)n--LZF~-Lp-- is ”(CH2)5C(O)NH--(CH2CH2O)8--(CH2)2NHC(O)--mGlu--.In some embodiments, -Lx--(CH2CH2O)n-L / p-L1'- is−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlu−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−PABA−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−PABA−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−PABA−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlc−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−mGlc−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(oGlc-a)−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(mGlc-a)−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−mGlu−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is −(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−oGlu−. In some embodiments, −LX−(CH2CH2O)n−LZP−LC− is bonded to a payload moiety at its −C(O)−. LRX

[0181] In some embodiments, LXis a covalent bond. In some embodiments, LXis an optionally substituted bivalent or polyvalent straight or branched C1-20(e.g., C1-6, C1-10, C1-15, C2-8, C5-10, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, etc.) aliphatic wherein 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, 1-3, 1-2, etc.) methylene units of LXare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−. In some embodiments, LXis a covalent bond or an optionally substituted bivalent or polyvalent straight or branched C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic wherein 1-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) methylene units of LXare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−. In some embodiments, at least one methylene unit is replaced with −Cy−. In some embodiments, −Cy− is . In some embodiments, −Cy− is. In some embodiments, -Cy- is. / \2H ' J — <f X >A — / N . In some embodiments, al least one methylene unit is replaced with -S-. In some embodiments, at least one methylene unit is replaced with -C(O)-.

[0182] In some embodiments, each LKXis independently -LRX:-LRX!-, wherein each of LRX' and LRX2is independently as described herein.

[0183] In some embodiments, ~LRA1~ is -S-. In some embodiments, -LRX1- is -S-, and the -S~ is of a Cys residue of a target binding moiety. In some embodiments. -LxX 1- is S- and the -S- is of a Cy s residue in an antibody which Cys residue forms an interchain disulfide bonds in an unconjugated antibody. In some embodiments. -LRX I- is -S-. and the ~S - is of a Cys residue of a target binding moiety, wherein the Cys residue forms an inter-heavy and light chain disulfide in an unconjugated target binding moiety. In some embodiments. -~LRx’‘- is -S-. and the -S~ is of a Cys residue of a target binding moiety, wherein the Cys residue is derived through partial or complete reduction of the interchain disulfide bonds.

[0184] In some embodiments, LRX !isIn some embodiments. LRX1is ---Nil- which is of a Lys residue of a target binding moiety. In some embodiments, LxX1is -NH- which is of a Lys residue of an antibody or an antigen-binding fragment thereof.

[0185] In some embodiments, -Lsx“- is or comprises optionally substituted, wherein the nitrogen is bonded to Lx, and the carbon is bonded to LRX1. In some embodiments, -LRX2- is or comprises, wherein the nitrogen is bonded to L*. and the carbon is bonded to LKXI. In some embodiments, -LRX*- is or comprises, wherein “# represents a point of atachment to Lx, and represents a point of attachment to LxX i. In some embodiments, LRXzis -S

[0186] In some embodiments, LRX2is or comprises -C(O)~. In some embodiments, the ~C(O)~ is bonded io -NH- of LRX I.

[0187] In some embodiments, LxXis or comprises -S-S-. In some embodiments, LxXis or comprises -S-CH2~C(O)-. In some embodiments, LRXis or comprises optionally substituted

[0188] In some embodiments, −LRX− is or comprises optionally substituted wherein−C(O)− is bonded to LX. In some embodiments, −LRX− is or comprises wherein −C(O)− is bonded to LX. RX

[0189] In some embodiments, L is or comprises −NH−C(O)−.

[0190] In some embodiments, LRXis or comprises a click chemistry product moiety. In some embodiments, LRXis or comprises an optionally substituted triazole ring. In some embodiments, LRXis or me the 5- mbered ringis bonded to LX.

[0191] In some embodiments, LRXis a covalent bond. In some embodiments, LRXis a moiety that results from a reaction between a group present on the unconjugated target binding moiety (e.g., LRXT, LRX1, etc.) and a group present on an agent comprising LX−(CH2CH2O)n−LZP−LC− and a payload moiety (e.g., LRXP, LRX2, etc.). In some embodiments, LRXis a moiety that results from a reaction between a group present on the unconjugated target binding moiety (e.g., LRXT, LRX1, etc.) and a group present on an agent comprising LX’and optionally a payload moiety (e.g., LRXP, LRX2, etc.).

[0192] In some embodiments, each LRXis independently a moiety that results from a reaction between an unbound linker and a group present on an unconjugated target binding moiety.

[0193] In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker and a group present on an unconjugated target binding moiety. In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker and a group present on an antibody or antigen-binding fragment thereof.

[0194] In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker and a group present on an arginine, asparagine, aspartic acid, cysteine, glutamic acid,glutamine, histidine, lysine, serine, threonine, tryptophan, or tyrosine within a target binding moiety, e.g., an antibody or antigen-binding fragment thereof. In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker and a group present on a cysteine, lysine, serine, threonine, or tyrosine within a target binding moiety, e.g., an antibody or antigen-binding fragment thereof. In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker and a group present on a cysteine within a target binding moiety, e.g., an antibody or antigen-binding fragment thereof. In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker and a group present on a lysine within a target binding moiety, e.g., an antibody or antigen-binding fragment thereof. In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker and a thiol, amine, acid, or hydroxyl group within a target binding moiety, e.g., an antibody or antigen-binding fragment thereof. In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker and a thiol within a target binding moiety, e.g., an antibody or antigen-binding fragment thereof. In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker and an amine within a target binding moiety, e.g., an antibody or antigen-binding fragment thereof. In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker and a hydroxyl within a target binding moiety, e.g., an antibody or antigen-binding fragment thereof.

[0195] In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker and a group present on a target binding moiety, e.g., an antibody or antigen-binding fragment thereof, wherein the reaction is a conjugation with activated esters, sulfonyl chlorides, or isothiocyanates; reductive alkylation; aza-Michael addition; azetidinone chemistry; benzoyl fluoride- based chemistry; or click chemistry. Examples are provided in, e.g., Sletten and Bertozzi. Agew. Chem. Int. Ed. Engl.2009, 48(38), 6974-6998.

[0196] In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker comprising a moiety capable of reacting with an arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, lysine, serine, threonine, tryptophan, or tyrosine; and a group present on a target binding moiety, e.g., an antibody or antigen-binding fragment thereof. In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker comprising a moiety capable of reacting with a cysteine, lysine, serine, threonine, or tyrosine; and a group present on a target binding moiety, e.g., an antibody or antigen-binding fragment thereof. In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker comprising a moiety capable of reacting with a cysteine and a group present on a target binding moiety, e.g., an antibody or antigen-binding fragment thereof. In some embodiments, a linker comprises a moiety that results from a reaction between an unbound linker comprising a moiety capable of reacting with a lysine and a group present on a target binding moiety, e.g., an antibody or antigen-binding fragment thereof.

[0197] In some embodiments, a moiety capable of reacting with a cysteine is or comprises a maleimide, haloacetamide (e.g., fluoroacetamide, chloroacetamide, bromoacetamide, or iodoacetamide),or a Michael acceptor (e.g., α,β-unsaturated carbonyl, such as acrylamide or α,β-unsaturated ketone). In some embodiments, a moiety capable of reacting with a cysteine is a maleimide. In some embodiments, a moiety capable of reacting with a cysteine is a haloacetamide (e.g., fluoroacetamide, chloroacetamide, bromoacetamide, or iodoacetamide). In some embodiments, a moiety capable of reacting with a cysteine is a Michael acceptor (e.g., α,β-unsaturated carbonyl, such as acrylamide or α,β-unsaturated ketone). In some embodiments, a moiety capable of reacting with a cysteine is a maleimide, chloroacetamide, bromoacetamide, acrylamide, or an α,β-unsaturated ketone. In some embodiments, a moiety capable of reacting with a cysteine is a chloroacetamide. In some embodiments, a moiety capable of reacting with a cysteine is a bromoacetamide. In some embodiments, a moiety capable of reacting with a cysteine is an iodoacetamide. In some embodiments, a moiety capable of reacting with a cysteine is an acrylamide. In some embodiments, a moiety capable of reacting with a cysteine is an α,β-unsaturated ketone.

[0198] In some embodiments, a linker compris , wherein: # represents a point of attachment to a target binding moiety; and * represe tachment to the remainder of thelinker. In some embodiments, a linker comprises , wherein R is as described herein, # represents a point of attachment to a target binding moiety; and * represents a point of attachment to the remainder of the linker. In some embodiments, a linker comprise , wherein R is as described herein, # represents a point of attachment to a target binand * represents a point of attachment to the remainder of the linker. In some embodiments, a linker comprise , wherein # represents a point of attachment to a target binding moiety; and * represents a point of attachment to the remainder of the linker. In some embodiments, a linker compris , wherein # represents a point of attachment to a target binding moiety; and * represp attachment to the remainder of the linker. In some embodiments, a linker comprises , wherein * represents a point of attachment to a target binding moiety; and # represents a point of attachment to the remainder of the linker. In some embodiments, a linker compri ,wherein # represents a point of attachment to the anti-HHLA2 antibody or antigen-binding fragment thereof; and * represents a point of attachment to the remainder of the linker. In some embodiments, In some embodiments, a linker comprise , wherein R is as described herein, # represents a point of attachment to an antibody or fragment thereof; and * represents a point ofattachment to the remainder of the linker. In some embodiments, a linker comprises , wherein R is as described herein, # represents a point of attachment to an antibody dingfragment thereof; and * represents a point of attachment to the remainder of the linker. In some embodiments, a linker comprises , wherein # represents a point of attachment to an antibody or antigen-binding fragnd * represents a point of attachment to the remainder of the linker. In some embodiments, a linker comprises , wherein # represents a point of attachment to an antibody or antigen-binding fragmd * represents a point of attachment to the remainder of the linker. In some embodiments, a linker compris , wherein * represents a point of attachment to an antibody or antigen-binding frof; and # represents a point of attachment to the remainder of the linker.

[0199] In some embodiments, a target binding moiety is engineered to incorporate a reactive group. For example, in some embodiments, an antibody or antigen-binding fragment thereof is engineered to incorporate Cys, Lys, etc. at certain positions for conjugation. In some embodiments, unnatural amino acid residues, e.g., those comprising −N3, alkyne, etc., are incorporated. In some embodiments, glycosylation is modified to introduce reactive groups for conjugation.

[0200] Various technologies including useful groups and reactions, e.g., LRX1, LRX2, LRX, etc., are reported and can be utilized in accordance with the present disclosure, e.g., those described in Fu, Z., Li, S., Han, S. et al. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Sig Transduct Target Ther 7, 93 (2022). https: / / doi.org / 10.1038 / s41392-022-00947-7; Su Z, Xiao D, Xie F, Liu L, Wang Y, Fan S, Zhou X, Li S. Antibody-drug conjugates: Recent advances in linker chemistry. Acta Pharm Sin B.2021 Dec;11(12):3889-3907. doi: 10.1016 / j.apsb.2021.03.042. Epub 2021 Apr 6. PMID: 35024314; PMCID: PMC8727783; Sheyi R, de la Torre BG, Albericio F. Linkers: An Assurance for Controlled Delivery of Antibody-Drug Conjugate. Pharmaceutics.2022 Feb 11;14(2):396. doi: 10.3390 / pharmaceutics14020396. PMID: 35214128; PMCID: PMC8874516; etc.

[0201] In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−. In some embodiments,−LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlc−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−mGlc−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(oGlc-a)−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(mGlc-a)−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−mGlu−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−oGlu−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlc−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−mGlc−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(oGlc-a)−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(mGlc-a)−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−mGlu−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−oGlu−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is bonded to a payload moiety at its −C(O)−. In some embodiments, the −S− in −SM is of a Cys residues as described herein.

[0202] In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−. In some embodiments,−LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlc−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−mGlc−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(oGlc- a)−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(mGlc-a)−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−mGlu−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−oGlu−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlc−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−mGlc−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(oGlc-a)−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(mGlc-a)−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−mGlu−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−oGlu−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is bonded to a payload moiety at its −C(O)−. In some embodiments, the −S− is of a Cys residues as described herein.

[0203] In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−PABA−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlc−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−mGlc−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(oGlc- a)−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(mGlc-a)−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−mGlu−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is −S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−oGlu−. In some embodiments, −LRX−LX−(CH2CH2O)n−LZP−LC− is bonded to a payload moiety at its −C(O)−. In some embodiments, the −S− is of a Cys residues as described herein. LT

[0204] In some embodiments, LTis a covalent bond. In some embodiments, LTis an optionally substituted bivalent straight or branched C1-20(e.g., C1-6, C1-10, C1-15, C2-8, C5-10, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, etc.) aliphatic wherein 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, 1-3, 1-2, etc.) methylene units of LTare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, and −S(O)2(NR’)−. In some embodiments, LTis an optionally substituted bivalent straight or branched C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic wherein 1-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) methylene units of LTare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, and −S(O)2(NR’)−. In some embodiments, LTis anoptionally substituted bivalent straight or branched C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic group. In some embodiments, LTis a bivalent straight or branched C1-20(e.g., C1-6, C1-10, C1-15, C2-8, C5-10, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, etc.) aliphatic group. In some embodiments, LTis an optionally substituted bivalent straight or branched C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) alkylene group. In some embodiments, LTis an optionally substituted bivalent straight C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) alkylene group. In some embodiments, LTis optionally substituted −(CH2)1−5−. In some embodiments, LTis optionally substituted −(CH2)1−5−. In some embodiments, LTis − (CH2)1-5−. In some embodiments, LTis −CH2−. In some embodiments, LTis –(CH2)4−. In some embodiments, wherein the target binding moiety comprises an amino acid residue, LTis bonded to the backbone atom of the amino acid residue. In some embodiments, wherein the target binding moiety comprises an amino acid residue, LTis bonded to the alpha-carbon of the amino acid residue. In some embodiments, LTis part of an amino acid residue (e.g., Cys, Lys, etc.) of a target binding moiety prior to conjugation.

[0205] In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlc−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−mGlc−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(oGlc- a)−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(mGlc-a)−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−mGlu−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−oGlu−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−. In some embodiments,−LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlc−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−mGlc−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(oGlc- a)−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(mGlc-a)−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−mGlu−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−SM−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−oGlu−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is bonded to a payload moiety at its −C(O)−. In some embodiments, the −S− in −SM is of a Cys residues as described herein. In some embodiments, the −CH2−S− is of a Cys residues. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− bonds to a carbon atom (e.g., alpha carbon) of a polypeptide chain and a payload moiety.

[0206] In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlc−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−mGlc−. In some embodiments,−LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(oGlc-a)−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(mGlc-a)−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−mGlu−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)5C(O)NH−(CH2CH2O)8−(CH2)2C(O)−oGlu−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlc−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−mGlc−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(oGlc-a)−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(mGlc-a)−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−mGlu−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2)3C(O)NH−(CH2CH2O)8−(CH2)2C(O)−oGlu−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−GGFG−PABA−. In some embodiments,−LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Ala−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−Val−Cit−PABA−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−oGlc−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2NHC(O)−mGlc−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(oGlc-a)−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−(mGlc-a)−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−mGlu−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is −CH2−S−CH2C(O)NH−(CH2CH2O)8−(CH2)2C(O)−oGlu−. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− is bonded to a payload moiety at its −C(O)−. In some embodiments, the −S− is of a Cys residues as described herein. In some embodiments, the −CH2−S− is of a Cys residues. In some embodiments, −LT−LRX−LX−(CH2CH2O)n−LZP−LC− bonds to a carbon atom (e.g., alpha carbon) of a polypeptide chain and a payload moiety. LX'

[0207] In some embodiments, a linker is or comprises LX’. In some embodiments, LX’ is a covalent bond. In some embodiments, LX’ is an optionally substituted bivalent or polyvalent straight or branched C1-20(e.g., C1-6, C1-10, C1-15, C2-8, C5-10, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, etc.) aliphatic wherein 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, 1-3, 1-2, etc.) methylene units of LX’are optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−;−C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−. In some embodiments, LX’ is an optionally substituted bivalent or polyvalent straight or branched C1-20(e.g., C1-6, C1-10, C1-15, C2-8, C5-10, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, etc.) aliphatic wherein 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, 1-3, 1-2, etc.) methylene units of LX’are optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−;−C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−. In some embodiments, LX’ is an optionally substituted bivalent or polyvalent straight or branched C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic wherein 1-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) methylene units of LX’are optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−;−C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−. In some embodiments, LX’ is bivalent. In some embodiments, LX’ is polyvalent. For example, in some embodiments, LX’is optionally substituted, wherein the phenyl ring is bonded to “(CILCILOjn-. In some embodiments,embodiments,1 J ahas the structuresome embodiments, each -S~ is independently of a Cys residue in the same target binding moiety. In some embodiments, each -CHj-S- is independently of a Cys residue in the same target binding moiety In some embodiments, the two Cys residues form an inter- chain disulfide bond in an unconjugated target binding moiety' .

[0208] In some embodiments, a is 1. In some embodiments, a is 2-10. In some embodiments, a is 2. In some embodiments, a is 3. 4. 5, 6, 7, 8, 9. or 10.

[0209] In some embodiments, b is 1. In some embodiments, b is 2-10. In some embodiments, b is 2. In some embodiments, b is 3, 4, 5, 6, 7, 8, 9, or 10.Cy

[0210] As used herein, Cy is an optionally substituted bivalent 3-20 (e.g., 3, 4, 5, 6. 7, 8, 9, 10, 11, 12, 13, 14, 15. 16, 17, 18, 19. 2.0, 3-15, 3-14, 3-10, 5-10, 3-7. 3-6, etc.) membered ring having 0-10 (e.g., 0. 1, 2, 3, 4, 5. 6. 7, 8, 9, 10, 1-10. 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy is an optionally substituted bivalent 3-20 (e.g.. 3, 4, 5, 6. 7. 8, 9, 10, 11. 12. 13. 14. 15. 16. 17, 18, 19. 20. 3-15, 3-14, 3-10, 5-10. 3-7. 3-6, etc.) membered ring having 0-10 (e.g,. 0, 1. 2, 3. 4. 5, 6. 7, 8. 9. 10. 1-10. 0-5, 1-5. etc. ) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, Cy is monocyclic. In some embodiments, Cy is bicyclic. In some embodiments, Cy is polycyclic. In some embodiments, each monocyclic ring unit is independently7an optionally substituted 3-10 (e.g.. 3. 4, 5, 6, 7. 8. 9, 10. 3-8. 3-7, 3-6. 5-8. etc.) membered ring having 0-5 (e g . 1. 2, 3, 4, 5, 1-5. 1-4. 1-2, etc.) heteroatoms independently7selected from silicon, nitrogen, oxygen, phosphorus and sulfur and 1-10 (e.g., 1 , 2. 3, 4, 5. 6, 7. 8, 9, 10. 1- 5. 1-4, etc.) carbon atoms. In some embodiments, a monocyclic ring unit is an optionally substituted saturated ring In some embodiments, a monocyclic ring unit is an optionally7substituted partially unsaturated ring. In some embodiments, a monocyclic ring unit is an optionally7substituted aromatic ring. In some embodiments, a monocyclic ring unit is an optionally7substituted phenyl ring. In someembodiments, a monocyclic ring unit is an optionally substituted 5-membered heteroaromatic having 1-4 (e.g., 1, 2, 3. 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6-membered heteroaromatic having 1-4 (e.g., 1. 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur Each monocyclic ring unit is independently optionally substituted In some embodiments, a monocyclic ring unit is unsaturated. In some embodiments, a monocyclic ring unit is saturated. In some embodiments, Cy is an optionally substituted saturated ring. In some embodiments, Cy is an optionally substituted partially unsaturated ring. In some embodiments. Cy is an optionally substituted aromatic ring.

[0211] In some embodiments, Cy is an optionally substituted bivalent 3-10 (e.g., 3, 4. 5, 6, 7, 8, 9. or 10) membered monocyclic cycloaliphatic ring. In some embodiments, Cy is an optionally substituted 3- 10 (e.g.. 3, 4, 5, 6, 7. 8, 9, or 10) membered monocyclic cycloalkyl ring. In some embodiments, Cy is an optionally substituted 3-10 (e.g., 3, 4. 5, 6, 7, 8, 9, or 10) membered monocyclic heteroaliphatic ring having 1-5 heteroatoms, hi some embodiments. Cy is an optionally substituted 3-10 (e.g,. 3. 4. 5, 6, 7, 8.9. or 10) membered monocyclic heteroalky l ring having 1-5 heteroatoms. In some embodiments. Cy is an optionally substituted bivalent 5-15 (e.g., 5. 6. 7, 8, 9, 10, 11, 12. 13. 14, or 15) membered bicyclic or polycyclic cycloaliphatic group. In some embodiments. Cy is an optionally substituted bivalent 5-15 (e.g., 5, 6, 7, 8. 9. 10. II, 12, 13, 14. or 15) membered bicyclic or polycyclic cycloalkyl group. In some embodiments, Cy is an optionally substituted 5-15 (e.g., 5. 6, 7. 8. 9, 10. 11. 12, 13, 14, or 15) membered bicyclic or polycyclic heteroaliphatic ring having 1-5 heteroatoms In some embodiments. Cy is an optionally substituted 5-15 (e.g., 5, 6, 7, 8. 9, 10. 11, 12, 13, 14. or 15) membered bicyclic or polycyclic beterocyclyl ring having 1-5 heteroatoms. In some embodiments, a cycloaliphatic, cycloalkyd, heteroaliphatic or heteroalkyl ring is 3-membered. In some embodiments, it is 4-membered. In some embodiments, it is 5 -membered. In some embodiments, it is 6-membered, in some embodiments, it is 7- membered. In some embodiments, it is 8-membered. In some embodiments, it is 9-membered. In some embodiments, it is 10-membered. In some embodiments, it is II -membered. In some embodiments, it is 12-membered. In some embodiments, Cy is optionally substituted phenylene. In some embodiments, Cy is an optionally substituted bivalent 10-membered bicyclic aryl ring. In some embodiments, Cy is an optionally substituted 5-membered heteroaryl ring having I -4 heieroatoms. In some embodiments, Cy is an optionally substituted 6-membered heteroaryl ring having 1 -4 heteroatoms. In some embodiments, Cy is an optionally substituted 9-rnembered bicyclic heteroaryl ring having 1-5 heteroatoms. In some embodiments, Cy is an optionally substituted 10-membered bicyclic heteroaryl ring having 1 -5 heteroatoms. In some embodiments, a heteroaliphatic, heterocyclyl or heteroaryl ring contains no more than 1 heteroatom. Its some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur.|0212] In some embodiments, Cy is an optionally substituted 4-7 membered ring having 0-3 heteroatoms. In some embodiments, Cy is an optionally substituted 6-membered aryl ring. In some embodiments, an aryl ring is substituted. In some embodiments, it is substituted with one or morehalogen. In some embodiments, it is substituted with one or more -F. In some embodiments, it is not substituted. In some embodiments, it is optionally substituted. fnsome embodiments, it isIn some embodiments. Cy is an optionally substituted 5 -membered heteroaryl ring having 1-3 heteroatoms. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur. In some embodiments, Cy is optionallyN=N N=NA-AX bt substituted * . In some embodiments. Cy is. In some embodiments, -Cy- is optionally substitutedsome embodiments,R ’

[0213] Certain embodiments for R’ are described below. Various variables can be R", and embodiments for R’ can also be applied to such variables that can be R’.

[0214] In some embodiments, R’ is R as described herein. In some embodiments, R’ is -II. In someembodiments, R’ is not -H. In some embodiments, R' is optionally substituted Cris aliphatic.

[0215] In some embodiments, R’ is -C(O)R wherein R is as described herein. In some embodiments, R’ is -CO2R wherein R is as described herein. In some embodiments, R’ is -S(O)2R wherein R is as described herein. In some embodiments, as described herein, R is not -H.

[0216] In some embodiments, two or more R’ are taken together with their intervening alom(s) to form an optionally substituted 3-20 (e.g., 3-15, 3-10, 3-6, 5-10. 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1- 10, 1 -5, 1-4. 1-3, 1-2, 1, 2, 3, 4. 5, 6, 7, 8, 9, 10, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, two or more R' on the same atom are taken together with the atom to which they are attached to form an optionally substituted 3-20 (e.g, 3-15, 3-10, 3-6, 5-10, 5-6, 3. 4, 5, 6, 7, 8. 9. 10. 11. 12. 13. 14. 15, 16, 17, 18. 19, 20, etc.) membered ring having, in addition to the intervening atom(s). 0-10 (e.g., 0. 1 -10. 1-5, 1-4, 1-3, 1-2, 1. 2. 3. 4, 5, 6. 7. 8. 9, 10, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, two R’ on the same atom are taken together with the atom to which they are atached to form an optionally substituted 3-20 (e.g., 3-15. 3-10. 3-6, 5-10. 5-6. 3, 4. 5, 6, 7, 8, 9, 10, 11, 12. 13. 14. 15, 16. 17. 18. 19, 20, etc.) membered ring having, in addition to the intervening atom(s). 0-10 (e.g., 0, 1- 10, 1-5, 1-4, 1 -3. 1 -2. 1 , 2, 3. 4. 5. 6. 7, 8, 9, 10, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

[0217] In some embodiments, each R’ is independently -R, ~C(O)R, -COR, or -S(O)2R, or two or more R‘ on the same atom are taken together with the atom to which they are attached to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-5 heteroatoms independently selected from silicon, nitrogen, oxy gen, phosphorus and sulfur.Ring

[0218] Compounds of the present disclosure (e.g., in a composition and / or a conjugate as described herein) may contain various rings. In some embodiments, a variable, e.g., R or a variable that can be R, can be of a ring as described herein. In some embodiments, two variables, e.g., two R' groups, may be taken together with their intervening atom(s) to form a ring as described herein. In some embodiments, a ring is monovalent. In some embodiments, a ring is bivalent. In some embodiments, a ring structure can be polyvalent. Rings are optionally substituted. In some embodiments, a ring is unsubstituted. In some embodiments, a ring is substituted.

[0219] Certain embodiments and features of rings are described below as examples.

[0220] In some embodiments, a ring is an optionally substituted 3-20 (e.g., 3. 4. 5, 6, 7, 8, 9, 10, 1 1,12, 13, 14. 15, 16, 17, 18. 19, 20, 3-15, 3-14, 3-10. 5-10, 3-7. 3-6, etc.) membered ring having 0-10 (e.g., 0, 1. 2, 3, 4, 5, 6. 7, 8, 9, 10, 1-10. 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, a ring is an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12. 13, 14, 15, 16, 17, 18, 19, 20, 3-15. 3-14, 3-10, 5-10, 3-7, 3-6. etc.)membered ring having 0-10 (e.g.. 0, 1, 2, 3, 4, 5. 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, a ring is monocyclic In some embodiments, a ring is bicyclic. In some embodiments, a ring is polycyclic.

[0221] In some embodiments, each monocyclic ring unit is independently an optionally substituted 3- 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10. 3-8, 3-7, 3-6, 5-8, etc.) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1- 4, 1-2, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur and 1-10 (e.g.. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 -5, 1-4, etc. ) carbon atoms In some embodiments, a monocyclic ring unit is an optionally substituted saturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted partially unsaturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted aromatic ring. In some embodiments, a monocyclic ring unit is an optionally substituted phenyl ring. In some embodiments, a monocy clic ring unit is an optionally substituted 5- membered heteroaromatic having 1 -4 (e.g., I . 2. 3. 4, 1-3, 1-2. etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6-membered heteroaromatic having 1-4 (e.g.. 1. 2, 3, 4, 1-3. 1 -2, etc ) heteroatoms independently selected from nitrogen, oxygen and sulfur. Flach monocyclic ring unit is independently optionally substituted. In some embodiments, a monocyclic ring unit is unsaturated. In some embodiments, a monocyclic ring unit is saturated.

[0222] In some embodiments, a ring is an optionally substituted saturated ring. In some embodiments, a ring is an optionally substituted partially unsaturated ring. In some embodiments, a ring is an optionally substituted aromatic ring.

[0223] In some embodiments, a ring is an optionally substituted 3-10 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atom(s), 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a ring is 3-9, 3-8, 3-7, 3-6, 4-10, 4-9, 4- 8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10-membered. In some embodiments, a ring is 3-9 membered. In some embodiments, a ring is 3-7 membered. In some embodiments, a ring is 4-10 membered. In some embodiments, a ring is 4-7 membered. In some embodiments, a ring is 5-10 membered. In some embodiments, a ring is 5-7 membered. In some embodiments, a ring is 3-membered. In some embodiments, a ring is 4-membered. In some embodiments, a ring is 5 -membered. In some embodiments, a ring is 6-membered. In some embodiments, a ring is 7-membered. In some embodiments, a ring is 8-membered. In some embodiments, a ring is 9-membered. In some embodiments, a ring is 10-membered In some embodiments, a ring is monocyclic. In some embodiments, a ring is bicyclic. In some embodiments, a ring is polycyclic. In some embodiments, a ring has no heteroatoms. In some embodiments, a ring has 1-6. e.g., 1-5, 1-3, or 1, 2, 3, 4. 5, or 6 heteroatoms. In some embodiments, a ring formed by two or more groups taken together with their intervening atom(s) has no heteroatoms in addition to the intervening atom(s). In some embodiments, a ring formed by two or more groups taken together with their intervening atom(s) has 1 -6. e.g., 1-5, 1-3. or 1, 2. 3. 4, 5. or 6 heteroatoms in addition to the intervening atom(s). In some embodiments, a ring is saturated In some embodiments, a ring is partially unsaturated. In some embodiments, a ring comprises one or morearomatic ring. In some embodiments, a ring is bicyclic or polycyclic, and each monocyclic ring unit is independently 3-10 (e g.. 3-9. 3-8, 3-7, 3-6, 4-10, 4-9. 4-8, 4-7, 4-6. 5-10, 5-9, 5-8. 5-7, 5-6, or 3. 4. 5, 6.7, 8, 9, or 10) membered, saturated, partially unsaturated or aromatic and having 0-5 (e.g., 0, 1-5, 1-3, 1 , 2, 3, 4, or 5) heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is saturated. In some embodiments, a monocyclic ring unit is partially unsaturated. In some embodiments, a monocyclic ring unit is aromatic. In some embodiments, a monocyclic ring unit is heteroaromatic. Those skilled in the art appreciate that intervening atom(s), e.g., of groups taken together to form a ring, are ty pically atoms on die shortest path connecting such groups if multiple paths exist.

[0224] In some embodiments, a ring has one or more heteroatoms. In some embodiments, a ring comprises a nitrogen atom. In some embodiments, a ring comprises an oxygen atom. In some embodiments, a ring comprises a sulfur atom . / i

[0225] Various variables in the present disclosure can independently be R and embodiments for R can also be applied to such variables that can be R. Certain embodiments for R are described below as examples. 'Those skilled in the art reading the present disclosure appreciate that embodiments that are described for a variable that can be R and fall within the definition of R can be embodiments for R as well Those skilled in the art reading the present disclosure further appreciate that embodiments for R, e.g., those described for R. those described for a variable that can be R and within the definition of R, etc., can be embodiments for a variable that can be R

[0226] In some embodiments, R is -H. In some embodiments, R is not -H. In some embodiments, R is optionally substituted Ci ic (e.g., Ci.(,, C2-8, C>, C2, C3, C.i, C5, C&, C?, Cs, C9, Cio, etc.) aliphatic. In some embodiments, R is optionally substituted Ci « aliphatic In some embodiments, R is optionally substituted Ci-g aliphatic. In some embodiments, R is optionally substituted Cno (e.g., Ci-s, CXs, Ci, Ci, C;, C4, C5, Cs, Ci, Cs, Cs, Cio, etc.) alkyl. In some embodiments, R is optionally substituted Cvs alkyl. In some embodiments, R is optionally substituted Cvs aliphatic In some embodiments, R is optionally substituted Cvs alkyl. In some embodiments. R is optionally substituted -CTfo -C3-6 cycloaliphatic. In some embodiments, R is optionally substituted --CH2--C36 cycloaliphatic. In some embodiments, R is optionally substituted -CH2-C3-6 cycloalkyl. In some embodiments, R is methyl. In some embodiments. R is ethyl. In some embodiments, R is isopropyl. In some embodiments. R is -CF3. In some embodiments. R is -CH2CF3. In some embodiments, R is butyl. In some embodiments. R is t -butyl.

[0227] In some embodiments, R is optionally substituted 3-10 membered (e.g.. 3-9. 3-8, 3-7, 3-6, 5- 7, 4. 5, 6, 7, 8, 9, 10. etc.) cycloaliphatic. In some embodiments. R is optionally substituted (\i« cycloalkyl. In some embodiments. R is optionally substituted cyclopropyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments. R is optionally substituted cyclopentyl. In some embodiments, R is optionally substituted cyclohexyl.

[0228] In some embodiments, R is optionally substituted Ct-io (e.g., C; 6, C2-8, Ci, C?„ C3, C<1, C;„ Cc,C?, Cg, Cs. Cjo, etc.) heteroaliphatic having 1-5 (e.g.. 1-4. 1-3, 1-2, 1, 2, 3. 4, 5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, R is optionally substituted Ci-s (e.g., C;.s, C2-8, Ci, C2, C3, C4, C5, C.s, C?, Cg, C9, C10, etc.) heteroaliphatic having 1-5 (e.g., 1-4. 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, R is optionally substituted C i-w (e.g., Ci- 6, C2-8, Ci, C2, C3, C4, C5, Cg, C?, Cg, Cg, C10, etc.) heteroaliphatic having 1-5 (e.g., 1-4. 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted Cj.g (e.g., Ci-6, C?-s, Ci, C2, C3, C4, C5, C«, C?, Cs, Cs, Cio, etc.) heteroaliphatic having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted Ci-s heteroaliphatic having 1 -3 heteroatoms independently selected from nitrogen, oxygen and sulfur Ci-g heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxy gen and sulfur. In some embodiments, R is optionally substituted Ci-e heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur Ci-s heteroaliphatic having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is heteroalkyl.

[0229] In some embodiments. R is optionally substituted 3-15 (e.g., 3. 4. 5, 6, 7, 8. 9. 10. 11. 12, 13. 14. 15. 3-10. 3-7. 4-10. 4-6, etc.) membered heterocyclic ring having 1-5 (e.g.. 1-4. 1 -3, 1-2. 1 , 2, 3. 4. 5. etc.) heteroatoms independently selected from silicon, nitrogen. oxygen, phosphorus and sulfur. In some embodiments. R is optionally substituted 3-15 (e.g., 3, 4, 5. 6. 7. 8, 9. 10. 11 . 12. 13. 14, 15, 3- 10. 3-7, 4- 10, 4-6, etc.) membered heterocyclic ring having 1-5 (e.g., 1 -4. 1 -3. 1 -2. 1 , 2, 3, 4. 5. etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted 3-10 (e.g., 3-9, 3-8, 3-7, 3-6. 5-7. 4, 5, 6, 7, 8. 9, 10. etc.) membered heterocyclyl having 1 -4 (e.g., 1 , 2, 3. 4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 3-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 3 -membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 4-membered heterocyclyl having 1 -2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 5-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 6-membered heterocyclyl having 1 -3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 8-membered heterocyclyl having 1 -3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments. R is optionally substituted 9-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments. R is optionally substituted 10-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, there is one carbon atom in a heterocyclyl ring. In some embodiments, there are two or more (e.g.. 2-14. 2-9. 2-6, 2-4, 3-10. 3-5. 2,3. 4. 5, 6, 7, 8, 9. 10, 11, 12, 13, 14, etc.) carbon atoms in a heterocyclyl ring.

[0230] In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is optionally substituted naphthyl. In some embodiments, R is optionally substituted 1 -naphthyl. In some embodiments. R is optionally substituted 2 -naphthyl. In some embodiments, R is naphthyl.

[0231] In some embodiments, R is optionally substituted 5-14 (e.g., 5, 6, 9. 10, 14, etc.) membered heteroaryl having 1-6 (e.g.. 1-5, 1-4, 1, 2, 3, 4, 5, 6, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments. R is optionally substituted 5-14 (e.g., 5, 6. 9, 10, 14, etc.) membered lieteroaryl having 1-6 (e.g., 1-5, 1-4. 1, 2. 3, 4, 5, 6. etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted 5-10 (e.g., 5, 6. 9. 10, etc.) membered lieteroaryl having 1-6 (e.g., 1-5, 1-4. 1, 2. 3, 4, 5. 6. etc.) heteroatoms independently selected from oxygen. nitrogen and sulfur, in some embodiments, R is optionally substituted 5-10 membered heteroaiyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a heteroaryl ring is monocyclic and is 5-membered. In some embodiments, a heteroaryl ring is monocyclic and is 6-membered. In some embodiments, a heteroaiyl ring is bicyclic and is 9-membered. In some embodiments, a heteroaryl ring is bicyclic and is 10-membered. In some embodiments, a heteroary! ring is tricyclic and is 14-membered. In some embodiments, R is optionally substituted 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 5 -membered heteroaryl hating 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 6-membered heteroaiyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 6-membered heteroaiyl having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 8- 10 membered aromatic ring having I -6 heteroatotns nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 9-membered aromatic ring having 1-6 heteroatoms nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 10- membered aromatic ring having 1-6 heteroatoms nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 9-membered aromatic ring having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 10-merabered aromatic ring having 1 heteroatom nitrogen, oxygen and sulfur. In some embodiments, at least one heteroatom is nitrogen. In some embodiments, at least one heteroatom is oxygen. In some embodiments, at least one heteroatom is sulfur. In some embodiments, each heteroatom is the same. In some embodiments, at least one heteroatom is different from another heteroatom.

[0232] In some embodiments, there are multiple bivalent moieties between two connected moieties. As appreciated by those skilled in the art. when each of these bivalent moieties is a covalen t bond, there is a single covalent bond between the connected moieties unless otherwise specified.

[0233] As described herein, various groups may be optionally substituted Substituents are routinely utilized in chemistry including in development of various therapeutics. Many substituents can be utilizedin accordance with the present disclosure. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. Substituents are preferably those that result in the formation of compounds for a desired property', activity, use, etc., as described herein. In some embodiments, compounds are stable for therapeutic use as described herein. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a substituent is a hydrocarbon group. In some embodiments, a substituent comprises a heteroatom. In some embodiments, a substituent comprises multiple heteroatoms. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, sulfur, phosphorus and silicon. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, and sulfur. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, fluorine, chlorine, bromine, iodine, nitrogen, oxygen, and sulfur. In some embodiments, the total number of carbon and tion-halogen heteroatom(s) in a substituent is about or no more than about 1 ; in some embodiments, it is no more than about 2; in some embodiments, it is no more than about 3; in some embodiments, it is no more than about 4; in some embodiments, it is no more than about 5; in some embodiments, it is no more than about 6; in some embodiments, it is no more than about 7; in some embodiments, it is no more than about 8; in some embodiments, it is no more than about 9; in some embodiments, it is no more than about 10: in some embodiments, it is no more than about 11 ; in some embodiments, it is no more than about i 2; in some embodiments, it is no more than about 13; in some embodiments, it is no more than about 14; in some embodiments, it is no more than about 15. in some embodiments, it is no more than about 20. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 20. In some embodiments, the total number of carbon and non-halogen heteroatom (s) in each substituent is independently’ no more than about 15. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 10. In some embodiments, the total number of carbon and non-balogen heteroatom(s) in each substituent is independently no more than about 6.Clem-able Unit[0234 j In some embodiments, a linker comprises a cleavable unit. In some embodiments. L'Jis a cleavable unit

[0235] In some embodiments, a cleavable unit is a chemically cleavable unit. Such a cleavable unit is cleavable under certain chemical conditions without catalysis of an enzyme. In some embodiments, a cleavable unit an acid cleavable unit. In some embodiments, a cleavable unit is or comprises a hydrazone group In some embodiments, a cleavable unit is or comprises a carbonate group. In some embodiments, a cleavable unit is or comprises a silyl group. In some embodiments, a cleavable unit is or comprises ~S“S“. In some embodiments, a cleavable unit is cleavable in the presence of GSH. In someembodiments, a cleavable unit is cleavable in the presence of Fe (II). In some embodiments, a cleavable unit is or comprises 1,2,4-trioxolane moiety.

[0236] In some embodiments, a cleavable unit is an enzyme cleavable unit (i.e., a unit or a portion thereof that is cleaved by an enzyme). In some embodiments, an enzyme cleavable unit comprises a sequence of amino acids that is cleaved by a protease, e.g., a protease within a ceil. In some embodiments, a protease breaks an amide bond between a sequence of amino acids within a cleavable unit. In some embodiments, an enzyme cleavable unit comprises an amino acid sequence that is cleaved by a protease (e.g., a human protease within a cell). In some embodiments, an enzyme cleavable unit comprises an amino acid sequence that is cleaved by a cathepsin (e.g., human cathepsin L, B, F, or S).

[9237] In some embodiments, an enzyme cleavable unit comprises between 1 and 12 amino acids. In some embodiments, an enzyme cleavable unit comprises between 2 and 6 ammo acids. In some embodiments, an enzyme cleavable unit comprises between 2 and 5 amino acids. In some embodiments, an enzyme cleavable unit comprises between 2 and 4 ammo acids. In some embodiments, an enzyme cleavable unit comprises 2, or 3 amino acids. In some embodiments, an enzyme cleavable unit comprises 3 or 4 amino acids. In some embodiments, an enzyme cleavable unit comprises 2 amino acids. In some embodiments, an enzyme cleavable unit comprises 3 amino acids. In some embodiments, an enzyme cleavable unit comprises 4 ammo acids. In some embodiments, an enzyme cleavable unit comprises 5 amino acids In some embodiments, an enzyme cleavable unit comprises 6 amino acids.

[0238] In some embodiments, an enzyme cleavable unit is -DGGFG-, -KGGFG-, --GGFG— , -GGFGG-, -GGFGGG- -KGGF-, -DGGF-, -V-Cit-, -VA-, -FK-, -AA-, -VQ-, -LQ-, -FQ-, -TT-. -AAA-, --EA-, YR . -FR-. -YM-, VR -MT-, -VT-, VM . I M -AN-, -GGR-, -D-Val-D-GIn-, -D-Ala-D-Ala-, -DVA-, or -FM-. In some embodiments, an enzyme cleavable unit is an amino acid sequence selected from: -V~Cit~, -VA-, or -AA-. In some embodiments, an enzyme cleavable unit is an amino acid sequence selected from; -GGFG-, V Git . AAA , or -DVA-. In some embodiments, an enzyme cleavable unit is an amino acid sequence selected from: —DGGFG—, -KGGFG—, -GGFG-, — GGFGG-, —GGFGGG— , -KGGF-, or — DGGF-. In some embodiments, an enzyme cleavable unit is an amino acid sequence selected from: -V-Cit-, -VA-, VQ-, - VR-. --VT-. -VM-, or -D-Val-D-Gln-. In some embodiments, an enzyme cleavable unit is an amino acid sequence selected from: -GGFG- or -VA-. In some embodiments, an enzyme cleavable unit is an amino acid sequence selected from: -VQ-, or -LQ. In some embodiments, an enzyme cleavable unit is an amino acid sequence selected from: -LQ-. -FQ-, -TT-, -AAA- or -EA-.

[0239] In some embodiments, an enzyme cleavable unit is -DGGFG—. In some embodiments, an enzyme cleavable unit is -KGGFG-. In some embodiments, an enzyme cleavable unit is -GGFG-. In some embodiments, an enzyme cleavable unit is -GGFGG-. In some embodiments, an enzyme cleavable unit is -GGFGGG-. In some embodiments, an enzyme cleavable unit is -KGGF-. In some embodiments, an enzyme cleavable unit is -DGGF-. In some embodiments, an enzyme cleavable unit is -V-Cit-. In some embodiments, an enzyme cleavable unit is -VA-. In some embodiments, an enzyme cleavable unit is -FK-. In some embodiments, an enzyme cleavable unit is -AA-. In some embodiments, an enzy mecleavable unit is -VQ-. In some embodiments, an enzyme cleavable unit is - YR-. In some embodiments, an enzyme cleavable unit is -FR-, In some embodiments, an enzyme clear able unit is -YM-. In some embodiments, an enzyme cleavable unit is -VR-. In some embodiments, an enzyme cleavable unit is -MT-. In some embodiments, an enzyme cleavable unit is -VT-. In some embodiments, an enzyme cleavable unit is -VM-. In some embodiments, an enzyme cleavable unit is --LM-. In some embodiments, an enzyme clcavablc unit is -AN-. In some embodiments, an enzymic clcavablc unit isGGR . In some embodiments, an enzyme cleavable unit is 1) Vai D Gin-. In some embodiments, an enzyme cleavable unit is -D-Aia-D-AIa-. In some embodiments, an enzyme cleavable unit is -FM-. In some embodiments, an enzyme cleavable unit is -GGFG- or ~VA~.

[0240] In some embodiments, a cleavable unit is cleavable in the presence of a glycosidase. In some embodiments, a cleavable unit is cleavable in the presence of beta-glucuronidase (e.g., in lysosomes). In some embodiments, a cleavable unit is or comprises a beta-glucuronide moiety . Its some embodiments, a cleavable unit is cleavable in the presence of beta-galactosidase (e.g.. in lysosomes). In some embodiments, a cleavable unit is or comprises a galactoside moiety.

[0241] In some embodiments, a cleavable unit is a phosphatase cleavable unit. In some embodiments, a cleavable unit is a pyrophosphates cleavable unit. In some embodiments, a cleavable unit is or comprises pyrophosphate. In some embodiments, a cleavable unit is cleavable in the presence of a phosphatase or pyrophosphates (e.g , in lysosomes).

[0242] In some embodiments, a cleavable unit is a sulfatase cleavable unit. In some embodiments, a cleavable unit is or comprises an arylsulfate moiety. In some embodiments, a cleavable unit is cleavable in the presence of a sulfatase (e.g., io lysosomes).

[0243] In some embodiments, a cleavable unit is a photo-responsive cleavable unit. In some embodiments, a cleavable unit is or comprises a heptame thine cyanine fluorophore moiety. In some embodiments, it is cleavable by irradiation with NIR light (A = 650-900 nm). In some embodiments, a cleavable unit is or comprises an o-nitrobenzyl moiety . In some embodiments, it is cleavable by irradiation with UV light (X = 365 nm). In some embodiments, a cleavable unit is or comprises PC4AP moiety. In some embodiments, it is cleavable by irradiation with near -infrared (NIR) light (X ~ 365 nm) and intramolecular addition reaction with nearby amine.

[0244] In some embodiments, a cleavable unit is a bioorthogonal cleavable unit. In some embodiments, it is or comprises a dsProc moiety. In some embodiments, it is cleavable by the bioorthogonal cleavage pair: Cu(I)-BTTAA / dsProc.

[0245] Various other cleavable units are reported and can be utilized in accordance with the present disclosure, e.g., those described in Fu. Z., Li, S . Han, S. et al. Antibody drug conjugate: the ’‘biological missile’’ for targeted cancer therapy. Sig Transduct Target T'her 7, 93 (2022). https: / / doi org / 10.1038 / s41392-022-00947-7; Su Z, Xiao D, Xie F, Liu L, Wang Y. Fan S, Zhou X. Li S. Antibody -drug conjugates: Recent advances in linker chemistry. Acta Pharin Sin B. 2021 Dec;ll(I2):3889-3907. doi: 10.1016 / j.apsb.2021.03.042. Epub 2021 Apr 6. PMID: 35024314; PMCID: PMC8727783; Sheyi R, de la Torre BG, Albericio F. Linkers: Art Assurance for Controlled Delivery ofAntibody-Drag Conjugate. Pharmaceutics. 2022 Feb 1 1;14(2):396. doi: 10.3390 / pharmaceuticsl4020396.PMID: 35214128; PMCID: PMC8874516; etc.Spacer Moieties

[0246] In sonic embodiments, a linker comprises a spacer moiety (e.g., at least one spacer moiety). In some embodiments, a spacer moiety comprises an optionally substituted bivalent Cl-12 aliphatic, aiyl, heteroaryl, polyether, polyester, poly (N-(2.-hydroxypropyl)methaciylamide) (pHPMA), polylactic-co- gly colic acid (PLGA), polymers of alkylene diamines, polysarcosine, saccharide, or combinations thereof. In some embodiments, a spacer moiety comprises an optionally substituted bivalent Cl-12 aliphatic, polyether, polyester, poly(N-(2-hydroxj propyl)methacrylamide) (pHPMA), polylactic-co-gly colic acid (PLGA), polymers of alkylene diamines, poly sarcosine, saccharide, or combinations thereof. In some embodiments, a spacer moiety comprises an optionally substituted bivalent polyether, polysarcosine, saccharide, or combinations thereof.

[0247] In some embodiments, a spacer moiety comprises an optionally substituted bivalent Ci-m aliphatic. In some embodiments, a spacer moiety comprises an optionally substituted bivalent Ci.« aliphatic. In some embodiments, a spacer moiety is an optionally substituted bivalent Ci.s aliphatic. In some embodiments, a spacer moiety comprises an optionally substituted bivalent CXs aliphatic In some embodiments, a spacer moiety comprises an optionally substituted bivalent C.M aliphatic. In some embodiments, a spacer moiety comprises an optionally substituted bivalent CM aliphatic. In some embodiments, a spacer moiety comprises an optionally substituted bivalent Cs or Cs aliphatic. In some embodiments, a spacer moiety comprises an optionally substituted bivalent C3 aliphatic.

[0248] In some embodiments, a spacer moiety’ comprises polyethylene glycol har ing a structure -(CI-LCI-LOin-- , wherein n is an integer between 0 and 24. In some embodiments, n is an integer between 1 and 2.4, In some embodiments, n is an integer between 1 and 12. In some embodiments, n is an integer between 1 and 11. In some embodiments, n is an integer between I and 10. In some embodiments, n is an integer between 1 and 9. In some embodiments, n is an integer between 1 and 8. In some embodiments, n is an integer between 2 and 8. In some embodiments, n is an integer between 3 and 8. In some embodiments, n is an integer between 4 and 8. In some embodiments, n is an integer between 6 and 8. In some embodiments, n is 7 or 8, In some embodiments, n is 1, In some embodiments, n is 2. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12.

[0249] In some embodiments, a spacer moiety’ comprises polysarcosine having a structure:

[0251] wherein n is as described herein.|0252] In some embodiments, a spacer moiety comprises a monosaccharide, disaccharide, or oligosaccharides. In some embodiments, a spacer moiety comprises a monosaccharide. In some embodiments, a spacer moiety comprises a glycoside. In some embodiments, a spacer moiety comprises a uronic acid or derivative thereof. In some embodiments, a spacer moiety comprises glucuronic acid or derivativ e thereof. In some embodiments, a spacer moiety comprises a glucuronide.

[0253] In some embodiments, a spacer moiety is optionally substituted. In some embodiments, a spacer moiety

[0254] In some embodiments, a linker is or comprises a structure of formulae A, B, or C:A B C or a pharmaceutically acceptable salt thereof, wherein:# represents a point of attachment to a target binding moiety, e.g., anti-HHLA2 antibody or anti ge n -binding frag merit;% represents a point of attachment to a payload moiety, e.g., exatecan or a derivative or an analog thereof, or pharmaceutically acceptable salt thereof;X is a moiety that results from the reaction of the unbound linker and a group present on the anti- HHL.A2 antibody or antigen-binding fragment thereof (e.g., as described herein);Y is a cleavable unit (e.g , an enzyme cleavable unit) as described herein; andZ is a spacer moiety as described herein.

[0255] Various other spacer moieties are reported and can be utilized in accordance with the present disclosure, e.g., those described in Fu, Z._ Li, S.. Han, S. et al. Antibody drug conjugate: the "biological missile’’ for targeted cancer therapy. Sig Transduct Target Ther 7, 93 (2022). https: / / doi.org / 10.1038 / s41392-022-00947-7: Su Z, Xiao D, Xie F, Liu L, Wang Y, Fan S, Zhou X. Li S. Antibody -drug conjugates: Recent advances in linker chemistry. Acta Pharm Sin B. 2021Dec;l 1 (12):3889-3907. doi : 10.1016 / j.apsb.202l .03.042. Epub 2021 Apr 6 PMID: 35024314; PMCID: PMC8727783; Sheyi R, de la Torre BG, Albericio F. Linkers: An Assurance for Controlled Delivery of Antibody -Drug Conjugate. Pharmaceutics. 2022 Feb 11;14(2):396. doi: 10.3390 / pharmaceuticsl4020396. PMID: 35214128; PMCID: PMC88745I6; etc

[0256] In some embodiments, a linker is or comprises -LRX-Lx-(CH2CH2O)n--L / jp-LL-- wherein each variable is independently as described herein. In some embodiments, a linker is or comprises -L1--LRX--Lx-(CH2CH2O)n-L'<!'-L' wherein each variable is independently as described herein. In some embodiments, a linker is or comprises “SMl--Lx--(CH2CH2O)n- T / “ -Lc- wherein SMI iswherein the carbon atom is bonded to a target binding moiety (e.g.. an antibody ), and each variable is independently as described herein. In some embodiments, a linker is or comprises “SM1~(CH2)X“C(O)“N(R’)-(CH2CH2O)B~(CH2)Z-C(O)~LC-, wherein each variable is independently as described herein. In some embodiments, a linker is or comprises -SMl-(CH2)x-C(O)-NH-(CH2CH2O)n-(CH2)z-C(O)-Lt'-, wherein each variable is independently as described herein. In some embodiments, a linker is or comprises-SMl -(CHj)x-C(O)-N(R’)-(CH2CH2O)n-(CH2)z-C(O)-GGFG-, wherein each variable is independently as described herein. In some embodiments, a linker is or comprises --SMl“(CH2)x“C(O)“NH-(CH2CH2O)n-(CH2)z-C(O)-GGFG-, wherein each variable is independently as described herein. In some embodiments, a linker is or comprises -SMl-(CH2)x~C(O)~N(R’)-(CH2CH2O)n-(CH2)z-C(O)-Val-Ala-PABA-, wherein each variable is independently as described herein. In some embodiments, a linker is or comprises- SMl-(CH2)x~C(O)-NH-(CH2CH2O)n--(CH2)z-C(O)-Val-Ala~PABA-?wherein each variable is independently as described herein. In some embodiments, a linker is or comprises-SM 1 -(CH2)X-C(O)-N (R’)-(CH2CH2O)n-(CH2)z-C(O)- Val-Cit-P AB A- wherein each variable is independently as described herein. In some embodiments, a linker is or comprises -SMI-(CH2)x-C(O)-NH-(CH2CH2O)n-(CH2)z-C(O)-Val-Cit-PABA-, wherein each variable is independently as described herein. In some embodiments, a linker is or comprises -SMl-(CH2)x-C(0)-N(R’)-(CH2CH20)n-(CH2)z-N(R’)-C(0)-oGlu-. wherein each variable is independently as described herein. In some embodiments, a linker is or comprises-SM 1 - •(CH2)x-C(O)“NH“(CH2CH2O)n~(CH?)Z“NH- C(O)-oGlu-- . wherein each variable is independently as described herein. In some embodiments, a linker is or comprises "SMl~(CH2)x”C(O)”N(R’)”(CH2CH2O)n-(CH2)z”N(R’)--C(O)”mGlii“. wherein each variable is independently as described herein. In some embodiments, a linker is or comprises-SM 1 ■; i ' H )-, ( 'tOi X H if H. CH. ( Im •;(" H • i . X H ( t ( Is m-Ghi . wherein each variable is independently as described herein. In some embodiments, x is 2-10. In some embodiments, n is 2-10. Tn some embodiments, z is 2-10. In some embodiments, x is 2, n is 8 and z is 2. In some embodiments, x is3, n is 8. and z is 2. In some embodiments, x is 5, n is 8 and z is 2. In some embodiments. SMI is attached to -S- of a cysteine residue Various conjugates comprising such linkers are described herein

[0257] In some embodiments, a linker-payload moiety is or comprises -LRX-Lx-(CH2CH2O)n-LZr-Lv-Rpwherein each variable is independently as described herein, hi some embodiments, a linker-payload moiety is or comprises -Lr-LR5t-L-’i-(CH2CH2O)n-Lzp-L<--Rpwherein each -variable is independently as described herein. In some embodiments, a linker -pay load moiety is orcomprises -SMl-LA-(CH2CH2O)n-LZ!>--L''-Rp, whereinwherein she carbon atom is bonded to a target binding moiety (e g , an antibody), and each variable is independent!} as described herein In some embodiments, a linker-payload moiety is or comprises -SMl-(CH2)x-C(O)-N(R’)-(CH2CH2O)n-(CH2)z-C(O)-Lc-Rp, wherein each variable is independently as described herein. In some embodiments, a linker-payload moiety is or comprises “SMl“-(CH2)}:-C(O)“NH-(CH2CR2O)n~(CH2)z“C(O)~L’J--Rp, wherein each variable is independently as described herein. In some embodiments, a linker-payload moiety is or comprises--SMl --(CH2)x-- C(O)--N(R )-(CH2CH2O)n--(CH2)z-- C(O)--GGFG-Rp, wherein each variable is independently as described herein. In some embodiments, a linker-payload moiety is or comprises -SMl-(CH2)x-C(O)-NH-(CH2CH2O)n-(CH2)2-C(O)-GGFG-Rp, wherein each variable is independently as described herein. In some embodiments, a linker -payload moiety is or comprises -SM 1 -(CH2)x-C(O)-N (R’)-(CH2CH2O)n-(CH2)z-C(O)-Val-Ala-PABA-Rp, wherein each variable is independently as described herein. In some embodiments, a linker-payload moiety is or comprises ~SM 1 -(CH2)x-C(O)-NH-(CH2CH2O)n-(CH2)z-C(O)-Val-Ala-PABA-Rp, wherein each variable is independently as described herein. In some embodiments, a linker-payload moiety is or comprises --SMl--(CH2)>:--C(O)~N(R’)-(CH2CH2O)B-(CH2)z-C(O)“Val-Cit“PABA-Ri', wherein each variable is independently as described herein. In some embodiments, a linker-payload moiety is or comprises ~SMl"(CH2)x“C(O)“NH--(CH2CH2O)n“(CH2)z"C(O)“Val--Cit“PABA“Rr. wherein each variable is independently as described herein. In some embodiments, a linker-payload moiety is or comprises -SMl-(CH2)x-C(0)-N(R’)-(CH2CH20)n-(CH2)z-N(R’)-C(0)-oGIu-Rp. wherein each variable is independently as described herein. In some embodiments, a linker-payload moiety is or comprises -SMI-(CH2)x-C(O)-NH-(CH2CH2O)n-(CH2)z-NH-C(O)-oGlu-Rpwherein each variable is independently as described herein. In some embodiments, a linker-payload moiety is or comprises ~SM 1 -(CH2)X“C(O)-N (R’)-(CH2CH2O)n-(CH2)z-N(R’)-C(O)-mGlu-Rp, w’herein each variable is independently as described herein. In some embodiments, a linker-payload moiety is or comprisesSM I ri l l !• CtO) \ H tCH -CI t trio t( l I ). Xi 1 CtG) m(n:.t to . wherein each variable is independently as described herein. In some embodiments, x is 2-10. In some embodiments, n is 2-10. In some embodiments, z is 2-10. In some embodiments, x is 2, n is 8 and z is 2. In some embodiments, x is 3. n is 8. and z is 2. In some embodiments, x is 5, n is 8 and z is 2. In some embodiments. Rpis a exatecan payload moiety . In some embodiments,conjugates comprising such linker-payload moieties are described herein. For example, in some embodiments, a target binding moiety is or comprises an antibody or an antigen-binding fragment thereof. In some embodiments, a target binding moiety is or comprises an anti-HHLA2 antibody or an antigen- binding fragment thereof. In some embodiments, a target binding moiety is or comprises Hu2C4-H3L3, 65872, 65889, or 887-IDE, or an antigen-binding fragment thereof In some embodiments, a target binding moiety comprises 1, 2, 3, 4, 5, or 6 CDRs of an antibody, e.g., Hu2C4-H3L3, 65872, 65889, or 887-IDE. In some embodiments, a target binding moiety is Hu2C4-H3L3, 65872, 65889, or 887-IDE.Conjugates

[0258] In some embodiments, the present disclosure provides a conjugate comprising a target binding moiety, a payload moiety, and a linker that connects the target binding moiety and the pay load moiety. In some embodiments, a linker moiety comprises a PEG moiety. In some embodiments, a linker is or comprises -(Cl-LClLOjii- wherein n is 1-24. In some embodiments, n is 4. In some embodiments, n is 8. In some embodiments, --(CHeCEfcOjn--- in a linker of a conjugate is - (CHjCHzOj.r-. In some embodiments. -(CHzCHzOjn- in a linker of a conjugate is -(CHzCfchOjs- In some embodiments, the PEG moiety in a linker or conjugate is PEG4. In some embodiments, the PEG moiety in a linker or conjugate is PEGS. In some embodiments, a payload moiety is or comprises a moiety of exatecan or a derivative or an analog thereof, or a pharmaceutically acceptable salt thereof.

[0259] In some embodiments, the present disclosure provides a conjugate comprising: i) a target binding moiety; ii) a payload moiety; and iii) a linker that connects the target binding moietyrand the payload moiety ; wherein: the linker comprises -(CHjCHeOjn --- and I? ; n is 0-24;Lcis bonded to a pay load moiety and is L'1Lc0;Luis a cleavable unit; andLc0is a covalent bond, or a spacer moiety (e.g., optionally substitutedw herein the carbonyl is bonded to a pay load moiety).

[0260] For example, in some embodiments, the present disclosure provides conjugates comprising: i) a target binding moiety; iii a payload moiety; and iii) a linker that connects the target binding moiety and the payload moiety; wherein: the linker comprises -(CHzCHjOjn- and Lc;n is 0-24;Lcis bonded to a payload moietywherein the phenyl ring and the -CH2- is optionally substituted, and the carbonyl is bonded to Lc'\ and RL;iis or comprises a sugar moiety;L‘-° is a covalent bond, or optionally substitutedwherein the carbonyl is bonded to a pay load moiety ; each R’ is independently -R, -C(O)R, -CCtyR, or -S(O)jR, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C; . ;o aliphatic. Ci .io heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. C.vi4 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sttlfur. and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

[0261] In some embodiments, the present disclosure provides a conjugate, comprising: i) a target binding moiety; ii) a payload moiety : and iii) a linker that connects the target binding moiety and the payload moiety; wherein: the linker comprises -(CHaCItyOjn-- and Lc; n is 0-24:Lcis bonded to a pay load moiety and is -Lt ’-L1'0-;LCOis a covalent bond, or optionally substitute wherein the carbonyl is bonded to a payload moiety.

[0262] In some embodiments, a linker comprises aPEG moiety. In some embodiments, a linker comprises −(CH2CH2O)n− wherein n is 1-24. In some embodiments, a PEG moiety is PEG4. In some embodiments, a PEG moiety is PEG8. Among other things, the present disclosure demonstrates that antibody-drug conjugates comprising linkers that comprise PEG moieties can provide various benefits and advantages. For example, in some embodiments, with such linkers payload moieties can be directly connected to cleavable units, e.g., GGFG, without spacers as utilized in reported products, to provide antibody-drug conjugates with comparable or improved properties and / or activities. In some embodiments, conjugates with such linkers have reduced aggregation compared to reference conjugates without such linkers. For example, in some embodiments, the present disclosure provides a conjugate, comprising: i) a target binding moiety; ii) a payload moiety; and iii) a linker that connects the target binding moiety and the payload moiety; wherein: the linker comprises –(CH2CH2O)n− and LC; n is 1-24; LCis bonded to a payload moiety and is −LC1−LCO−; LC1is a cleavable unit; and LCOis a covalent bond, or a spacer moiety (e.g., optionally substitute wherein the carbonyl is bonded to a payload moiety).

[0263] For example, in some embodiments, the present disclosure provides a conjugate, comprising: i) a target binding moiety; ii) a payload moiety; and iii) a linker that connects the target binding moiety and the payload moiety; wherein: the linker comprises –(CH2CH2O)n− and LC; n is 1-24; LCis bonded to a payload moiety and is −LC1−LCO−; LC1is −Gly−Gly−Phe−Gly−, −Val−Ala−, −Val–Cit–, LC1S, −Gly−Gly−Phe−Gly−N(R’)−LC1S−, −Val−Ala−N(R’)−LC1S−, or −Val–Cit–N(R’)−LC1S−;, wherein the phenyl ring and the -CH2- is optionally substituted and the carbonyl is bonded to Lco, and R1"’ is or comprises a sugar moiety;Lc0is a covalent bond, or optionally' substitutedwherein the carbonyl is bonded to a pay load moiety; each R’ is independently -R, ~C(O)R, --CO2R, or -SfOtyR, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from Ci-10 aliphatic.Ci-iu heteroaliphatic having 1-5 heieroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. C6.14 aryl, a 5- 14 membered heteroaryl ring having I -5 heieroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

[0264] In some embodiments, the present disclosure provides a conjugate, comprising: i) a target binding moiety; li) a payload moiety'; and iii) a linker that connects the target binding moiety and the payload moiety; wherein: the linker comprises ---(CJ-tyCI-tyOin- and Lc: n is 1-24:LGis bonded to a payload moiety and is -Lu-Lv0-;LC,Jis a covalent bond, or optionally substitutedwherein the carbonyl is bonded to a pay load moiety.

[0265] In some embodiments, a conjugate is a compound having a structure of Formula A-l or a salt thereof:wherein each variable is independently as described herein.

[0266] In some embodiments, a conjugate is a compound having a structure of Formula .A-l or a salt thereof:wherein each variable is independently as described herein.

[0267] Various embodiments of certain variables are described, e.g.. in Linkers section, as examples.Additional embodiments for variables are described below as examples.

[0268] In some embodiments, each RAis independently a target binding moiety as described herein. In some embodiments, each RAis independently a target binding moiety comprising an antibody or an antigen-binding fragment thereof. In some embodiments, each occurrence of a target binding moiety is an antibody or an anti gen -binding fragment thereof. In some embodiments, each occurrence of a target binding moiety is an antibody. In some embodiments, each occurrence of a target binding moiety is a monoclonal antibody. In some embodiments, each occurrence of a target binding moiety is not trastuzumab. In some embodiments, each occurrence of a target binding moiety shares less than about 90%, 95%, or 99% sequence identity to trastuzumab. In some embodiments, each occurrence of a target binding moiety shares less than about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%. or 99% sequence identity to trastuzumab. In some embodiments, each occurrence of a target binding moiety is not an anti-HER2 antibody. In some embodiments, each occurrence of a target binding moiety is not an anti-HER2 antibody or an antigen-binding fragment thereof.

[0269] In some embodiments, each target binding moiety of a provided conjugate targets the same agent. In some embodiments, each target binding moiety targets the same agent, wherein the agent is or comprises a polypeptide, a nucleic acid, or a lipid. In some embodiments, each target binding moiety targets the same agent, wherein the agent is a polypeptide. In some embodiments, each target binding moiety’ targets tire same antigen. In some embodiments, each target binding moiety is independently an antibody or an antigen-binding fragment thereof, and each target binding moiety shares about 90%. 95%. 96%, 97%, 98% or 99% sequence identity. In some embodiments, each target binding moiety targets the same antigen. In some embodiments, each target binding moiety is independently an antibody or an antigen-binding fragment thereof, and each target binding moiety shares the same amino acid sequence. In some embodiments, each target binding moiety’ is the same.

[0270] In some embodiments, a target binding moiety is or comprises an antibody or an antigen- binding fragment thereof. In some embodiments, a target binding moiety is or comprises an anti-HHLA2 antibody or an antigen-binding fragment thereof. In some embodiments, a target binding moiety is or comprises Hu2C4-H3L3, 65872, 65889, or 887-1DE, or an antigen-binding fragment thereof. In some embodiments, a target binding moiety comprises 1, 2, 3, 4, 5, or 6 CDRs of an antibody, e.g., Hu2C4- H3L3, 65872, 65889, or 887-1DE. In some embodiments, a target binding moiety is Hu2C4-H3L3, 65872, 65889, or 887-1DE. s

[0271] In some embodiments, a conjugate contains a single target binding moiety. In some embodiments, a conjugate contains two or more target binding moieties.

[0272] In some embodiments, s is 1. In some embodiments, s is 2-20, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. a

[0273] In some embodiments, a linker is bonded to a single site on a target binding moiety. In some embodiments, an occurrence of a is 1. In some embodiments, each occurrence of a is 1.

[0274] In some embodiments, a linker is bonded to two or more target binding moieties. In some embodiments, a linker bonds is bonded to two or more sites on a target binding moiety (e.g., two or more Cys residues of an antibody or an antigen-binding fragment thereof). In some embodiments, a is greater than 1. In some embodiments, an occurrence of a is 2-10, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10. In some embodiments, an occurrence of a is 2. In some embodiments, an occurrence of a is 3-10.

[0275] In some embodiments, each a is the same.

[0276] For each , in some embodiments, each LTis the same; in some ebodiments, each −LT−LRX− is the same.

[0277] In some embodiments, each LTis the same. In some embodiments, each LRXis the same. In some embodiments, each −LT−LRX− is the same. b

[0278] In some embodiments, a linker is bonded to a single site on a payload moiety. In some embodiments, an occurrence of b is 1. In some embodiments, each occurrence of b is 1.

[0279] In some embodiments, a linker is bonded to two or more payload moieties. In some embodiments, a linker bonds is bonded to two or more sites on a payload moiety. In some embodiments, b is greater than 1. In some embodiments, an occurrence of b is 2-10, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10. In some embodiments, an occurrence of b is 2. In some embodiments, an occurrence of b is 3-10.

[0280] In some embodiments, b is the same.

[0281] In some embodiments, each LX’ is the same.

[0282] In some embodiments, at least one occurrence of n is independently 1-24. In some embodiments, each occurrence of n is independently 1-24. In some embodiments, each n is 8. For each , in some embodiments, each n is the same; in some ZPmbodiments, each LCis the same; in some embodiments,each RPis the same; in some embodiments, each −(CH2CH2O)n−LZP− is the same; in some embodiments, each −(CH2CH2O)n−LZP−LC− is the same; in some embodiments, each −(CH2CH2O)n−LZP−LC−RPis the same; in some embodiments, each −LC−RPis the same; in some embodiments, −LZP−LC−RPis the same.

[0283] In some embodiments, each n is the same. In some embodiments, each LZPis the same. In some embodiments, each LCis the same. In some embodiments, each RPis the same. In some embodiments, each −(CH2CH2O)n−LZP− is the same. In some embodiments, each −(CH2CH2O)n−LZP−LC− is the same. In some embodiments, each −(CH2CH2O)n−LZP−LC−RPis the same. In some embodiments, each −LC−RPis the same. In some embodiments, −LZP−LC−RPis the same. t

[0284] In some embodiments, a conjugate contains a single linker moiety. In some embodiments, a conjugate contains two or more linker moieties.

[0285] In some embodiments, t is 1. In some embodiments, t is 2-20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 2-15, 2-10, 2-8, etc.). In some embodiments, t is about 1-8. In some embodiments, t is about 2-8. In some embodiments, t is about between 1 and 16. In some embodiments, t is about between 1 and 12. In some embodiments, t is about between 2 and 10. In some embodiments, t is about between 4 and 8. In some embodiments, t is about 1. In some embodiments, t is about 2. In some embodiments, t is about 3. In some embodiments, t is about 4. In some embodiments, t is about 5. In some embodiments, t is about 6. In some embodiments, t is about 7. In some embodiments, t is about 8. In some embodiments, t is about an integer between about 7 and about 9. In some embodiments, t is about an integer between about 6 and about 10.

[0286] In some embodiments, s is 1, a is 1 and b is 1, and t is a DAR as described herein. In some embodiments, for a conjugate of formula A-2 or a salt thereof, t is a DAR as described herein.

[0287] For example, in some embodiments, each occurrence of LXis independently a covalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic, wherein 1-10 methylene units of LXare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−. In some embodiments, each occurrence of LXis −(CH2)X−C(O)−N(R’)−, wherein x is 1-19, and −N(R’)− is bonded to −(CH2CH2O)n−. In someembodiments, each occurrence of LXis −(CH2)X−C(O)−NH−, wherein x is 1-19, and −NH− is bonded to −(CH2CH2O)n−. In some embodiments, each occurrence of LXis −(CH2)X−C(O)−N(R’)− or −(CH2)X−C(O)−NH−, and x is 1-6. In some embodiments, each occurrence of LXis −(CH2)5−C(O)−N(R’)−, wherein −N(R’)− is bonded to −(CH2CH2O)n−. In some embodiments, each occurrence of LXis −(CH2)5−C(O)−NH−, wherein −NH− is bonded to −(CH2CH2O)n−. In someembodiments, each occurrence of LXis −(CH2)3−C(O)−N(R’)−, wherein −N(R’)− is bonded to −(CH2CH2O)n−. In some embodiments, each occurrence of LXis −(CH2)3−C(O)−NH−, wherein −NH− is bonded to −(CH2CH2O)n−. In some embodiments, each occurrence of LXis the same.

[0288] In some embodiments, an occurrence of LTis a covalent bond. In some embodiments, an occurrence of LTis an optionally substituted bivalent straight or branched C1-20aliphatic, wherein 1-10 methylene units of LTare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, and −S(O)2(NR’)−. In some embodiments, an occurrence of LTis a covalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic group. In some embodiments, an occurrence of LTis a bivalent straight or branched C1-20aliphatic group. In some embodiments, an occurrence of LTis an optionally substituted −(CH2)1−5−. In some embodiments, an occurrence of LTis −(CH2)1-5−. In some embodiments, an occurrence of LTis −CH2−. In some embodiments, an occurrence of LTis bonded to a backbone atom of an amino acid residue in a target binding moiety. In some embodiments, an occurrence of LTis independently bonded to a backbone atom of an amino acid residue in the same target binding moiety. In some embodiments, an occurrence of LTis bonded to a different backbone atom of an amino acid residue in the same target binding moiety. In some embodiments, an occurrence of LTis bonded to an alpha atom of an amino acid residue in a target binding moiety. In some embodiments, an occurrence of LTis bonded to an alpha atom of an amino acid residue in the same target binding moiety. In some embodiments, an occurrence of LTis bonded to a different alpha atom of an amino acid residue in the same target binding moiety. In some embodiments, each occurrence of LTis the same.

[0289] In some embodiments, an occurrence of LRXis a covalent bond. In some embodiments, an occurrence of LRXis a moiety that results from a reaction between a group present on the unconjugated target binding moiety and a group present on an agent comprising −LX−(CH2CH2O)n−LZP−LC− and a payload moiety. In some embodiments, an occurrence of LRXis a covalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LRXare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−, wherein each −Cy− is independently an optionally substituted 3-12 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0290] In some embodiments, an occurrence of LRXis −LRX1−LRX2−, wherein each of LRX1and LRX2is independently as described herein.

[0291] In some embodiments, an occurrence of −LRX1− is −S−. In some embodiments, an occurrence of −LRX1− is −S−, and the −S− is of a Cys residue of the target binding moiety. In some embodiments, an occurrence of −LRX1− is −S−, and the −S− is of a Cys residue in an antibody wherein the Cys residue forms an interchain disulfide bonds in an unconjugated antibody. In some embodiments, an occurrence of −LRX1− is −S−, and the −S− is of a Cys residue in an antibody wherein the Cys residue forms an inter- heavy- and light-chain disulfide bond in an unconjugated antibody. In some embodiments, an occurrence of −LRX1− is −S−, and the −S− is of a Cys residue of the target binding moiety, wherein the Cys residue is derived through partial or complete reduction of the interchain disulfide bonds.

[0292] In some embodiments, an occurrence. wherein the nitrogen is bonded to Lx. and the carbon is bonded to LRxl. In some embodiments, an occurrence of --LBis -S~.In some embodiments, an occurrence of LRxis or comprises a click chemistry product moiety. In some embodiments, LRXis or comprises a click chemistry product moiety . In some embodiments, an occurrenceA^^NA of LRXis or comprises N-N jn soraeembodiments, an occurrence of wherein LRXis or. n some em o men s, e n rogen n e -mem ere r ng s on ed to Lx. In some embodiments, the carbon or the nitrogen in the 8-membered ring is bonded to Lx.

[0293] In some embodiments, an occurrence of n is 1-24. In some embodiments, an occurrence of n is 4-24. In some embodiments, an occurrence of n is 7-20. In some embodiments, each occurrence of n is independently 4-24. In some embodiments, each occurrence of n is independently 7-20. In some embodiments, an occurrence of n is 8 In some embodiments, each n is the same. In some embodiments, each n is 8.

[0294] In some embodiments, an occurrence of L"pis a covalent bond. In some embodiments, an occurrence of LzPis an optionally substituted bivalent straight or branched Ci.-x-. aliphatic wherein 1 -10 methylene units of L / jare optionally and independently replaced by a group selected from -O-. --N(R’)--.--C(O)--, -S-, ~S(O)~, --S(O)2-, --C(O)N(R’)--. ~S(O)?(NR’)~. and ~Cy--. In some embodiments, an occurrence of Lzpis -(CH2)z-C(O)-, wherein z is 1 -19. In some embodiments, an occurrence of LApis ---(CH2)?--C(O)--, wherein -C(O)- is bonded to the amino group of the first amino acid in -Lc-. In some embodiments, each Lzpis the same.Rp

[0295] As used herein, each Rpis independently payload moiety. Various payload moictics arc available and cart be utilized in accordance with the present disclosure. In some embodiments, each Rris the same. In some embodiments, an occurrence of Rpis a cytotoxic agent. In some embodiments, each Rpis independently a cytotoxic agent. In some embodiments, an occurrence of R'° is exatecan or a derivative thereof. In some embodiments, each RRis independently exatecan or a deriv ative thereof. In someembodiments, an occurrenc In some embodiments, each RPis RPP isbodiments, an occurrence of −LC−RPis −GGFG−RP. In some embodiments, it is −Val−Ala−PABA−RP. In some embodiments, it is −Val−Cit−PABA−RP. In some embodiments, it is −Val−Ala−NH−oGlu−RP. In some embodiments, it is −Val−Ala−NH−mGlu−RP. In some embodiments, it is −Val−Cit−NH−oGLu−RP. In some embodiments, it is −Val−Cit−NH−mGLu−RP. In some embodiments, it is −oGlu−RP. In some embodiments, it is −mGlu−RP. In some embodiments, RPcomprises a nitrogen atom and is bonded at the nitrogen atom, e.g., to the rest of a conjugate or other compound. In some embodiments, RPis REX. In some embodiments, each occurrence of −LC−RPis the same.

[0297] In some embodiments, an occurrence of −LC−RPis ,

[0298] In some embodiments, an occurrence. In some embodiments, each −LC−RPis the same. urrencC Pe of −L−R is ., is independently

[0301] In some embodiments, an occurrence of Iis

[0302] In some embodiments, each occurrence of -L''-R?is

[0303] In some embodiments, an occurrence of -L' -Rpis

[0304] In some embodiments, each occurrence of -LC-RHis[0305 [ In some embodiments, an occurrence of-L(-RpisIn some embodiments, each occurrence ofembodiments, an occurrence o. In some embodiments, each occurrence osomeembodiments, each occurrence

[0306] In some embodiments, a conjugate comprises -IAP-LC-RP. In some embodiments, an occurrence of “L / f" Lc-R!is-(CH2)zC(O)--GGFG --Rp. In some embodiments, it is ~(CH2)2C(O)-Val-Aia~PABA-Rp. In some embodiments, it is -(CH2)ZC(O)-Val-Cit-PABA-R1'. In some embodiments, it is -(CH2)zC(O)-Val-Ala-NH-oGlu-R!>. In some embodiments, it is -~(CH2)7C(O)~Val-Ala“NH-mGlu-Rp. In some embodiments, it is -(CH2)2C(O)-VaI-Cit-NH-oGLu-Rp. In some embodiments, it is “(CH2)zC(O)-Val“Cit“NH--mGLu“RpIn some embodiments, it is -(CH2)zNHC(O)-oGlu-Rp. In some embodiments, it is -(CH2)zNHC(O)-mGlu-Rp. In some embodiments, z is 2. In some embodiments, Rpcomprises a nitrogen atom and is bonded at the nitrogen atom, e.g.. to the rest of a conjugate or other compound. In some embodiments, Rpis RtX. In some embodiments, z is 2 and Rpis RK<In some embodiments, each occurrence of -Lzp-Lc-Rpis the same.

[0307] In some embodiments, an occurrence of -IAP-I..c--Rpissame.

[0308] In some embodiments, an occurrence of L ' I .R issome embodiments, each occurrence is the same.|0309] In some embodiments, an occurrence of -L'j3-- L'"-Rt’ is or comprises

[0310] In some embodiments, each occurrence of -LzP-Lc-Rris or comprises

[0312] In some embodiments, each occurrence of -LzP-Lc-Rris or comprises|0313] In some embodiments, an occurrence of-LzP-Lt'-Rpis or comprises

[0314] In some embodiments, each occurrence of ~LZP“LU~R“ is or comprises

[0315] In some embodiments, an occurrence of ~LzP-Lc-Rpis or comprises

[0316] In some embodiments, an occurrence of--R" is or comprises. In some embodiments, each occurrence ofembodiments, an occurrence of -LZt'-LL-R1>is or comprisesembodiments, an occurrence of --LzP-Lc--R1’ is or comprisesIn some embodiments, each occurrence ofembodiments, an occurrence of-LZr-Lc-Rpss or comprisesembodiments, an occurrence of --L'"p--Lc'-Rpis or comprisesIn some embodiments, each occurrence ofmeIn some embodiments, each occurrence of −LZP−LC−RPis or comprises .

[0317] In so e e o e s, a co ugae co p ses H2CH2O)n−LZP−LC−RP. In someembodiments, an occurrence of −(CH2CH2O)n−LZP−LC−RPis −(CH2CH2O)n−(CH2)zC(O)−GGFG−RP. In some embodiments, it is −(CH2CH2O)n−(CH2)zC(O)−Val−Ala−PABA−RP. In some embodiments, it is −(CH2CH2O)n−(CH2)zC(O)−Val−Cit−PABA−RP. In some embodiments, it is −(CH2CH2O)n−(CH2)zC(O)Val−Ala−NH−oGlu−RP. In some embodiments, it is −(CH2CH2O)n−(CH2)zC(O)−Val−Ala−NH−mGlu−RP. In some embodiments, it is −(CH2CH2O)n−(CH2)zC(O)−Val−Cit−NH−oGLu−RP. In some embodiments, it is −(CH2CH2O)n−(CH2)zC(O)−Val−Cit−NH−mGLu−RP. In some embodiments, it is −(CH2CH2O)n−(CH2)zNHC(O)−oGlu−RP. In some embodiments, it is −(CH2CH2O)n−(CH2)zNHC(O)−mGlu−RP. In some embodiments, n is 8. In some embodiments, z is 2. In some embodiments, RPcomprises a nitrogen atom and is bonded at the nitrogen atom, e.g., to the rest of a conjugate or other compound. In some embodiments, RPis REX. In some embodiments, z is 2 and RPis REX. In some embodiments, n is 8, z is 2 and RPis REX. In some embodiments, each occurrence of −(CH2CH2O)n−LZP−LC−RPis the same.

[0318] In some embodiments, an occurrence of −(CH2CH2O)n−LZP−LC−RPis or comprises ,. In some embodiments, each

[0319] In some embodiments, an occurrence of −(CH2CH2O)n−LZP−LC−RPis or comprises or . In some embodiments, each occurrence is the.

[0320] In some embodiments, an occurrence of −(CH2CH2O)n−LZP−LC−RPis or comprises

[0322] In some embodiments, an occurrence of-(CH2CH2O)n-Lz?-Lc-Rpis or comprises

[0323] In some embodiments, each occurrence of ~(CH2CH2O)n~Lzp-Lc~Ri' is or comprises

[0324] In some embodiments, an occurrence of --(CH2CH2O)n---Lzp-L'— R1’ is or comprises. prises. risesInnce e of−(CH2CH2O)n−LZP−LC−RPis or comprise . In some embodiments, each occurrence of −(ofnce e ofnce

[0327] In some embodiments, a conjugate comprises -LA-(CH2CH2O)n-Lzp-Lc-Rp. in some embodiments, an occurrence of -Lx-(CH2CH2O)n-LZE-L' -R1’ is ---(CH2)yC(O)NH--(CH?CH2O)n---(CH2)zC(O)--GGFG--Rp. In some embodiments, it is -(CH3)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)-Val-Ala-PABA-Rp. In some embodiments, it is --(CH2)xC(O)NH-(C'H2CH2O)n-(CH2)zC(O)-Val-C'it-PABA-RF. In some embodiments, it is -(CH2XC(O)NH-(CH;CH2O)n-(CH2)zC(O)’Val-Ala-NH-oGIu-Rr. In some embodiments, it is ~(CH2)...C(O)NH”(CH2CH2O)n~(CH2)zC(O)” Val--Ah~NH-mGlu~Rp. In some embodiments, it is --(CH2)xC(O)NH---(CH2CH2O)n--(CH2)zC(O)---Val-Cit--NH---oGLu-Rr. In some embodiments, it is -(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)-Val-Cit-NH-mGLu-Rp. In some embodiments, it is “(CH2)xC(O)NH”(CH2CH2O)ii“(CH2)zNHC(O)-oGlu“Rp. In some embodiments, it is -(CH:)xC(O)NH-(CH2CH2O)n-(CH2)zNHC(O)-inGlu-Rp. In some embodiments, x is 2. In some embodiments, x is 3 In some embodiments, x is 5. In some embodiments, n is 8. In some embodiments, z is 2. In some embodiments, Rpcomprises a nitrogen atom and is bonded at the nitrogen atom, e.g., to the rest of a conjugate or other compound. In some embodiments, Rpis R11XIn some embodiments, z is 2 and REis RK';. In some embodiments, n is 8, z is 2 and Rpis Rr'x. In some embodiments, x is 2, n is 8, z is 2 and Rpis R“x. In some embodiments, x is 3, n is 8, z is 2 and Rris REX. In some embodiments, x is 5. n is 8, z is 2 and Rpis R" In some embodiments, each occurrence of ~Lx~(CH2CH2O)n-d7'p~Lc--Rpis the same.

[0328] In some embodiments, an occurrence of -Lx-(CH2CH2O)n-Lzp-Lt-Rris or comprisesembodiments, each occurrence is the same.[03291 In some embodiments, an occurrence of -Lx-(CH2CH2O)n-Lz'1-L' ■'-Rxis or comprisesembodiments, each occurrence is the same.

[0330] In some embodiments, an occurrence of -Lx-(CH2CH2O)n-LZt'-LL-R1>is or comprises

[0331] In some embodiments, each occurrence of -Lx-(CH2CH2O)n-LzP-Lc-Rpis or comprises

[0332] In some embodiments, an occurrence of HLx-(CH2CH2O)n~LZr”Lc-~Rris or comprises

[0334] In some embodiments, an occurrence of -Lx-(CH2CH2O)n-LZr-Le-Rt' is or comprises

[0335] In some embodiments, each occurrence of ~LA~(CH2CH2O)n-Lzp-Lc~Rpis or comprises

[0336] In some embodiments, an occurrence of -LA-(CH2CH2O)n--L / jP-Lc--Rpis or comprisesIn some embodiments, an occurrence of-Lx-(CH2CH2O)n-LZ1'-Lc-R?is or comprises,−LX−(CH2CH2O)n−LZP−LC−RPis or comprise . In some embodiments, each occurrence of −LXof f2 2poccurrence of ~Lx^CH2CH2O)n~Lzp~Ll--Rpis or comprisesoccurrence of ~Lx~(CH2CH2O)n~Lzp~Lc~Rpis or comprisesIn some embodiments,each occurrence of −LX−(CH2CH2O)n−LZP−LC−RPis or comprises ses ,me

[0338] In some embodiments, an occurrence of −L −(CH2CH2O)n−L −L −R is or comprises In some embodiments,

[0339] In some embodiments, an occurrence of −LX−(CH2CH2O)n−LZP−LC−RPis or comprises. prises. rises.prises . ses .

[0344] In some embodiments, each occurrence of −LX−(CH2CH2O)n−LZP−LC−RPis or comprises . rises. In some embodiments, each occurrence of.ofIn some embodiments, an occurrence of-Lx-(CH2CH2O)n-Lzp-Lc-Rpis or comprisesIn some embodiments, each occurrence of -L-'-(CH2CH2O)n-L"p-Lc-Rpis or comprises, ence of-Lx-(CH2CH2O)n-LZB'-L'--R1>is or comprises. s. each occurrence of -LA-(CH2CH2O)n-Lzp-Lc-Rpis or compriseseach occurrence of -LA-(CH2CH2O)n-L / p-Lc-Rpis or comprises

[0346] In some embodiments, a conjugate comprises --L1?A--Lx--(Cri2CH2O)n-LZ!'--L’:'-R1>. In some embodiments, an occurrence of ---L.RX---T.x---(CH2CH2O)n-LZ1'-Lc--Ri' is-S-SM-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)-GGFG-Rp. In some embodiments, it is “S-SM”(CH2)xC(O)NH“(CH2CH2O)n-(CH2)zC(O)“Val" •Aia-PABA-Rp. In some embodiments, it is -S-SM-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)-Val-Cit-PABA-Rp. In some embodiments, it is --S~SM“(CH2)xC(O)NH“(CH2CH2O)n“(CH2)zC(O)Val~Ala~NH--oGlu--Rp. In some embodiments, it is ~S-SM-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)-V al-Ala-NH -tnGlu-Rp. In some embodiments, it is -S-SM-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)-Val-Cit-NH-oGLu-Rt'. In some embodiments, it is -S-SM-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)-Val-Cit-NH-niGLti-Rp. In some embodiments, it is -S-SM-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zNHC(O)-oGlu-Rp. In some embodiments, it is -- S-- SM--(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zNI-IC(O)--mGlu-R' . In someembodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 5. In some embodiments, n is 8. In some embodiments, z is 2 In some embodiments, Rpcomprises a nitrogen atom and is bonded at the nitrogen atom, e.g., to the rest of a conjugate or other compound. In some embodiments. Rpis RBx. In some embodiments, z is 2 and Rpis RnX. In some embodiments, n is 8. z is 2 and R? is REXIn some embodiments, x is 2, n is 8. z is 2. and Rris REXIn some embodiments, x is 3, n is 8, z is 2. and Rpis REX. In some embodiments, x is 5, n is 8, z is 2 and Rpis R11X. In some embodiments, each occurrence ofthe same.|0347] In some embodiments, an occurrence of-LRX-Lx-(CH2CH2O)n-LZt'-Lc-Rpis or comprisesembodiments, each occurrence is the same.

[0349] In some embodiments, an occurrence of -LRX-L>i-(CH2CH2O)n-L / J>-Lc'”RPis or comprises

[0350] In some embodiments, each occurrence of ~LRX-Lx-(CH2CH2O)n-Lzp-Lc-Rt' is or comprises|0351] In some embodiments, an occurrence of -L” ■•’s-Lx-(CH2CH2O)n-LZ!~L’ ~RPis or comprises

[0352] In some embodiments, each occurrence of -LRX-LX-- (CH2CH2O)n-d.,zp--Lc-Rpis or comprises

[0354] In some embodiments, each occurrence of --LRX-Lx-(CH2CH2O)n“LzP-Lc-Rris or comprises|0355] In some embodiments, an occurrence of ~LRX-Lx-(CH2CH2O)n-Lzt-L"-RE' is or comprisesof f ce ofof e of. In some embodiments, an occurrence ofof f. In somesome embodiments, an occurrence of -LRX-Lx-(CH2CH2O)n-LZ1'-Lc-R1>is or comprisesIn some embodiments, each occurrence of -LRX-Lx-(CH2CH2O)n-Lzp-Lc-R1' is or comprisesembodiments, each occurrence is the same.embodiments, each occurrence is the same.

[0358] In some embodiments, an occurrence of -LRX-Lx-(CH2CH2O)n-LZt'-LL'-Rpis or comprises

[0359] In some embodiments, each occurrence of -LRX-Lx-(CH2CH2O)n-Lzp-Le-Rt' is or comprises

[0360] In some embodiments, an occurrence of “LRX-Lx-(CH2CH2O)n-Lzp-Lc-Rpis or comprises

[0361] In some embodiments, each occurrence of -LRX-Lx-(CH2CH2O)n-Lz p-Lr-Rris or comprises

[0362] In some embodiments, an occurrence of-LRX-Lx-(CH2CH2O)n-Lz’p-Lc-Rpis or comprises[6363 [ In some embodiments, each occurrence of -LEX-Lx-(CH2CH2O)n-L^E-Lc-R‘ is or comprises

[0364] In some embodiments, an occurrence of “LRX“LX“(CH2CH2O)n~L‘““L"-Ri’ is or comprises, ,-LRX-Lx-(CH2CH2O)n-L^!'-Lc-R1>is or comprises,“LRX-Lx~(CH2CH2O)ti"Lzp-Lc~Rpis or comprises. Iii some embodiments, each occurrence of -LKX-Lx-(CH2CH2O)n-LZP“Lc-Rt' is or comprises. In some rises.n−LZP−LC−RP. In some embodiments, an occurrence of −LRX−LX−(CH2CH2O)n−LZP−LC−RPis −S−CH2−C(O)NH−(CH2)xC(O)NH−(CH2CH2O)n−(CH2)zC(O)−GGFG−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2)xC(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Ala−PABA−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2)xC(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Cit−PABA−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2)xC(O)NH−(CH2CH2O)n−(CH2)zC(O)Val−Ala−NH−oGlu−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2)xC(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Ala−NH−mGlu−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2)xC(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Cit−NH−oGLu−RP. In someembodiments, it is −S−CH2−C(O)NH−(CH2)xC(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Cit−NH−mGLu−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2)xC(O)NH−(CH2CH2O)n−(CH2)zNHC(O)−oGlu−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2)xC(O)NH−(CH2CH2O)n−(CH2)zNHC(O)−mGlu−RP. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 5. In some embodiments, n is 8. In some embodiments, z is 2. In some embodiments, RPcomprises a nitrogen atom and is bonded at the nitrogen atom, e.g., to the rest of a conjugate or other compound. In some embodiments, RPis REX. In some embodiments, z is 2 and RPis REX. In some embodiments, n is 8, z is 2 and RPis REX. In some embodiments, x is 2, n is 8, z is 2 and RPis REX. In some embodiments, x is 3, n is 8, z is 2 and RPis REX. In some embodiments, x is 5, n is 8, z is 2 and RPis REX. In some embodiments, each occurrence of −LRX−LX−(CH2CH2O)n−LZP−LC−RPis the same.

[0366] In some embodiments, an occurrence of −LRX−LX−(CH2CH2O)n−LZP−LC−RPis or comprises , , ,some embodiments, each occurrence is the same.

[0369] ID some embodiments, each occurrence of “LRX-Lx-(CH2CH2O)n~Lzp“Lc-Rpis or comprises

[0370] In some embodiments, an occurrence of ~LRX-Lx“(CH2CH2O)n-Lz' '-L'— Rpis or comprises

[0371] In some embodiments, each occurrence of --L1?x-Lx-(CH2CH2O)n-L / 'r-LG-R1is or comprises

[0372] In some embodiments, an occurrence of -LRX-Lx-(CH2CH2O)n-LZr-L' -Rpis or comprises

[0373] In some embodiments, each occurrence of -LRX-Lx-(CH2CH2O)n-LzP-Lt'-Rris or comprises

[0374] In some embodiments, an occurrence of -LRX-L5i-(CH2CH2O)n-L / -p-Lc-Rf’ is or comprises

[0375] In some embodiments, an occurrence of -LRX-Lx-(CH2CH2O)n-Lzp-Lk'-Rpis or comprises,-LRX-Lx-(CH2CH2O)n-Lz'E>-Lc-Rpis or comprisesIn some embodiments, each occurrence of -LRX~LX~ (CHzCHzOin-I?1'- -Lc-Rpis or comprisese embodiments, each occurrence of -LRX-Lx-(CH2CH2O)n-Lzp-L'— R1,is or comprises. e embodiments, each occurrence of -- LxX-Lx-(CH2.CH2O)n--T.,zp--Iri -Rpis or comprisesembodiments, each occurrence is the same.

[0378] In some embodiments, an occurrence of ~LRX-Lx-(CH2CH2O)n~Lzl'-Lc-Rpis or comprises

[0379] In some embodiments, each occurrence of “LRX-LX-(CH2CH2O)II-LZ'F'-LC-R'' is or comprises

[0380] In some embodiments, an occurrence of-LRX-Lx-(CH2CH2O)n-LZr-Lv-Rpis or comprises

[0381] In some embodiments, each occurrence of -LRX-Lx-(CH2CH2O)n-L£P-Lc-Rris or

[0383] In some embodiments, each occurrence of “LR>:“LA"(CH2CH2O)n-~RPis orcomprises

[0384] In some embodiments, an occurrence of -LRX-Lx-(CH2CH2O)n-L£j'-LL'-Rpis or comprises. ,-•LRX“Lx~(CH2CH2O)n-LZ1'~Lc-Ri' is or comprisesIn some embodiments, each occurrence of. −LZP−LC−RP. In someembodiments, an occurrence of −LRX−LX−(CH2CH2O)n−LZP−LC−RPis −S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−GGFG−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Ala−PABA−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Cit−PABA−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)Val−Ala−NH−oGlu−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Ala−NH−mGlu−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Cit−NH−oGLu−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Cit−NH−mGLu−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zNHC(O)−oGlu−RP. In some embodiments, it is −S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zNHC(O)−mGlu−RP. In some embodiments, n is 8. In some embodiments, z is 2. In some embodiments, RPcomprises a nitrogen atom and is bonded at the nitrogen atom, e.g., to the rest of a conjugate or other compound. In some embodiments, RPis REX. In some embodiments, z is 2 and RPis REX. In some embodiments, n is 8, z is 2 and RPis REX. In some embodiments, x is 5, n is 8, z is 2 and RPis REX. In some embodiments, each occurrence of −LRX−LX−(CH2CH2O)n−LZP−LC−RPis the same.

[0386] In some embodiments, an occurrence of −LRX−LX−(CH2CH2O)n−LZP−LC−RPis or comprises ,some embodiments, each occurrence is the same.

[0388] In some embodiments, an occurrence of -LRX-Lx-(CH2CH2O)n-Lzp-Lc-Rpis or comprises

[0389] In some embodiments, each occurrence of ---LRX-I.x-(CH2CH2O)n-T.; / jP--I> '-Rpis or comprises

[0391] In some embodiments, each occurrence of -LkX---L ’1-- (CH2CH2O)n -L / P-- L<-Rpis or comprises

[0393] In some embodiments, each occurrence of -LR>,-LA-(CH2CH2O)n-Lz,p-Lc-R?is or comprises

[0394] In some embodiments, an occurrence of-LRX-Lx-(CH2CH2O)n-LZr-L''-Rpis or comprises. ,"LRX“LX”(CH2CH2O)B“LZP”LC“R1>is or comprises. In some embodiments, each occurrence of“LRX-Lx-(CH2CH2O)n-L'-p-Lc-Rpis or comprises. , ence of-LRX-Lx-(CH2CH2O)ti“Lzp-LC“Rpis or comprises, In some embodiments, an occurrence of"LRX“LX“(CH2CH2O)B“LZP”LC“RPis or comprises, occurrence of ---LRX---Lx--(CH2CH:;O)n--I,zp--LL--Rpis or comprises

[0395] In some embodiments, a conjugate comprises -LT~LRX“-LX“-(CH2CH2O)n--LZt'-Lc~Rr. In some embodiments, an occurrence of-Li-LRk-LK-(CH2CH2O)n-LZ1>-L!-'-Rpis -CH2-S -SM -(CH2)XC(O)NH (CH2CH2O)n (CH2)ZC(O) -GGFG -RpIn some embodiments, it is -CH2-S-SM-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)-Val-Ala-PABA~Rp. In some embodiments, it is CH S SM s( i I 1X s CH -CH -Ojii s( i I Vai Cn PABA R . In some embodiments, it is “CH2-S“SM-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)Val-Ala-NH--oGlu-Rp. In some embodiments, it is -<H2-- S---SM-<CH2)xC(O)NH---(CH2CH2O)n--(CH2)zC(O)---Val---Ala--NH--mGlu---R' . In some embodiments, it is “CH2-S“SM~(CH2)xC(O)NH~(CH2CH2O)n-(CH2)zC(O)-Val”Cit“NH-oGLu“R?. In some embodiments, it is -CH2-S-SM-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)-Va]-Cit-]SIH-mGLu-Rp. In someembodiments, it is -CH2-S-SM-(CH2)>.C(O)NH-(CH2CIl2O)n-(CPl2)iiNHC(O)-oG]u-Rp. In some embodiments, it is -<'H2---S--GM-<CH2)xC(O)NH--<CH2CH2O)n--(CH2);NHC(O)--mGlu --Rp. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 5. In some embodiments, n is 8. In some embodiments, z is 2. In some embodiments, REcomprises a nitrogen atom and is bonded at the nitrogen atom, e.g., to the rest of a conjugate or other compound. In some embodiments. Rpis RtX. In some embodiments, z is 2 and Rpis RhA. In some embodiments, n is 8, z is 2 and Rpis R"x. In some embodiments, x is 2, n is 8, z is 2 and Rpis RkX. In some embodiments, x is 3, n is 8, z is 2 and Rpis Rbx. In some embodiments, x is 5, n is 8, z is 2 and Rpis RBX. In some embodiments, each occurrence ofthe same.

[0396] In some embodiments, an occurrence of -L1-LRX-Lx-(CH2CH2O)n-LZt'-Lc-R?is or comprisessome embodiments, each occurrence is the same.

[0397] In some embodiments, an occurrence of-L1-LRX-Lx-(CH2CH2O)n-Lz'p-L"'-Ri’ is orsome embodiments, each occurrence is the same.

[0398] In some embodiments, an occurrence of ”Ll-~LRX“LX“(CH2CH2O)n“Lz'1'“Lt~R1' is or comprises

[0399] In some embodiments, each occurrence of -Lr-L^A-Lx-(CH2CH2O)n-L‘:'p-Lc-Rpis or comprises

[0400] In some embodiments, an occurrence of -L1“LRX-Lx-(CH2CH2O)n-Lzp-L,J-R!>is or comprises

[0401] In some embodiments, each occurrence of ~ Lr--LKX-Lx~ (CI^CTLO)!! -Lzp-L’ ■'•~RPis or comprises

[0402] In some embodiments, an occurrence of -L1-LRX-Lx-(CH2CH2O)n-LZt'-L ~R:>ss or comprises

[0403] In some embodiments, each occurrence of ~Lt“LKX-Lx-(CH2CH2O)n-Lzp-Lc-Rpis or comprises

[0404] In some embodiments, an occurrence of-I. / -LKX-Lx-(CHjCH2O)n-LZr-L''-Rpis orsome embodiments, each occurrence of -L1-LKX-Lx-(CH2CH2O)n-Lzf’-Lc-Rpis or comprisesIn some embodiments, an occurrence of-~LT”LRX~LX“(CH2CH2O)n“Lzp~Lc-Rpis or comprises. ,-LT-LRX-Lx-(CH^H2O)n-LZP-Lc-Rpis or comprisesembodiments, each occurrence of -LT~-LRX-LX-(CH2CH2O)II-LZ'P-LC-RPis or comprisesembodiments, an occurrence of “LT“LRX-Lx~(CH2CH2O)n“Lzp~Lc~Rpis or comprisesIn some embodiments, each occurrence of -L'~LRX-LX-(CH2CH2O)II-LZ'I>-LC-RPis or comprises

[0405] In some embodiments, an occurrence of ~LT“LEX~Lx-"(CH2CH2O)n~LZ1'-"Lc-Rpis or comprisessome embodiments, each occurrence is the same.

[0406] In some embodiments, an occurrence of -L[-LRX-L>— (CHjCILOfn-L' -p-Lc--R“ is or comprises

[0408] in some embodiments, each occurrence of -L1-LKX-Lx-(CH2CH2O)n-Lzp-Lc-Rpis or comprises

[0409] In some embodiments, an occurrence of “LT~LRX-Lx~(CH2CH2O)ii“LZr~Lv~Rris or comprises

[0410] In some embodiments, each occurrence of -L!-LliX-Lx-(CH2CH2O)n-LZf’-Lc-RE' is or comprises

[0411] In some embodiments, an occurrence of -Lr-LRX-Lx-(CH2CH2O)n-Lz,p-L"'-Rpis or comprises

[0412] In some embodiments, each occurrence of -L(-LKX-LA-(CH2CH2O)n-L‘'p-Lc-Rpis or comprises

[0413] In some embodiments, an occurrence of --L[---LRX---L.x-- (CH2CH2O)n--L'J3-L,c--R“ is or, ence of-LI-LRX-Lx-(CH2CzH20)n-Lz'p-Lc-Rpis or comprises, ,-LI-LRX-Lx-(CH2CH2O)!i-I / p-Lc-Rpis or comprises. embodiments, each occurrence of-L1-LRx-Lx-(CH2CH2O)n-Lzp-Lc-Rpis or comprisesembodiments, an occurrence of -L3-LRX-Lx-(CH2CH2O)n-L2P-Lc-Rpis or comprises. hi some embodiments, each occurrence of -L1-LKX-Lx-(CH2CH2O)n-L2P-Lc-Rpis or comprises|0414] In some embodiments, a conjugate comprises -L[-LRX-L>,-(CH2CH2O)n-Lzp-Lc-Rf'. In some embodiments, an occurrence of “LI-LEX-Lx-(CH2CH2O)n-Lzp-Lc-Rpis “CH2“S“CH2“C(O)NH-(CH2)xC(O)NH~(CH2CH2O)n-(CH2)zC(O)”GGFCi-Rp. In some embodiments, it is ( H r-S- -CH2--C(O)NI I t t 'U •;.( • ( )f\ H {f i i CH Om t ( 'H : ({( };. Vai- Ala PABA l< . In some embodiments, it is -CH2-S-CH2-C(O)NH-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)2C(O)-Val-Cit-PABA-Rp. In some embodiments, it is -CH2-S-CH2-C(O)NH-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)X’(O)Val-Ala-NH-oGlu-Rp. In some embodiments, it is -CH2-S-CH2-C(O)NH-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)-’Val-Ala-NH-mGlu-Rp. In some embodiments, it is ---CH2--S--CH2--C(O)NH--(CH2)xC(O)NH--(CH2CH2O)n--(CH2)zC(O)---Vai--Cit--NH--oGLii---RF. In some embodiments, it is -CH2-S-CH2-C(O)NH-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)zC(O)-VaI--Cii-NH-mGLti-RF. In some embodiments, it is -CH2-S-CH2-C(O)NH-(CH2)xC(O)NH-(CH2CH2O)n-(CH2)2NHC(O)-oGlu-Rp. In some embodiments, it is --CH2-"S---CH2--C(O)NH---(CH2)xC(O)NH--(CH2CH2O)n-(CH2)zNHC(O)--mGlu-RpIn some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 5. In some embodiments, n is 8. In some embodiments, z is 2. In some embodiments, REcomprises a nitrogen atom and is bonded at the nitrogen atom, e.g., to the rest of a conjugate or other compound. In some embodiments, Rpis RHX. In some embodiments, z is 2 and Rpis R* A In some embodiments, n is 8, z is 2 and Rpis R"x. In some embodiments, x is 2, n is 8, z is 2 and Rpis REX. In some embodiments, x is 3, n is 8, z is 2 and Rpis REX. In some embodiments, x is 5, n is 8, z is 2 and Rpis IVA In some embodiments, each occurrence of -L[-LRX-Lx-(CH2C'H2O)n--Lzp-Lc-Rpis the same.

[0415] In some embodiments, an occurrence of -L1-LEX-Lx-(CH2CH2O)n-LZt'-Lc-R!>is orcomprisesIn some embodiments, each occurrence is the same.|0416] In some embodiments, an occurrence of -L[-LRX-L>i-(CH2CH2O)n-Lz'?-Lv'-Rjris or comprisesembodiments, each occurrence is the same.

[0417] In some embodiments, an occurrence of -Lr-LRX-L‘ '-(CftCHsO^-L^-L^-R* is or comprises

[0418] In some embodiments, each occurrence of --L1--L;'x--Lx---(CH2CH2O)n--L / p---Lc-RE' is or comprises

[0419] In some embodiments, an occurrence of ~L‘--LRX-Lx-(CH2CH2O)n~L''-p-Lc-Rpis or comprises

[0420] In some embodiments, each occurrence of --L1--L!!X-Lx-(CH2CH2O)n-L / 'p-Lc-RE' is or comprisesIn some embodiments, an occurrence of-Ll-LRX-Lx-(CH2CH2O)n-Lz'p-L<:-Rpis or comprises

[0421] in some embodiments, each occurrence of -Lr-LEA-Ls-(CH2CH2O)n-Lzp-Lc-Rpis or comprises|0422] In some embodiments, an occurrence of -Ll-LRX-Lx-(CH2CI-l2O)n-L':,p-Lc-Rpis or,-L1-LRX-Lx-(CH2CH2O)n-LZ!'-Lc-R1>is or comprises, f“I..I”LRX-Lx~(CH2CH2O)n~LAp~Lc~Rpis or comprisessome embodiments, each occurrence of -L1-LRX-Lx-(CH2CH2O)n-L / ,f'-L' ~RPis or comprisesembodiments, an occurrence of -LT-LRX-LA-(CH2CH2O)n-Lzp-Lc-Rpis or comprisessome embodiments, each occurrence of -Lr-LRX-L5!-(CH2CH2O)n-LzP-Lc-Rpis or comprisesIn some embodiments, each occurrence is the same.|0424] In some embodiments, an occurrence of-L[-LRX-L>,-(CH2CH2O)n-Lz'p-Lc-Rf' is or comprisessome embodiments. each occurrence is the same.

[0425] In some embodiments, an occurrence of ”LT~LRX“LX“(CH2CH2O)n~Lz'1'-"Lc~Ri' is or|0428] In some embodiments, each occurrence of -L(-LRX-L-’l-(CH2CH2O)n-L / 'p-Lc-Rpis or comprises[04301 In some embodiments, each occurrence of -L!-Lpx-Lx-(CH2CH2O)n-Lzp-Lc-RE’ is or comprises|0431] In some embodiments, an occurrence of-Lr-LRX-Lx-(CH2CH2O)n-L‘!p-Lc-Rpis or comprises. In some embodiments, each occurrence of ~L[---LxX---L / i--(CH:'CH2O)n--l / / J’--Lc--Rpis or comprises, ce of-LT-LRX-Lx-(CH2CH2O)n-LZ1'-Lc-R?is or comprisesIn some embodiments, an occurrence of-LI-LRX-LX- (CH2CH2O)n-LzM>-R!' is or comprisesembodiments, each occurrence of -L -L'A-Lx-(CH2CH2O)n-L',P-LC-RPis or comprisesembodiments, an occurrence of-LT-LRX-LA— (CH2CH2O)n-Lzp-Lc-Rpis or comprises. In some mprises.)n−LZP−LC−RP. In some embodiments, an occurrence of −LT−LRX−LX−(CH2CH2O)n−LZP−LC−RPis −CH2−S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−GGFG−RP. In some embodiments, it is −CH2−S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Ala−PABA−RP. In some embodiments, it is −CH2−S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Cit−PABA−RP. In some embodiments, it is −CH2−S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)Val−Ala−NH−oGlu−RP. In some embodiments, it is −CH2−S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Ala−NH−mGlu−RP. In some embodiments, it is −CH2−S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Cit−NH−oGLu−RP. In some embodiments, it is −CH2−S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zC(O)−Val−Cit−NH−mGLu−RP. In some embodiments, it is −CH2−S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zNHC(O)−oGlu−RP. In some embodiments, it is −CH2−S−CH2−C(O)NH−(CH2CH2O)n−(CH2)zNHC(O)−mGlu−RP. In someembodiments, n is 8. In some embodiments, z is 2. In some embodiments, Rpcomprises a nitrogen atom and is bonded at the nitrogen atom, e.g., to the rest of a conjugate or other compound. In some embodiments, Rpis REX. In some embodiments, z is 2 and Rris REX. In some embodiments, n is 8, z is 2 and Rpis Rr'x. In some embodiments, x is 5, n is 8, z is 2 and Rpis RnXIn some embodiments, each occurrence of-LT-LxX- Lx-(CH?,CH:iO)n-Lzp--LL--Rpis the same.

[0433] In some embodiments, an occurrence of -L1-LRX-Lx-(CH2CH2O)n-LZt'-L ~R:>is orembodiments, each occurrence is the same.

[0434] In some embodiments, an occurrence of -L’-LR<-Lx-(CH2CH2O)n-LZt'-L ~R:>is or compriseseach occurrence is the same.

[0435] In some embodiments, an occurrence of “Lr”LRX”LX“(CH2CH2O)n~Lxp“L"'“RFis or

[0436] In some embodiments, each occurrence of -L1-LRX-Lx-(CH2CH2O)n-Lzp-Ll'-Rpis or comprises

[0437] In some embodiments, an occurrence of-L1-LRX-Lx-(CH2CH2O)n-LZ!'-L'"-R1>is or comprises|0438] In some embodiments, each occurrence of-Lr-Lp“’i-LA-(CH2CH2O)n-Lzp-Lc-Rpis or comprises

[0439] In some embodiments, an occurrence of-L1-LRX-Lx-(CH2CH2O)n-LZt'-L“-R1>is or comprises

[0440] In some embodiments, each occurrence of -LT-LEX-Lx-(CH2CH2O)n-LzP-Lc-Rpis or comprises|0441] In some embodiments, an occurrence of -L'-L^-L^-^CH / CTLOIn-L' ' -T^-Rris or,-LT-LRX-Lx-(CH2CH2O)n-Lzp-Lc-R1>is or comprises— L1— LRX-Lx-(CH2CH2O)n-LZr-L '■-R!>is or comprises, an occurrence of ~Lr~L&A~Ls~(CH2CH2O)n~Lzp~Lc- Rpis or comprisesnts,ome embodiments, “is or comprises” is “comprises”.

[0443] In some embodiments, a target binding moiety is or comprises an amino acid residue, and −LT−LRX−LX−(CH2CH2O)n−LZP−LC−RPis bonded to a backbone atom of an amino acid residue. In some embodiments, a target binding moiety is or comprises an amino acid residue, and −LT−LRX−LX−(CH2CH2O)n−LZP−LC−RPis bonded to an alpha-carbon of an amino acid residue. In some embodiments, each target binding moiety is independently an antibody or an antigen-binding fragment thereof. In some embodiments, each target binding moiety is independently an antibody. In some embodiments, each target binding moiety is independently a monoclonal antibody. In some embodiments, the target binding moiety is not trastuzumab. In some embodiments, the antibody shares less than about 90%, 95% or 99% sequence identity to trastuzumab. In some embodiments, the target binding moiety isnot an anti-HER2 antibody. In some embodiments, the target binding moiety is not an anti-HER2 antibody or an antigen-binding fragment thereof.

[0444] In some embodiments, t is 1-10. In some embodiments, t is 2-8. In some embodiments, t is 3- 5. In some embodiments, t is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, t is 1. In some embodiments, t is about 2. In some embodiments, t is about 4. In some embodiments, t is about 6. In some embodiments, t is about 8.

[0445] In some embodiments, a conjugate comprises ,

[0446] In some embodiments, a conjugate comprises

[0447] In some embodiments, a conjugate comprises

[0448] In some embodiments, a conjugate comprises

[0449] In some embodiments, a conjugate comprises, g p

[0450] In some embodiments, a conjugate comprises

[0452] In some embodiments, a conjugate comprises

[0453] In some embodiments, a conjugate comprises

[0454] In some embodiments, a conjugate comprises[0455 [ In some embodiments, a conjugate comprisessome embodiments, a conjugate comprisesIn some embodiments, a conjugate comprises

[0456] In some embodiments, a conjugate comprises

[0457] In some embodiments, a conjugate comprises.

[0458] In some embodiments, a conjugate comprises[0459 [ In some embodiments, a conjugate comprises

[0460] In some embodiments, a conjugate comprises

[0461] In some embodiments, a conjugate comprisessome embodiments, a conjugate comprisesembodiments, a conjugate comprisessome embodiments, a conjugate comprises

[0464] In some embodiments. a conjugate comprises

[0465] In some embodiments, a conjugate comprises0466] In some embodiments, a conjugate comprisessome embodiments, a conjugate comprisescomprisessortie embodiments, a conjugate

[0467] In some embodiments, a conjugate comprisesembodiments, a conjugate comprises

[0468] In some embodiments, a conjugate comprises

[0469] In some embodiments, a conjugate comprises

[0470] In some embodiments, a conjugate comprises[04711 In some embodiments, a conjugate comprises|0472] In some embodiments, a conjugate comprises,

[0473] In some embodiments, a conjugate comprisesIn some embodiments, aconjugate comprises[0474j In some embodiments, a conjugate comprises

[0478] In sonic embodiments, a conjugate comprisesa[0479 j In some embodiments, a conjugate comprisesme.,

[0482] In some embodiments, a conjugate comprises

[0483] In some embodiments, a conjugate comprises

[0484] In some embodiments, a conjugate compriseseIn some embodiments, a conjugate comprises

[0486] In some embodiments, a conjugate comprises

[0488] In some embodiments, a conjugate comprises

[0489] In some embodiments, a conjugate comprises

[0490] in some embodiments, a conjugate comprisesconjugate comprisesIn some

[0491] In some embodiments, a conjugate comprisesembodiments, a conjugate comprises

[0492] In some embodiments, a conjugate comprises

[0493] In seme embodiments, a conjugate comprises

[0494] In some embodiments, a conjugate comprises

[0495] In some embodiments, a conjugate comprises

[0496] In some embodiments, a conjugate comprises|0497] In some embodiments, a conjugate comprisesIn some embodiments, a conjugate comprises

[0498] In some embodiments, a conjugate has a structure of formula I-A, I-B, or I-C:or a pharmaceutically acceptablesa t t ereo , w ere n: RAis a target binding moiety; t is an integer between 1 and 16; X is a moiety that results from the reaction of the unbound linker and a group present on RA; Y is or comprises −LC–; and Z is or comprises −(CH2CH2O)n− wherein n is 0-24.

[0499] As described herein, in some embodiments, n is 1-24.

[0500] In some embodiments, X is or comprises LRXas described herein. In some embodimen...

Claims

CLAIMS1 . A conjugate, comprising: i) a target binding moiety targeting HHI.. A2; is) a payload moiety having the structureiii) a linker that connects the target binding moiety and the pay load moiety; wherein: the linker comprises -(CHjCHjOjn- and Lri; n is 0-24;bonded to the payload moiety .

2. The conjugate of claim 1, wherein the targeting binding moiety is an antibody selected from Hu2C4-H3L3, 65872, 65889, or 887-IDE.

3. The conjugate of claim 2. wherein n is 1 -244. The conjugate of claim 3, wherein5. The conjugate of claim 2, wherein6. A conjugate, comprising: i) a target binding moiety; ti) a payload moiety ; and iii) a linker that connects the targe: binding moiety and tire payload moiety; wherein: the linker comprises -(CHzCHjOjn- and L -; n is 0-24;LLis bonded to a payload moiety and is -LC1-LC°-;L'1is a cleavable unit; or LClis -Gly-Gly-Phe-Giy- -Vai- Ala- -Val-Cit- L’ls, -Gly-Gly-Phe-Gly-N(R’)-Lc', s-. vat Ala XtR' l I . " . or -Val~-Cit-N(R')-L0, s-;, wherein the phenyl ring and the -CH?- is optionally substituted. and the carbonyl is bonded to lA'J, and R1'3is or comprises a sugar moiety;Lcuis a covalent bond, or a spacer moiety (e g , optionally substitutedwherein the carbonyl is bonded to a payload moiety); each R’ is independently -R, -C(O)R, -CO2R. or -S(O)?R. or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from CMC aliphatic, Ci-to beteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, Cg.i4 aryl, a 5-14 membered heteroaryl ring having 1 -5 heteroatoms independentlyselected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

7. The conjugate of claim 6. wherein the target binding moiety comprises an antibody or an antigen- binding fragment thereof.

8. The conj ugate of claim 6 or 7, wherein the pay load moiety is9. The conjugate of any one of the preceding claims, wherein the payload moiety to target binding moiety ratio of the conjugate (DAR) is about 2-8.

10. The conjugate of any one of the preceding claims, wherein the linker comprises -(CH2C1 hOjn-l / '-L' wherein :I / ” is a covalent bond or an optionally substituted bivalent straight or branched C 1-20 aliphatic wherein 1-10 methylene units of LiPare optionally and independently replaced by a group selected from -O-, -N(R')-. -C(O)-. S . -S(O)-, -S(O)2-,-C(O)N(R’)-, -S(O)2(NR’)- and Cv : each -Cy- is independently an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; andR is optionally substituted Ci.6 aliphatic11 . The conjugate of any one of the preceding claims, wherein the linker comprises -L.x-(CH2CH2O)n--L / jP-L5 wherein:Lxis a covalent bond or an optionally substituted bivalent or polyvalent straight or branched Ci-20 aliphatic wherein 1-10 methylene units of Lxare optionally and independently replaced by a group selected from -O-, -N(R’j- -C(O)-, S . -S(O)-_ -S(O)2-. CtOfMlV ■ . -S(O)2(NR')-, and -Cy-;Lzpis a covalent bond or an optionally substituted bivalent straight or branched Cj.20 aliphatic wherein 1-10 methylene units of L / Eare optionally and independently replaced by a group selected from -O-, -N(R’)~, -C(O)-, -S-, -S(O)~, -S(O);- -C(O)N(R’)-, -S(O)2(NR’)-, and -Cy-; each -Cy- is independently an optionally substituted 3-12 membered ring having 0-4 hctcroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen or optionally substituted Ci-6 aliphatic.

12. The conjugate of any one of the preceding claims, wherein the linker is or comprises -LRX-Lx-(CH2CH2O)n-L4r-Lv-, wherein:LxXis a covalent bond or a moiety that results from a reaction between a group present on the unconjugated target binding moiety and a group present on an agent comprising -LA-(CH2CH2O)n-LzP-Lc- and a pay load moiety, wherein -Lc- is bonded to the pay load moiety; or LRXis a covalent bond or an optionally substituted bivalent straight or branched C1.20 aliphatic wherein 1-10methylene units of LRXare optionally and independently replaced by a group selected from -O-,Lxis a covalent bond or an optionally7substituted bivalent straight or branched CM aliphatic wherein 1-10 methylene units of Lxare optionally and independently replaced by a group selected front -O -N(R')-, ( •()) -S~, -S(O)-, ()) ■ -C(O)N(R")-, -S(O)2(NR’)- -, and -Cy-;Lzpis a covalent bond or an optionally substituted bivalent straight or branched CM aliphatic wherein 1 -10 methy lene units of Lzpare optionally and independently replaced by a group selected from -O-, -N(R')-. -C(O)-, -S- -S(O)-, -S(O)2- -C(O)N(R‘)- -S(O)2(NR’)-, and -Cy-; each -Cy- is independently an optionally substituted 3-12 membered ring har ing 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen or optionally substituted CM aliphatic.

13. The conjugate of any one of the preceding claims, wherein the linker is or comprises wherein:L1is a covalent bond or an optionally substituted bivalent straight or branched Ci.2o aliphatic wherein 1-10 methylene units of 17 are optionally and independently replaced by a group selected from -O-, -N(R’)- — C(O)— , -S-, — S(O)— , -S(O)2- -C(O)N(R’)~, -S(O)2(NR’)~ and -Cy-;LxXis a covalent bond or a moiety that results from a reaction between a group present on the unconjugated target binding moiety and a group present on an agent comprising -Lx-(CH2CH2O)n-LZE-L'— and a pay load moiety, wherein -Lc- is bonded to the payload moiety; or LRXis a covalent bond or an optionally substituted bivalent straight or branched Ct-ao aliphatic wherein 1-10 methylene units of LRXare optionally and independently replaced by a group selected from -O-, --N(R’)-, -C(O)-. S -S(O)-, -S(O)2-. -C(O)N(R’)”- -S(O)2(NR’ )- . and -Cy-;Lxis a covalent bond or an optionally- substituted bivalent or polyvalent straight or branched Cj2o aliphatic wherein 1-10 methylene units of Lxare optionally and independently replaced by a group selected from -O-, -N(R’)-, -C(O)~, -S-, -S(O)-. ~S(O)2~, -C(O)N(R’)-, -S(O)2(NR’)-, and -Cy-;Lzpis a covalent bond or an optionally7substituted bivalent straight or branched C1.20 aliphatic wherein 1 -10 methylene units of Lzpare optionally and independently replaced by a group selected from -O-, -N(R’)~, -C(O)~, -S-, -S(O)-, -S(O)2- -C(O)N(R’)-, -S(O)2(NR’)-, and -Cy-; each -Cy- is independently an optionally substituted 3-12 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen or optionally substituted CM aliphatic.

14. The conjugate of any one of claims 10-13. wherein LZpis a covalent bond or an optionally substituted bivalent straight or branched C1.20 aliphatic wherein 1-10 methylene units off / are optionally and independently replaced by a group selected from -O-, -N(R’)~, -C(O)-, ~S~, -S(O)~, -S(O)2-, -C(O)JSI(R’)-. and -S(O)2(NR')-.

15. The conjugate of claim 14, wherein LZ1>is -(CH2)z“N(R')C(O)“, -(CH2)z-C(O)--, or — (CH2)z— C(O)N(R’)— . wherein z is 1-19.

16. The conjugate of any one of claims 6-15, wherein L' is -Gly-Gly-Phe-Gly--Val-Ala-PABA- -Val-Cit-PABA- mGhi or oGlu.

17. The conjugate of any one of the preceding claims, wherein n is 8.

18. The conjugate of any one of claims 11 -17, wherein I..xis a covalent bond or an optionally substituted bivalent straight or branched C1.20 aliphatic wherein 1-10 methylene units of Lxare optionally and independently replaced by a group selected from -O-, -N(R’)-, -C(O)~, -S-, •~S(O)-~, -S(O)2-, -C(O)N(R’)— , -S(O)2(NR')- and -Cy-19. The conjugate of any one of claims 12-18, wherein each L:?xis independently ~LR <)- L!?X2-, wherein: each LRX1is independently a covalent bond or an optionally substituted bivalent or polyvalent straight or branched CMO aliphatic wherein 1-5 methylene units of LRX’!are optionally and independently replaced by a group selected from -O-. -N(R’)-, -C(O)-. -S-, -S(O)-, -S(O)2~ ~C(O)N(R‘)~, ~S(O)2(NR')~, and -Cy-; each LRX2is independently a covalent bond or an optionally substituted bivalent straight or branched Q-K. aliphatic wherein 1-5 methylene units of LRX2are optionally and independently replaced by a group selected from -O-, ~N(R’)~. -C(O)~. -S- -S(O)-. -S(O)2~, -C(O)N(R’)- -S(O)2(NR')-, and -Cy-; each -Cy- is independently an optionally substituted 3-12 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxy gen, and sulfur: each LRX2is bonded to Lx: and each R is independently hydrogen or optionally substituted Coe aliphatic.

20. The conjugate of any one of claims 13-19, wherein L1is a covalent bond or an optionally substituted bivalent straight or branched Ci2o aliphatic wherein 1-10 methylene units of LTare optionally and independently replaced bv a group selected from -O-, -N(R’)-, -C(O)-, -S-, -S(O)-, -S(O)2-, -C(O)N(R’)-. and -S(O)2(NR')-21. The conjugate of any one of claims 13-20. wherein L1is -CH2~.

22. The conjugate of any one of claims 13-21. wherein the target binding moiety comprises an amino acid residue, and 1 / is bonded to the backbone atom of the amino acid residue.

23. The conjugate of any one of claims 6-10, wherein the linker is or comprises, wherein: each LRXis independently a covalent bond or a moiety that results from a reaction between a group present on the unconjugated target binding moiety' and a group present on an agent comprising Lxand optionally a payload moiety, wherein -Lc- is bonded to the payload moiety; or each LRxis independently a covalent bond or an optionally substituted bivalent straight or branched C:2o aliphatic wherein 1-10 methylene units of LRXare optionally and independently replaced by a group selected from -O-, -N(R')-. -C(O)-, S . -S(O)-, -S(O)2-. -C '(O)N(R’)- -. -S(O)2(NR’)-, and -Cy-: each of a and b is independently I -10;Lxis a covalent bond or an optionally substituted bivalent or polyvalent straight or branched Cwoaliphatic wherein 1-10 methylene units of Lxare optionally and independently replaced by a group selected from O -N(R’)-, GO) . S . StO) . StO) . -C(O)N(R’)-. St C )5 t X R > and -Cy— C(O)N(R’)-, -S(O)2(NR’)- and -Cy-; each n is independently 0-24; each Lzpis independently a covalent bond or an optionally substituted bivalent straight or branched C1-20 aliphatic wherein 1-10 methylene units of L“;>arc optionally and independently replaced by a group selected from O -N(R> ( ((.);• . S . StO; . SoQr . CsOtSt i<‘ ) . StOtoXIV ; . and ~Cy~; each L' is independently L.!-L'x’--; each LC!is independently -Gly— Gly-Phe-Gly- -Vai-Ala-, -Val-Cit- LUIS, -Gly-Gly-Phe-Gly-N(R‘)-Lcl s- -Val-Ala-N(R’)-Lcl s- or -Val-Cii-N(R’)-Lcls-; each LCI Sis independently. wherein the phenyl ring and tire -CH?- is optionally substituted, and the carbonyl is bonded to Lco, and RLSis or comprises a sugar moiety; each L'1is independently absent or optionally substinttedwherein the carbonyl is bonded to a payload moiety’: each Lcis independently bonded to a payload moiety; each -Cy- is independently an optionally substituted 3-12 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently -R. -C(O)R. -CO2R. or -S(OhR. or two or more R' are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring har ing, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen or optionally substituted Ci^ aliphatic.

24. The conjugate of any one of claims 6-10, wherein die linker is or comprises., wherein; each LTis independently a covalent bond or an optionally substituted bivalent straight or branched Ci-2o aliphatic wherein 1-10 methylene units of L1are optionally and independently replaced by a group selected from -O-, -N(R’)-. -C(O)~, ~S~. -S(O)~. -S(O)2~. -C(O)N(R’)-. ~S(O)2(NR‘)~ and -Cy~; each LRXis independently a covalent bond or a moiety’ that results from a reaction between a group present on the unconjugated target binding moiety and a group present on an agent comprising Lxand optionally a payload moiety, wherein -Lc- is bonded to the payload moiety; or each LRXis independently a covalent bond or an optionally substituted bivalent straight or branched CI.JO aliphaticwherein 1-10 methylene units of LRXare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each of a and b is independently 1-10; LX’is a covalent bond or an optionally substituted bivalent or polyvalent straight or branched C1-30aliphatic wherein 1-10 methylene units of LX’are optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each n is independently 0-24; each LZPis independently a covalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LZPare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, −S(O)2(NR’)−, and −Cy−; each LCis independently −LC1−LCO−; each LC1is independently −Gly−Gly−Phe−Gly−, −Val−Ala−, −Val–Cit–, LC1S, −Gly−Gly−Phe−Gly−N(R’)−LC1S−, −Val−Ala−N(R’)−LC1S−, or −Val–Cit–N(R’)−LC1S−; each LC1Sis independently , wherein the phenyl ring and the −CH2− is optionally substituted, and the car and RLSis or comprises a sugar moiety;each LCOis independently absent or optionally substitute wherein the carbonyl is bonded to a payload moiety;each LCis independently bonded to a payload moiety; each −Cy− is independently an optionally substituted 3-12 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen or optionally substituted C1-6aliphatic.

25. The conjugate of claim 24, wherein each LTis independently a covalent bond or an optionally substituted bivalent straight or branched C1-20aliphatic wherein 1-10 methylene units of LTare optionally and independently replaced by a group selected from −O−, −N(R’)−, −C(O)−, −S−, −S(O)−, −S(O)2−, −C(O)N(R’)−, and −S(O)2(NR’)−.

26. The conjugate of any one of claims 24-25, wherein each occurrence of LTis −CH2−.

27. The conjugate of any one of the preceding claims, wherein the linker is or comprises a structure of formula B:wherein:# represents the point of atachment to the target binding moiety;% represents tire point of attachment to a payload moiety;X is a moiety that results from the reaction of an unbound linker and a group present on the target binding moiety;Y is Lc; andZ is or comprises -(CH2CH2O)n-.

28. A conjugate, wherein the conjugate is a compound of formula A-l or a salt thereof:A-l wherein: each RAis independently a target binding moiety; s is 1-2.0; each L1is independently a covalent bond or an optionally substituted bivalent straight or branched Cj 2o aliphatic wherein 1-10 methylene units of L1are optionally and independently replaced by a group selected from -O~, ~N(R’)~. -C(O)-, -S-. -S(O)-, -S(O)2-. -C(O)N(R’)-. -S(O)2(NR’)-, and -Cy-; each LRXis independently a covalent bond, a moiety that results from a reaction between a group present on the unconjugated target binding moiety and a group present on an agent comprising 1 / , or an optionally substituted bivalent straight or branched Cuo aliphatic wherein 1-10 methylene units of LxXare optionally and independently replaced by a group selected from -O-, --N(R’) -C(O)-. -S-, -S(O)-~. — S(O)2— , ~C(O)N(R’)~, — S(O);(NR’)— , and ~Cy~; or each LRxis independently a covalent bond or an optionally' substituted bivalent straight or branched C;2o aliphatic wherein 1-10 methylene units of LKXare optionally and independently replaced by a group selected from -O-, --N(R’)--, ~C(O)~. -S-, -S(O)-. -S(O)2-, -C(O)N(R’)- -S(O)2(NR’)- and -Cy-; each of a and b is independently 1-10; each Lxis independently a covalent bond or an optionally substituted bivalent or polyvalent straight or branched C1.30 aliphatic wherein 1-10 methylene units of Lxare optionally and independently replaced by a group selected from -O-, -N(R’)~, -C(O)~, ~S~, ~S(O)~, -S(O)2-, -C(O)N(R’)-, -S(O)2(NR’)-, and -Cy-; each n is independently 0-24; each Lzpis independently a covalent bond or an optionally substituted bivalent straight or branched C1-20 aliphatic wherein 1-10 methylene units of L‘"'1>are optionally and independently replaced by a group selected from -O~. -N(R")-, -C(O)~, -S-, ~S(Q)~, -S(O)2~, -C(O)N(R’)-, -S(O)2(NR‘)-» and -Cy-;each Lcis independently’ -LC 1--LC0--; each L'JIis independently a cleavable unit, or each L,JIis independently ---Gly-Gly-Phe---Gly-, or -Val-Cit-, wherein the phenyl ring and the - CH2 ■ is optionally substituted, and the carbonyl is bonded to Lc'\ and RL;iis or comprises a sugar moiety; each L'?" is independently a covalent bond or an optionally substituted bivalent straight or branched Ci-20 aliphatic wherein 1-10 methylene units of Lc0are optionally and independently replaced by a group selected from -O-, -N(R’)-, -C(O)~, -S-, -S(O)~, -S(O)2~, -C(O)N(R’)-, -S(O)2(NR’)-, and ( } . each Rpis independently a payload moiety; t is 1-20; each -Cy- is independently an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently -R. ~C(O)R. -CO2R. or -S(O)2R. or two or more R' are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to tlie intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, Ci-io heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C<5-i-r aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxy gen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

29. The conjugate of claim 28, wherein s is 1.

30. The conjugate of any one of claims 28-29, wherein an occurrence of a is 2-1031. The conjugate of any one of claims 28-30, wherein an occurrence of b is 2-10.

32. A conjugate, w herein the conjugate is a compound of formula A-2 or a salt thereof:A-2 wherein:RAis a target binding moiety; each Lris independently a covalent bond or an optionally substituted bivalent straight or branched Ci.20 aliphatic wherein 1-10 methylene units of L[are optionally and independently replaced by a group selected from -O-, -N(R’)-, -C(O)- -S-, -S(O)-, -S(O)2- -C(O)N(R’)-, -S(O)2(NR-)-, and -Cy-;each LRXis independently a covalent bond, a moiety' that results from a reaction between a group present on the unconjugated target binding moiety and a group present on an agent comprising -Lx-(CH2CH2O)n-Lzp-LL-R1>, or an optionally substituted bivalent straight or branched C1.20 aliphatic wherein 1-10 methylene units of LR -<are optionally and independently replaced by a group selected from -O-, -N(R‘)-, ( • ()) -S-, -S(O)-, S(O; -C(O)N(R ')-, -S(O)2(NR’)-, and -Cy-; each Lxis independently a covalent bond or an optionally substituted bivalent straight or branched Ci.20 aliphatic wherein 1-10 methylene units of Lxare optionally and independently replaced by a group selected from -O-, -N(R’)-, ~C(O)-, -S-, -S(O)-. -S(O)2~, -C(O)N(R’)-, -SfOhCNR*)-, and -Cy-; each n is independently 0-24; each I / '1' is independently a covalent bond or an optionally substituted bivalent straight or branched Ci-20 aliphatic wherein 1-10 methylene units of Lzpare optionally and independently replaced by a group selected from -O-, -N(R’)-. -C(O)~, -S-, -S(O)~ -S(O)2~, -C(O)N(R’)-, -S(O)2(NR’)~, and -Cy--; each LIJis independently -LC|-LCO-; each L'1is independently a cleavable unit; each Lc" is independently a covalent bond or an optionally substituted bivalent straight or branched Cj.20 aliphatic wherein 1-10 methylene units oi'LCuare optionally and independently replaced by a group selected from -O-. -N(R’)- -C(O)-. -S-, -S(O)-, -S(O)2-, -Cf O)N(R')-, -S(O)2(NR’)-, and -Cy-; each Rt-is independently a pay load moiety; t is 1 -20: each -Cy- is independently an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently -R, -C(O)R, -CO2R, or -SlCThR, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from Ci-w aliphatic, Ci-to hctcroaliphatic having 1-5 hctcroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, Co-io aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxy gen, phosphorus and sulfur.

33. The conjugate of claim 32, wherein RAis or comprises an antibody or an antigen-binding fragment thereof.

34. The conjugate of any one of claims 32-33. wherein an occurrence of Lxis a covalent bond or an optionally substituted bivalent straight or branched Croo aliphatic wherein 1-10 methylene units of Lxare optionally and independently replaced by a group selected from -O-, -N(R’)-, -C(O)~ -S-, -S(O)-.-S(0)2-, -C(O)N(R’)-, — S(O)2(NR’)— , and -Cy-35. The conjugate of any one of claims 28-34. wherein an occurrence of L!is a covalent bond or an optionally substituted bivalent straight or branched Cs-zo aliphatic wherein 1-10 methylene units of L1are optionally and independently replaced by a group selected from -O-, --N(R’)~, -C(O)-, --S-, ~S(O)~, ~S(O)2~, -C(O)N(R’)-, -S(O):(NR’)~. and -Cy.

36. The conjugate of any one of claims 28-35. wherein an occurrence of L‘ is -CH2-37. The conjugate of any one of claims 28-36, wherein an occurrence of L1!Xis a covalent bond or a moiety that results from a reaction between a group present on the unconjugated target binding moiety and a group present on an agent comprising -LA-(CH2CH2O)n-Lzp-Lc-- and a pay load moiety, or wherein an occurrence of t . ' is a covalent bond or an optionally substituted bivalent straight or branched C|.2o aliphatic wherein 1-10 methylene units of 1. ' are optionally and independently replaced by a group selected from () -N(R‘)-, GO) . S . SiO) . Set); . ~C(O)N(RV. St O) t X R > and 0} . wherein each -Cy— is independently an optionally substituted 3-12 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

38. The conjugate of any one of claims 28-37. wherein an occurrence of n is 8.

39. The conjugate of any one of claims 28-38. wherein an occurrence of Lzpis a covalent bond or an optionally substituted bivalent straight or branched Ci.?o aliphatic wherein 1-10 methylene units of IT are optionally and independently replaced by a group selected from -O-, -N(R’)-. -C(O)~ -S-. -S(O)-. -S(O )2- ", -C(O)N(R')-, -S(O)2(NR’)-, and -Cy-.

40. The conjugate of any one of claims 28-39, wherein each Rpis41. The conjugate of any one of claims 28-33, wherein each -Lc-R1' is independently42. The conjugate of any one of claims 28-33. wherein each occurrence of ~LAP-LC“R1’ is or43. The conjugate of any one of claims 28-33. wherein each occurrence of -(CH2CH2O)n-LZ1>-L -Rpis or comprises44. The conjugate of any one of claims 28-33. wherein an occurrence of~L '-(CH2CH?O)n~L / P~Lc~Rris or comprises45. The conjugate of any one of claims 28-33. wherein each occurrence of -~LEX“Lx-(CH2CH2O)n-Lzp-Lc--Rt' is or comprises46. The conjugate of any one of claims 28-33, wherein each occurrence of-L1-LRX-Lx-(CH2CH2O)n-LZ!'-Lc-R1>is or comprises47. The conjugate of any one of claims 28-46. wherein the target binding moiety comprises an amino acid residue, and -LT-LEX-Lx-(CH2CH2O)n-LZp-I.,c-Rpis bonded to the backbone atom of the amino acid residue.

48. The conjugate of claim 6, having a structure of formula X-C:X-C or a pharmaceutically acceptable salt thereof wherein:R ' is a target binding moiety; and t is an integer between 1 and 16.

49. The conjugate of claim 6. having a structure of formula X-C’:X-C’ or a pharmaceutically acceptable salt thereof, wherein:RAis a target binding moiety; and t is an integer between i and 16.

50. The conjugate of claim 6. having a structure of formula X-G‘:or a pharmaceutically acceptable salt thereof wherein:RAis a target binding moiety; and t is an integer between 1 and 16.

51. The conjugate of claim 6, having a structure of formula X-H’:X-H’ or a pharmaceutically acceptable salt thereof, wherein:RAis a target binding moiety; and t is an integer between 1 and 1652. The conjugate of claim 6, having a structure of formula X-T:X-T or a pharmaceutically acceptable salt thereof, wherein:RAis a target binding moiety; and t is an integer between 1 and 16.

53. The conjugate of claim 6. having a structure of formula X-J’:or a pharmaceutically acceptable salt thereof, wherein:RAis a target binding moiety; and t is an integer between 1 and 16.

54. The conjugate of claim 6. having a structure of formula X-K’:X-K’ or a pharmaceutically acceptable salt thereof, wherein:R'xis a target binding moiety; and t is an integer between I and 16.

55. The conjugate of claim 6, having a structure of formula X-LX-L’ or a pharmaceutically acceptable salt thereof, wherein:R'xis a target binding moiety; and t is an integer between 1 and 16.

56. The conjugate of any one of claims 28-55. wherein t is about 2-8.

57. The conjugate of any one of the preceding claims, wherein each target binding moiety is independently an antibody or an antigen-binding fragment thereof58 The conjugate of any one of claims 6-56, wherein each target binding moiety is an anti-HHLA2 antibody or an antigen-binding fragment thereof.

59. The conjugate of claim 58, wherein the anti-HHLA2 antibody or an antigen-binding fragment thereof is or comprises:(a) a heavy chain variable region (VH) comprising one, two, or three VH CDR sequences each with at least about 90% identity to a VH CDR of Table 1; and / or(b) a light chain variable region (VL) comprising one, two, or three VL CDR sequences each with al least about 90% identity to a VL CDR of Table 1.

60. The conjugate of claim 58, wherein tire anti-HHLA2 or antigen-binding fragment thereof is or comprises:(a) a VH comprising or consisting of a VH of Table 1 ; and / or(b) a VL comprising or consisting of a VL of Table 1.

61. The conjugate of any one of claims 58-60. wherein the anti-HHLA2 antibody or an antigen- binding fragment thereof is or comprises: a heavy chain variable region (VH) comprising a VH CDR sequence with about or at least about 90% identity to HCDR1 of 887-IDE in Table 1: a heavy chain variable region (VH) comprising a VH CDR sequence with about or at least about 90% identity to HCDR2 of 887-IDE in Table 1; a heavy chain variable region ( VH) comprising a VH CDR sequence with about or at least about 90% identity to HCDR3 of 887- IDE in Table 1: a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90% identity to LCDR1 of 887- IDE in Table 1 : a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90% identity7to LCDR2 of 887-1 DE in Table 1; and / or a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90% identity to LCDR3 of 887-1 DE in Table 1.62 The conjugate of any one of claims 58-60. wherein the anti-HHLA2 antibody or an antigen- binding fragment thereof is or comprises: a heavy chain variable region (VH) comprising a VH CDR sequence with about or at least about 90% identity to HCDR1 of 65889 in Table 1; a heavy chain variable region (VH) comprising a VH CDR sequence with about or at least about 90% identity to HCDR2 of 65889 in Table 1; a heavy chain variable region (VH) comprising a VH CDR sequence with about or at least about 90% identity' to HCDR3 of 65889 in Tabic 1; a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90% identity to LCDR1 of 65889 in Table 1; a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90% identity to LCDR2 of 65889 in Table 1 ; and / or a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90% identity7to LCDR3 of 65889 in Table 1.

63. The conjugate of any one of claims 58-60. wherein the anti-HHLA2 antibody or an antigen- binding fragment thereof is or comprises:a heavy chain variable region (VH) comprising a VH CDR sequence with about or at least about 90% identity to HCDR1 of 65872 in Table 1 ; a heavy chain variable region (VH) comprising a VH CDR sequence with about or at least about 90% identity to HCDR2 of 65872 in Table 1; a heavy chain variable region (VH) comprising a VH CDR sequence with about or at least about 90% identity to HCDR3 of 65872 in Tabic 1; a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90% identity7to LCDRl of 65872 in Table 1; a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90% identity to LCDR2 of 65872 in Table 1; and / or a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90% identity to LCDR3 of 65872 tr: Table 1.

64. The conjugate of any one of claims 58-60. wherein the anti-HHLA2 antibody or an antigen- binding fragment thereof is or comprises: a heavy chain variable region ( VH) comprising a VH CDR sequence with about or at least about 90% identity to HCDR1 of Hu2C4-H3L3 in Table 1; a heavy chain variable region (VH) comprising a VH CDR sequence with about or at least about 90% identity to HCDR2 of Hu2C4-H3L3 in Table 1; a heavy chain variable region (VH) comprising a VH CDR sequence with about or at least about 90% identity7to HCDR3 of Hu2C4-H3L3 in Table 1: a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90% identity to LCDRl of Hu2C4-H3L3 in Table 1 ; a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90%. identity to LCDR2 of Hu2C4-H3L3 in Table 1: and / or a light chain variable region (VL) comprising a VL CDR sequence with about or at least about 90% identity to LCDR3 of Hu2C4-H3L3 in Table 1.

65. The conjugate of any one of claims 58-60, wherein the anti-HHLA2 antibody or an antigen- binding fragment thereof is or comprises 887-1 DE, 65889, 65872 or Hu2C4H3L3 in Table 1 .

66. The conjugate of any one of claims 58-60, which binds HHL.A.2 with a Kp of about 15 nM or less.

67. A conjugate, wherein the conjugate is a compound having the structure ofIDE, 65889. 65872 or Hu2C4H3L3 in Table 1, each ~S~ is independently of a Cys residue, and t is about 1-8.

68. The conjugate of claim 67, wherein t is about 2-869. The conjugate of any one of the preceding claims, wherein the conjugate is in a pharmaceutically acceptable salt form.

70. A composition comprising one or more conjugates each of which is independently a conjugate of any one of tire preceding claims.

71. The composition of claim 70, wherein the ratio of the pay load moiety to the target binding moiety of the composition is about 4-8.

72. The composition of any one of claims 70-71 , wherein the composition is a pharmaceutical composition.

73. The composition of any one of claims 79-72, wherein the composition comprises a pharmaceutically acceptable carrier.

74. A kit comprising a conjugate of any one of claims 1-69 or a composition of any one of claims 70- 73, and optionally instructions for use and / or administration.

75. A method of modulating an immune response in a subject comprising administering or delivering to a subject in need thereof a therapeutically effective amount of a conjugate or composition of any one of claims 1-73.

76. A method of treating a subject having a disease, disorder, or condition comprising administering or delivering to a subject in need thereof a therapeutically effective amount of a conjugate or composition of any one of claims 1-73.

77. The method of any one of claims 75-76, wherein the subject has cancer.

78. The method of any one of claims 75-77, wherein the subject has a solid tumor, or wherein the subject has a renal cancer, a bone cancer, a skin cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a lung cancer, an ovarian cancer, a liver cancer, a prostate cancer, a pancreatic cancer, cholangiocarcinoma, or a thyroid cancer, or wherein the subject has a hematological tumor, or wherein the subject has leukemia, or wherein the subject has acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic leukemia, or acute leukemia, or wherein the subject has lymphoma, or wherein the subject has Hodgkin lymphoma (HL), non-Hodgkin’s lymphoma, lymphocytic lymphoma, or diffuse large B cell lymphoma (DLBCL), or wherein the subject is at risk of developing a cancer.

79. The method of any one of claims 76-78. wherein the disease, disorder, or condition is associated with aberrant HHLA2 expression.

80. The method of any one of claims 75-79. wherein the conjugate is administered in combination with a second agent.

81. A method for inhibiting proliferation of diseased cells in a system, comprising administering to or delivering to the system a conjugate or composition of any one of claims 1 -73, wherein the diseased cells expresses or comprise an agent that a target binding moiety of the conjugate can bind.

82. A method for reduce number of diseased cells in a sy stem, comprising administering to or delivering to the system a conjugate or composition of any one of claims 1 -73, wherein the diseased cells expresses or comprise an agent that a target binding moiety of the conjugate can bind.

83. A method for delivering a payload to a target in a system, comprising administering to or delivering to the system a conjugate or composition of any one of claims 1 -73, wherein: a pay load moiety of the conjugate is a moiety of the pay load; and the target expresses or comprises an agent that a target binding moiety of the conjugate can bind.

84. A conjugate, composition or kit of any one of claims 1-74 for use in the treatment of a condition, disease or disorder, or for use in a method of any one of the preceding claims.

85. Use of a conjugate, composition or kit of any one of claims 1-74 for the manufacture of a medicament for the treatment of a condition, disease or disorder, or for the manufacture of a medicament for a method of any one of the preceding claims86. A method for preparing a conjugate or composition of any one of claims 1-73, comprising reacting a target binding agent and a payload agent, wherein: the target binding agent comprises a target binding moiety and a target binding agent reactivegroup; the payload agent comprises a payload moiety and a payload agent reactive group; and the target binding agent reactive group reacts with the payload agent reactive group to conjugate the payload moiety to the target binding moiety' optionally through a linker.

87. The method of claim 84, wherein the pay load agent is Compound 1 , Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, LP-A, LP-B, LP-C or LP-D.

88. A conjugate, composition, kit, method, or compound of any one of Embodiments 1-813.

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