Antibody drug conjugates comprising sting agonists and uses thereof

Abstract

The present disclosure relates to a conjugate comprising a STING agonist, linker and antibody or antigen-binding fragment thereof, and uses thereof for the treatment of diseases.

Description

[0001] ANTIBODY DRUG CONJUGATES COMPRISING STING

[0002] AGONISTS AND USES THEREOF

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 644,292, filed May 8, 2024, which is hereby incorporated by reference in its entirety.

[0005] BACKGROUND

[0006] Cancer is a disease caused by abnormal and uncontrolled cell growth in the tissues of the body and is the result of uncontrolled cell growth in a variety of tissues. Tumors in early-stage cancers may be removed through surgical and radiotherapeutic measures, and metastasized tumors are generally treated palliatively using chemotherapy. Most chemotherapy agents administered non-orally may induce unwanted adverse effects or serious toxicity as a result of systemic administration. Accordingly, the focus of development has been on developing novel chemotherapy agents to achieve improved efficacy and minimal toxicity / adverse effects through improved and selective action of chemotherapy agents on tumor cells or immediately adjacent tissues.

[0007] An antibody-drug conjugate (ADC) is a targeted technology where a toxin or drug is bonded to an antibody which in turn binds to an antigen, the toxin or drug released into a cell to cause cell death of tumor cells. The technology has superior efficacy over antibody drugs and is able to substantially reduce the risk of adverse effects compared to conventional anti-cancer agents, because it specifically delivers drugs to the target cancer cells with minimum impact to healthy cells, and only releases drugs under specific conditions.

[0008] The basic structure of an antibody-drug conjugate is “antibody-linker-small molecule drug (toxin)”. Here, the linker needs to play not only the functional role of linking the antibody and drug, but also ensure that the drug is released properly through antibodydrug dissociation (e.g. as a result of hydrolysis by enzyme) after being circulated through the body and reaching the target cells, and exhibits efficacy against the target cancer cells. In other words, the stability of the linker plays a very important role in the efficacy and systemic toxicity of an antibody-drug conjugate (Discovery Medicine 2010, 10(53): 329- 39). 85-8 2018-08-14).

[0009] The use of monoclonal antibodies for cancer treatment is having substantial success. Monoclonal antibodies are suitable for target-oriented addressing of tumor tissue and tumor cells. Antibody-drug conjugates have become a novel and powerful option for therapy of lymphomas and solid cancers, and recently, immunoregulatory antibodies are seeing significant success in clinical trials. Development of therapeutic antibodies is based on a profound understanding of cancer serology, protein engineering technology, mechanisms of action and resistance, and interactions between immune systems and cancer cells.

[0010] In view of the foregoing, there is an ongoing need for new antibody drug conjugates to treat diseases such as cancer.

[0011] SUMMARY OF THE INVENTION

[0012] The present invention provides, among other things, antibody-drug conjugates (ADCs), comprising a stimulator of interferon genes (STING) agonist moiety, active metabolites of such ADCs, methods for preparation of such ADCs, uses for such ADCs in treatment and / or prevention of illnesses (e.g., proliferative and / or angiogenetic diseases, for example, cancer). More particularly, the present invention provides antibody-drug conjugates comprising STING agonist thereof, and a pharmaceutical composition comprising the same.

[0013] In one aspect, the present disclosure provides conjugates having a structure represented by formula I:

[0014] ( DnD— LABAB

[0015] "DL<i) wherein:

[0016] AB is an antibody or antigen-binding fragment thereof;

[0017] LABis an antibody linker; nDis an integer selected from 1-10; nDLis an integer selected from 1-10; and each D is independently an active agent (e.g., a drug (e.g., an immune modulator), a toxin), wherein at least one D is a STING agonist, each such STING agonist independently selected from a moiety represented by structural formula (la): wherein:

[0018] V is selected from H, alkyl, alkenyl, alkynyl, aminoalkyl, amidoalkyl, alkylamido, carboxyl alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl and heteroarylalkyl; or V is a moiety coupled to LABand selected from alkylene, heteroalkylene and aminoalkylene; each instance of W1and W2is independently selected from alkyl, amino, amido, and hydrazido; n and m are each independently 0, 1, 2, or 3;

[0019] Z is selected from alkylene, alkenylene, and alkynylene;

[0020] A and B are each independently aryl or heteroaryl;

[0021] Xaand Xbare each independently selected from CH2, NH, O, -NHC(O)-, - C(O)NH-, -C(O)O-, -OC(O)-, -OC(O)NH-, -NHC(O)O-, and S;

[0022] L1is selected from alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, heteroalkenylene, heteroalkynylene *Y1-O-Y2**, and *Y3-NRY-Y4**;

[0023] L2is a bond or a moiety coupled to LABand selected from -NH-, alkylamino, -N(RL) -, -N(H)RL-, -NRLC(=NH)NH-, -C(=NH)NH-, alkylene, heteroarylene, heterocyclylene, or arylene, or L2is -NH2, alkylamino, -N(RL)2, -N(H)RL, -N(RL)C(=NH)NH2, -C(=NH)NH2, alkyl, heteroaryl, heterocyclyl or aryl, wherein each can be optionally substituted;

[0024] Y1and Y3are each independently selected from alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, heteroal kenylene, and heteroalkynylene,

[0025] Y2and Y4are each independently selected from a single bond, alkylene, and heterocyclylene;

[0026] * is the point of connection to Xa;

[0027] ** is the point of connection to L2; J is alkylene-heteroarylene, alkylene-heterocyclylene, heteroarylene-alkylene, heterocyclylene-alkylene , heteroarylene or heterocyclylene, wherein each can be optionally substituted;

[0028] RYis H, alkyl, or C(=NH)NH2.

[0029] RLis H, alkyl (e.g., alkyl substituted with carboxylic acid), heteroalkyl, ester, heterocyclyl, aryl, heteroaryl, or cycloalkyl; and provided that either V or L2is a moiety coupled to LAB.

[0030] Certain compounds encompassed by structural formula (I) are recited in PCT International Application No. PCT / IB23 / 00678, filed November 8, 2023, and PCT International Application No. PCT / IB23 / 00193, filed April 6, 2022, and the entire contents of which are hereby incorporated by reference.

[0031] Certain conjugates encompassed by structural formula (I) and / or linker are recited in US Provisional Application No. 63 / 802,463, filed May 8, 2025, and US Provisional Application No. 63 / 802,493, filed May 8, 2025, and the entire contents of each of which are hereby incorporated by reference

[0032] BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1. Tumor Cell Cytotoxicity by PBMCs (AIC4-induced tumor cell killing effect on SK-BR-3 tumor cells)

[0034] Figure 2. In vitro studies of tumor cell killing effect through PBMC activation of AICs (AIC5 and AIC6 induced tumor cell killing effect on SK-BR-3 tumor cells).

[0035] Figure 3. In vitro studies of tumor cell killing effect through PBMC activation of AIC(AIC7 induced tumor cell killing effect on SK-BR-3 tumor cells).

[0036] Figure 4. In vitro studies of tumor cell killing effect through PBMC activation of AIC(AIC8 induced tumor cell killing effect on SK-BR-3 tumor cells).

[0037] Figure 5. In vitro studies of tumor cell killing effect through PBMC activation of AIC(AIC9 induced tumor cell killing effect on SK-BR-3 tumor cells).

[0038] Figure 6. In vitro studies of tumor cell killing effect through PBMC activation of AIC(AIC10 induced tumor cell killing effect on SK-BR-3 tumor cells).

[0039] Figure 7. In vitro studies of tumor cell killing effect through PBMC activation of AIC(AIC11 induced tumor cell killing effect on SK-BR-3 tumor cells).

[0040] Figure 8. Immune Cell Activation In Vitro (Analysis of AIC -induced cytokine production in hPBMCs and BxPC3 cells)

[0041] Figure 9. Immune Cell Activation In Vitro (Analysis of AlC-induced cytokine production relating various immune cell functions (TNFa, IL-1 [3, IL-6, IL12p70, IL-8, IL- 4, and IL13 etc.))

[0042] Figure 10. In vivo study in Syngeneic Mouse Models (Inhibition effect of AIC1 in the CT26 syngeneic model)

[0043] Figure 11. In vivo study in Syngeneic Mouse Models (Analysis of AlC-induced tumor-specific memory responses)

[0044] Figure 12. In vivo study in Syngeneic Mouse Models (Inhibition effect of AIC1 and AIC2 in the CT26 syngeneic model)

[0045] Figure 13. In vivo study in Syngeneic Mouse Models (Inhibition effect of AIC1 and AIC3 in the CT26 syngeneic model)

[0046] Figure 14. In vivo study in Syngeneic Mouse Models (Inhibition effect of AIC2 in the CT26 syngeneic model)

[0047] Figure 15. In vivo study in Syngeneic Mouse Models (Inhibition effect of AIC2 in the MC38 / hPD-Ll mouse model)

[0048] Figure 16. In Vivo Activity in Cell Line-Derived Xenograft Model (Inhibition effect of AIC2 in the BxPC3 mouse xenograft model)

[0049] Figure 17. In Vivo Activity in Cell Line-Derived Xenograft Model (Inhibition effect of AIC2 in the JIMT1 CDX model)

[0050] Figure 18A. Immune Cell Activation in Tumor-Bearing Mice (Enhancement effect of AIC2 on CD4+cells in spleen)

[0051] Figure 18B. Immune Cell Activation in Tumor-Bearing Mice (Enhancement effect of AIC2 on CD8+cells in spleen)

[0052] Figure 18C. Immune Cell Activation in Tumor-Bearing Mice (Enhancement effect of AIC2 on NK cells in spleen)

[0053] Figure 19A. Immune Cell Activation in Tumor-Bearing Mice (Enhancement effect of AIC2 on CD4+cells in dLN)

[0054] Figure 19B. Immune Cell Activation in Tumor-Bearing Mice (Enhancement effect of AIC2 on CD8+cells in dLN)

[0055] Figure 19C. Immune Cell Activation in Tumor-Bearing Mice (Enhancement effect of AIC2 on NK cells in dLN) Figure 20. Plasma Cytokine Induction in Tumor-Bearing Mice (AIC2-induced production of cytokines IL-6, TNF, MIP-la, INF-y, IP- 10 and IL-2)

[0056] Figure 21. Direct cytotoxic effects of exemplified ADICs(ADIC5, ADIC6) on MDA-MB468 model.

[0057] Figure 22. Direct cytotoxic effects of exemplified ADICs(ADIC7) on JIMT1 model.

[0058] Figure 23. Direct cytotoxic effects of exemplified ADICs(ADIC7, ADIC8) on MDA-MB-468

[0059] Figure 24. Tumor Cell Cytotoxicity by PBMCs (Tumor cell killing effect of ADIC1, ADIC2 and ADIC4 on SK-BR-3)

[0060] Figure 25A. Tumor Cell Cytotoxicity by PBMCs (Tumor cell killing effect of ADIC2, ADIC3, compound 54 and compound 58 on HCC827+PBMC and HCC827)

[0061] Figure 25B. Tumor Cell Cytotoxicity by HCC827 (Tumor cell killing effect of ADIC2, ADIC3, compound 54 and compound 58 on HCC827)

[0062] Figure 26. Immune Cell Activation In Vitro (ADIC2, ADIC3 induced cytokine production)

[0063] Figure 27. Immune Cell Activation In Vitro (ADIC2 induced cytokines relating various immune cell function (IL12p70, IL-8, IL-2, IFN- y, IL-4, and IL13 etc.)

[0064] Figure 28. In vivo study in syngeneic mouse models (Inhibition effect of ADIC1, ADIC2 and ADIC4 in the CT26 syngeneic model)

[0065] Figure 29A. In vivo study in syngeneic mouse models (Inhibition effect of ADIC1 and ADIC2 in the CT26 syngeneic model)

[0066] Figure 29B. In vivo study in syngeneic mouse models (ADIC-induced tumorspecific memory responses)

[0067] Figure 30. In vivo study in syngeneic mouse models (Inhibition effect of ADIC2 and ADIC3 in the CT26 syngeneic model)

[0068] Figure 31. In vivo study in syngeneic mouse models (Inhibition effect of ADIC3 in the CT26 syngeneic model)

[0069] Figure 32. In vivo study in syngeneic mouse models (Inhibition effect of ADIC3 in the MC38 / hPD-Ll mouse model)

[0070] Figure 33. In Vivo Activity in Cell Line-Derived Xenograft Model (Anti-tumor in vivo efficacy of ADIC3 in BxPC3 mouse xenograft model) Figure 34. In Vivo Activity in Cell Line-Derived Xenograft Model (Anti-tumor in vivo efficacy of ADIC1 in JIMT1 mouse xenograft model)

[0071] Figure 35. Plasma Cytokine Induction in Tumor-Bearing Mouse (ADIC3 induced production of cytokines)

[0072] Figure 36A. Immune Cells Population in Tumor Bearing Mouse (Enhancement of ADIC3 of CD69 expression on CD4+cells in spleen)

[0073] Figure 36B. Immune Cells Population in Tumor Bearing Mouse (Enhancement of ADIC3 of CD69 expression on CD8+cells in spleen)

[0074] Figure 36C. Immune Cells Population in Tumor Bearing Mouse (Enhancement of ADIC3 of CD69 expression on NK cells in spleen)

[0075] Figure 37A. Immune Cells Population in Tumor Bearing Mouse (Enhancement of ADIC3 of CD69 expression on CD4+cells in dLN)

[0076] Figure 37B. Immune Cells Population in Tumor Bearing Mouse (Enhancement of ADIC3 of CD69 expression on CD8+cells in dLN)

[0077] Figure 37C. Immune Cells Population in Tumor Bearing Mouse (Enhancement of ADIC3 of CD69 expression on NK cells in dLN)

[0078] Figure 38. In Vivo Anti-Tumor Activity in Human Cancer Cell Line-Derived Xenograft (CDX) Models (Inhibition effect of ADIC9 on HCT15 CDX model)

[0079] Figure 39. In Vivo Anti-Tumor Activity in Human Cancer Cell Line-Derived Xenograft (CDX) Models(Inhibition effect of ADIC10, ADIC11 on HCT15 CDX model)

[0080] Figure 40. In Vivo Anti-Tumor Activity in Human Cancer Cell Line-Derived Xenograft (CDX) Models(Inhibition effect of ADIC11 on SNU840 model)

[0081] DETAILED DESCRIPTION OF THE INVENTION

[0082] The stimulator of interferon genes (STING) is a low-molecular-weight protein currently attracting attention as a target for cancer therapies. STING is an adapter protein in the cGAS (cyclic GMP-AMP synthase)-STING pathway, which is a sensing pathway that induces activation of type I IFN and other inflammatory cytokines, triggering antiviral and antitumor immune responses (Chen, Q. et al. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat. Immunol. 2016, 17, 1142-1149; Woo, S.R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 2014, 41, 830-842). In addition, STING activates signal transducer and activator of transcription 6 (STAT6) and transcription factor interferon regulatory factor 3 (IRF3) through TANK-binding kinase 1 (TBK1) in antiviral and innate immune responses (Burdette DL, Vance RE, STING and the innate immune response to nucleic acids in the cytosol, 2013, Nature Immunology. 14 (1): 19-26). STING agonists can also trigger expression of cytokines, giving rise to a T cell-mediated innate immune response which inhibits the growth of cancer cells. However, systemic delivery of STING agonists can cause widespread inflammation.

[0083] Various STING agonists have been tested in preclinical and clinical environments. A variety of agonists in the form of CDN (cyclic dinucleotide) compounds (ADU-S100, BISTING, GSK532, JNJ-4412, SB11285, MK-1454, TAK676, etc.), bacterial vectors (SYNB1891, STACT-TREX-1), non-cyclic dinucleotide (CDN), compounds (ALG- 031048, JNJ-6196, MK-2118, MSA-1, MSA-2, CRD-5500, etc.), nano vaccines (PC7ANP, cGAMP-NP, etc.) and ADCs (XMT-2056, TAK500, etc.) are under development by various strategies.

[0084] The most widely used preclinical compound, DMXAA (vascular disrupting agent), was used clinically in combination with paclitaxel and carboplatin, but its lack of efficacy was confirmed in phase 3. Further, ADU-S100, which was first used clinically as the STING agonist, was discontinued from use in 2020.

[0085] Examples of STING agonists are disclosed, for example, in WO2021 / 014365 (a macrocyclic compound as STING agonist), and US2021 / 0139473 (a heterocyclic amide- containing compound as protein modulator), US 2022 / 0073509 (a heterocyclic compound as STING activator), and KR 2022-0024467 (a heterocycle-containing STING agonist), each of which is incorporated herein by reference in its entirety.

[0086] However, existing STING agonists appear to exhibit only limited bioavailability and require local administration to tumors due to hyperactivation of cytokine expression or have to be used in combination with other compounds. Therefore, there remains a demand for development of therapeutically effective STING agonists, for example, an antibody-drug conjugate compromising STING agonist.

[0087] An antibody-drug conjugate (ADC) is a targeted technology for conjugating a toxin or a drug to an antibody that binds to an antigen, by which the toxin is released in a cell to cause death of cancer cells and the like. The ADC enables a drug to be accurately delivered to target cancer cells while minimally affecting healthy cells, and to be released only under specific conditions, and thus has excellent efficacy compared to antibody therapeutic agents themselves and can remarkably reduce the risk of side effects compared to existing anti cancer agents.

[0088] The basic structure of these antibody-drug conjugates is “antibody-linker-small molecule drug (toxin)”. In this structure, the linker plays a functional role in linking the antibody and the drug, but in some cases also ensures that the drug is released from the antibody at the appropriate time, for example after reaching target cells. That is, the stability of the linker can play a very important role in the efficacy and safety such as systemic toxicity of an antibody-drug conjugate (Discovery Medicine 2010, 10(53): 329-39).

[0089] The use of monoclonal antibodies for cancer treatment has had substantial success. For example, monoclonal antibodies are suitable for target-directed addressing of tumor tissue and tumor cells. Antibody-drug conjugates have become a novel and powerful option for the treatment of lymphomas and solid cancers, and immunomodulatory antibodies also have recently had considerable success in clinical trials. The development of therapeutic antibodies is based on deep understanding of cancer serology, protein engineering technology and the action thereof, mechanisms of resistance, and interactions between immune systems and cancer cells.

[0090] Antigens which are expressed on the surface of human cancer cells are defined as a broad range of targets which are over-expressed compared to normal tissues, mutated and selectively expressed. The key challenge is to identify antigens suitable for antibody-based therapies. These therapeutic agents mediate changes in antigen or receptor function (i.e., function as a stimulant or an antagonist), regulate the immune system through Fc and T cell activation, and exhibit efficacy through the delivery of specific drugs that bind to antibodies targeting specific antigens. Molecular techniques that can alter antibody pharmacokinetics, action function, size and immune stimulation are emerging as key factors in the development of novel antibody-based therapies. Evidence from clinical trials of therapeutic antibodies in cancer patients highlights the importance of approaches for selecting optimized antibodies, including affinity and binding of target antigens and antibodies, selection of an antibody structure, and therapeutic approaches (signaling blockade or immune function).

[0091] In certain aspects, the present disclosure provides antibody-linker-drug (e.g., toxin) systems which, by applying a linker optionally comprising a self-immolative group, is more stable in circulation (e.g., in plasma), enables a drug to be easily released in cancer cells to maximize efficacy, and enables a drug and / or toxin to stably reach a target cell.

[0092] In one aspect, the present disclosure provides a conjugate having a structure represented by formula I: wherein:

[0093] AB is an antibody or antigen-binding fragment thereof;

[0094] LABis an antibody linker; nDis an integer selected from 1-10; nDLis an integer selected from 1-10; and each D is independently an active agent (e.g., a drug(e.g., an immune modulator), a toxin), wherein at least one D is a STING agonist, each such STING agonist independently selected from a moiety represented by structural formula (la): wherein:

[0095] V is selected from H, alkyl, alkenyl, alkynyl, aminoalkyl, amidoalkyl, alkylamido, carboxyl alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl and heteroarylalkyl; or V is a moiety coupled to LABand selected from alkylene, heteroalkylene and aminoalkylene; each instance of W1and W2is independently selected from alkyl, amino, amido, and hydrazido; n and m are each independently 0, 1, 2, or 3;

[0096] Z is selected from alkylene, alkenylene, and alkynylene;

[0097] A and B are each independently aryl or heteroaryl; Xaand Xbare each independently selected from CH2, NH, O, -NHC(O)-, - C(O)NH-, -C(O)O-, -OC(O)-, -OC(O)NH-, -NHC(O)O-, and S;

[0098] L1is selected from alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, heteroalkenylene, heteroalkynylene *Y1-O-Y2**, and *Y3-NRY-Y4**;

[0099] L2is a bond or a moiety coupled to LABand selected from -NH-, alkylamino, -N(RL) -, -N(H)RL-, -NRLC(=NH)NH-, -C(=NH)NH-, alkylene, heteroarylene, heterocyclylene, and arylene, or L2is -NH2, alkylamino, -N(RL)2, -N(H)RL, -N(RL)C(=NH)NH2, - C(=NH)NH2, alkyl, heteroaryl, heterocyclyl or aryl, wherein each can be optionally substituted;

[0100] Y1and Y3are each independently selected from alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, heteroal kenylene, and heteroalkynylene,

[0101] Y2and Y4are each independently selected from a single bond, alkylene, and heterocyclylene;

[0102] * is the point of connection to Xa,

[0103] ** is the point of connection to L2;

[0104] J is alkylene-heteroarylene, alkylene-heterocyclylene, heteroarylene-alkylene, heterocyclylene-alkylene, heteroarylene or heterocyclylene, wherein each can be optionally substituted;

[0105] RYis H, alkyl, or C(=NH)NH2, and

[0106] RLis H, alkyl (e.g., alkyl substituted with carboxylic acid), heteroalkyl, ester, heterocyclyl, aryl, heteroaryl, or cycloalkyl; and provided that either V or L2is a moiety coupled to LAB.

[0107] In certain embodiments, D is a moiety represented by structural formula (la): wherein: V is selected from H, alkyl, alkenyl, alkynyl, aminoalkyl, amidoalkyl, alkylamido, carboxyl alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heterocyclylalkyl, and cycloalkylalkyl; and

[0108] L2is a bond or a moiety coupled to LABand selected from -NH-, alkylamino, -N(RL) -, -N(H)RL-, -N(RL)C(=NH)NH-, -C(=NH)NH-, alkylene, heteroarylene, heterocyclylene, and arylene.

[0109] In certain embodiments, D is a moiety represented by structural formula (la): wherein:

[0110] V is a moiety coupled to LABand selected from alkylene (e.g., alkylene substituted with alkoxy and / or amino) heteroalkylene, and aminoalkylene;

[0111] L2is selected from -NH2, alkylamino, -N(RL)2, -N(H)RL, -N(RL)C(=NH)NH2, - C(=NH)NH2, alkyl, heteroaryl, heterocyclyl, and aryl; preferably -NH(RL) and -N(RL)2, wherein each can be optionally substituted;

[0112] RLis H, alkyl, (e.g., alkyl substituted with carboxylic acid), heteroalkyl, ester, heterocyclyl, aryl, heteroaryl, or cycloalkyl.

[0113] In further embodiments, RLis a moiety represented by structural formula (Ia-RL) wherein: YRLis selected from -#NHC(O)-alkyl, -#C(O)NH- alkyl, and -#COO alkyl (e.g., alkyl substituted with alkoxy);

[0114] R1is -CH2OR1A, or -CO2R1B;

[0115] R1Ais H or a hydroxyl protecting group;

[0116] R1Bis H or a carboxyl protecting group; each R2is independently H or a hydroxyl protecting group;

[0117] # indicates the point of attachment to the phenyl ring and

[0118] ## indicates the point of attachment to the N to which RLis bonded.

[0119] In certain embodiments, V is wherein

[0120] * indicates the point of connection to Xb, and ** indicates the point of connection to LAB;

[0121] * indicates the point of connection to L1.

[0122] In certain embodiments, L1is selected from alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, heteroalkenylene, heteroalkynylene, *Y1-O-Y2**, and *Y3-NRY-Y4**; L2is a bond or a moiety coupled to LABand selected from -NH-, - N(RL)-, -N(RL)C(=NH)NH-, -C(=NH)NH-, alkylene, heteroarylene, heterocyclylene, and arylene; Y2and Y4are each independently selected from a single bond, alkylene, and heterocyclylene; and RYis H, alkyl, or C(=NH)NH2.

[0123] In certain embodiments, Xbis O.

[0124] In certain embodiments, V is H. In certain embodiments, V is alkyl. In certain such embodiments, V is methyl.

[0125] In certain embodiments, V is selected from -(alkylene)carboxylic acid, - (alkylene)heteroaryl, -(alkylene)guanidino, aminoalkyl, -(alkylene)NHC(O)CH2guanidino, -(alkylene)O(alkylene)guanidino, -(alkylene-O) nvaminoalkyl, -(alkylene-O-) nvalkoxylalkyl, and -(alkylene)amine; wherein each can be optionally substituted; wherein nv is an integer selected from 0 to 20. In certain embodiments, V is selected from -(alkylene)carboxylic acid, - (alkylene)guanidino, -(alkylene)NHC(O)CH2guanidino, -(alkylene)O(alkylene) guanidino, and -(alkylene)amine.

[0126] In certain such embodiments, V is C1-3 alkyl substituted with -COOH.

[0127] In certain embodiments, V is C1-6 alkyl substituted with five-membered heteroaryl, wherein the five-membered heteroaryl is optionally substituted one or more alkyl.

[0128] In certain embodiments, V is -(alkylene-O) nvaminoalkyl or -(alkylene-O) nvalkoxylalkyl, wherein nv is an integer selected from 0 to 10. In certain such embodiments, V is -(CH2CH2O)nv-aminoalkyl, wherein nv is an integer selected from 0 to 6.

[0129] In certain embodiments, V is C1-6 aminoalkyl.

[0130] In certain preferred embodiments, V is substituted with one or more RV1(e.g., one RV1), wherein each RV1is independently selected from alkyl, alkoxy, alkenyl, alkynyl, aminoalkyl, alkylamido, alkylthio, carboxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, amido, sulfhydryl, sulfinyl, sulfoximine, sulfonyl, or sulfonamide. In certain such embodiments, V is further substituted with one or more additional substituents. In certain embodiments, V is not further substituted in addition to the RV1substituent(s). In certain embodiments, RV1is amido. In certain embodiments, RV1is heteroaryl, e.g. pyrazole.

[0131] In certain embodiments, each RV1is independently selected from sulfinyl, sulfoximine, sulfonyl, or sulfonamide. In certain such embodiments, RV1is selected from - S(O)R’, -S(O)(=NR’)R”, -S(O)2R”, or -S(O)2NR’R’”, wherein each R’ and R’” is independently selected from H, alkyl, alkenyl, or alkynyl and each R” is independently selected from alkyl, alkenyl, or alkynyl. In certain such embodiments, RV1is -S(O)(=NH)R”. In certain embodiments, RV1is -S(O)(=NH)R”, wherein R” is C1-6 alkyl. In certain such embodiments, RV1is:

[0132] In certain embodiments, RV1is substituted with alkyl, which alkyl is optionally substituted with one or more RV2, each RV2being independently selected from hydroxyl, phosphino, phosphonyl, phosphonamidyl, and phosphate. In certain such embodiments, V is (alkyl)-Rvl-(alkyl)-(RV2) nv2, wherein nv2 is 1, 2, or 3. In certain such embodiments, R. is amido.

[0133] In certain embodiments, V is (alkyl)-Rvl-(alkyl)-(RV2)nv2, wherein each RV2is independently selected from hydroxyl, phosphonyl, phosphoryl, and phosphate.

[0134] In certain embodiments, V is (alkyl)-(amido)-(alkyl)-(RV2)nv2, and each RV2is independently selected from hydroxyl, phosphonyl, phosphoryl, and phosphate. In certain such embodiments, V is (alkyl)-(amido)-(alkyl)-(OH)(P(O)(OH)2))2.

[0135] In certain embodiments, W1is amido. In certain embodiments, W2is amido. In certain embodiments, W1is -C(0)NH2. In certain embodiments, W2is -C(0)NH2.

[0136] In certain preferred embodiments, D is represented by structural formula (lb):

[0137] In certain embodiments, A is heteroaryl. In certain such embodiments, A is 5- membered heteroaryl. In certain embodiments, B is heteroaryl. In certain such embodiments, B is 5-membered heteroaryl. In certain preferred embodiments, A and B are each independently represented by one of the following structural formulas:

[0138] Raand Rbare each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, halogen, OH, -OP(O)R’R”, -OR’, -NR’R”, -OCOR’, -CO2R’, -SOR’, -SO2R’, -CONR’R”, -SO2NR’R”, -OCONR’R”, -NR’ COR”, -NR’ SOR”, -NR’CO2R”, and -NR’SO2R”, and wherein

[0139] R’ and R” are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, and a C2- 6 alkynyl.

[0140] In certain preferred embodiments, A and B are each independently represented by 1 / VW

[0141] -

[0142] N=\b

[0143] R, wherein Raand Rbare each independently selected from H, C1-6 alkyl.

[0144] In certain preferred embodiments, A and B are each independently represented by

[0145] In certain even more preferred embodiments, D is represented by structural formula (Ic):

[0146] In certain embodiments, Z is alkenylene. In certain preferred embodiments, Z is - CH=CH-.

[0147] In certain preferred embodiments, Xais O.

[0148] In certain embodiments, L1comprises a moiety represented by one of the following structural formulas: wherein:

[0149] Q is phenyl or heteroarylene, and p and q are each independently 0, 1, 2, or 3, preferably 1 or 2.

[0150] In certain such embodiments, p is 1 and q is 0 or 1.

[0151] In certain such embodiments, L1is a moiety represented by one of the following structural formulas: wherein:

[0152] G’ is CH or N,

[0153] J is alkylene-heteroarylene, alkylene-heterocyclylene, heteroarylene-alkylene, heterocyclylene-alkylene, heteroarylene or heterocyclylene, wherein each can be optionally substituted; k is 1, 2, or 3, preferably 1 or 2, and

[0154] * indicates the point of attachment to Xa.

[0155] In certain preferred embodiments, L1is a moiety represented by the following structural formula:

[0156] In other embodiments, L1is a moiety represented by the following structural formula: In other preferred embodiments, L1is a moiety represented by the following

[0157] In certain such embodiments, G’ is CH.

[0158] In certain preferred embodiments, J is a moiety represented by one of the following structural formulas: wherein: nJis an integer between 1-10, and

[0159] ** indicates the point of attachment to L2when L2is present, or LABwhen L2is a bond. In certain preferred embodiments, L1is a moiety represented by the following structural formula: wherein ** indicates the point of attachment to L2when L2is present, or LABwhen L2is a bond.

[0160] In certain embodiments, L1is *Y1-O-Y2** or *Y3-NRY-Y4**; wherein * indicates the point of attachment to Xaand * * indicates the point of attachment to L2when L2is present, or LABwhen L2is a bond.

[0161] In certain such embodiments, L1is *Y1-O-Y2**. In certain such embodiments, Y1is selected from alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, heteroalkenylene, heteroalkynylene In certain such embodiments, Y1is C2-6 alkenylene or C2-6 alkynylene. In certain such embodiments, Y1is unsubstituted C4 alkenylene or unsubstituted C4 alkynylene.

[0162] In certain embodiments, Y1is selected from

[0163] In certain embodiments, Y2is a single bond.

[0164] In certain embodiments, L1is *Y3-NRY-Y4**. In certain such embodiments, Y3is selected from alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, heteroalkenylene, heteroalkynylene In certain such embodiments, Y3is C2-6 alkenylene or C2-6 alkynylene. In certain such embodiments, Y3is unsubstituted C4 alkenylene or unsubstituted C4 alkynylene.

[0165] In certain embodiments, Y3is selected from

[0166] In certain embodiments, Y4is C1-6 alkylene. In certain such embodiments, Y4is C1-3 alkylene optionally substituted with 1 to 3 substituents selected from C 1-5 alkyl, C1-5 haloalkyl, halogen, OH, oxo, -OR', -NR'R", -OCOR', -CO2R', -SOR', -SO2R', -CONR'R", - SO2NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", wherein R’ and R” are each independently selected from hydrogen, Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl. In other certain embodiments, Y4is unsubstituted C 1-3 alkylene.

[0167] In certain embodiments, RYis selected from H, unsubstituted C1-3 alkyl, or - C(=NH)NH2. In certain such preferred embodiments, RYis H. In other embodiments, RYis methyl or -C(=NH)NH2.

[0168] In certain embodiments, L2is selected from a bond, -NH-, alkylamino, -N(RL)-, - N(H)RL-, -NRLC(=NH)NH-, 5- to 12-membered heteroarylene, 5- to 12-membered heterocyclylene, and C6-12 arylene.

[0169] In certain embodiments, L2is -NRLC(=NH)NH-. In certain embodiments, RLis H, alkyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl. In certain preferred embodiments, RLis H.

[0170] In certain embodiments, L2is -N(RL)-. In certain such embodiments, RLis H, C1-6 alkyl, C1-6 alkyl carboxylic acid, or alkoxyl carboxylic acid. In further embodiments, RLis H, methyl, -CH2CH2COOH, -CH(CH2COOH)2, or -(CH2CH2O)2CH2COOH.

[0171] In certain embodiments L2is selected from 5- to 7-membered heteroarylene, 5- to 7- membered heterocyclylene, and Ce arylene. In certain such embodiments L2is 5- to 7- membered heteroarylene optionally independently substituted with 1 to 3 substituents selected from C1-5 alkyl, C1-5 haloalkyl, halogen, OH, C(=NH)NH2, -OP(O)(R’R”)2, -OR’, -NR’R”, -OCOR’, -CO2R’, -SOR’, -SO2R’, -CONR’R”, -CON(R’)R”N(R’”)-, - SO2NR’R”, -OCONR’R”, -NR’ COR”, -NR’ SOR”, -NR’CO2R”, and -NR’SO2R”, and wherein R’ R” and R’” are each independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl.

[0172] In other embodiments wherein L2is unsubstituted 5- to 7-membered heterocyclylene. It will be understood that, in embodiments where L2is a heteroarylene, heterocyclylene, and arylene, it may be coupled to L1and LABdirectly through a ring atom, or through a substituent (e.g., through the replacement of a hydrogen atom on the substituent instead of through the replacement of a hydrogen atom on the ring itself). Examples and embodiments of both types of coupling are described herein.

[0173] In certain embodiments, L2is a bond.

[0174] In other preferred embodiments, L2is a moiety represented by one of the following structural formulas:

[0175]

[0176] In certain preferred embodiments, L1is *Y1-O-Y2** and O-Y2-L2is a moiety represented by one of the following structural formulas:

[0177] wherein * in the structural formulas indicates the point of attachment to LAB.

[0178] In other preferred embodiments Li is Ys-NF -Y / *, and NRy-Y4-L2 is a moiety represented by one of the following structural formulas: wherein * in the structural formulas indicates the point of attachment to LAB.

[0179] In certain preferred embodiments, D is represented by structural formula (Id):

[0180] wherein:

[0181] W3is selected from H, alkyl, amino, amido and carboxyl; and

[0182] * indicates the point of attachment to LAB.

[0183] In certain such preferred embodiments, D is represented by structural formula (le): wherein:

[0184] W3is selected from H, alkyl, amino, amido and carboxyl, and

[0185] * indicates the point of attachment to LAB.

[0186] In certain embodiments, W3is selected from H, alkyl, and carboxyl. In certain such embodiments, W3is H. In other embodiments, W3is COOH.

[0187] In certain embodiments, D is represented by one of the following structural formula (If), (Ig) and (Ih):

[0188] wherein: * indicates the point of attachment to LAB.

[0189] In certain embodiments, the active agent D is selected from

[0190] (a) a microtubule targeting agent (e.g., maytansinoid, maytansine, DM1, DM4, maytansinol, auristatin, dolastatin 10, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), eribulin, Halichondrin B, tubulysin, cryptophycin, EG5 inhibitor, SB-715992 (ispinesib), or filanesib (ARRY-520));

[0191] (b) a DNA damaging agent (e.g., enediyne, calicheamicin, uncialamycin, topoisomerase inhibitor, topotecan, camptothecin, SN-38, irinotecan (CPT-11), exatecan, Dxd, pyrrolobenzodiazepine (PBD), PBD dimer, duocarmycin, Duocarmycin A, or CC-1065);

[0192] (c) an RNA targeting agent (e.g., thailanstatin, amatoxin, a-amanitin, or P-amanitin);

[0193] (d) an affinity ligand (e.g., the affinity ligand is a substrate, inhibitor, active agent, neurotransmitter, radioactive isotope, or mixtures thereof); (e) a radioactive label (e.g., 32P or 35S), a fluorescent dye, an electron dense reagent, an enzyme, a immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or mixtures thereof;

[0194] (f) an immunomodulatory compound, an anti-cancer agent, an anti-viral agent, an antibacterial agent, an anti-fungal agent, an anti-parasitic agent, or mixtures thereof;

[0195] (g) an estrogen receptor modulator (e.g., tamoxifen, raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, LY117018, onapristone or toremifene);

[0196] (h) an aromatase inhibitor (e.g., 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, letrozole or anastrozole);

[0197] (i) a nonsteroidal antiandrogen (NSAA) (e.g., flutamide, nilutamide, or bicalutamide);

[0198] (j) an aromatase inhibitor;

[0199] (k) a protein kinase inhibitor;

[0200] (l) a lipid kinase inhibitor;

[0201] (m) an antisense oligonucleotide;

[0202] (n) a ribozyme;

[0203] (o) a vaccine;

[0204] (p) an anti -angiogenic agent;

[0205] (q) a Bcl-xL inhibitor;

[0206] (r) a NAMPT inhibitor; and

[0207] (s) a Carmaphycin; and provided at least one D is a STING agonist.

[0208] In certain embodiments, LABcomprises one or more moieties selected from a peptide moiety, an oxime moiety, a phenyl moiety, a branched moiety, a saccharide moiety, and a - OCH2CH2- moiety.

[0209] In certain embodiments, LABcomprises a moiety represented by structural formula (II-OXMI): wherein:

[0210] Rioxmancj R2oxm jnc[epenc[ent|y jq, alkyl, or cycloalkyl, preferably alkyl; or Rioxmanj R2oxmcombinet0form acycloalkyl. In certain embodiments, LABcomprises a moiety represented by structural formula

[0211] (II-OXM2): wherein:

[0212] X1and X2are each independently N(R4oxm), O, or S, preferably X1is N(R4oxm) and X2is O; and

[0213] R4oxmp[ alkyl, aryl, or aralkyl, preferably H;

[0214] Rloxmand R2oxmare each independently H, alkyl, or cycloalkyl, preferably alkyl; or Rloxmand R2oxmcombine to form a cycloalkyl.

[0215] In certain embodiments, LABcomprises a moiety represented by:

[0216] In certain embodiments, the conjugate comprises a moiety represented by structural formula (III -TAB): wherein:

[0217] L1Ais a linkage to the remainder of LAB, wherein L1Acomprises a C1-C100 alkylene;

[0218] X3and X4are each independently N(R5), O, or S;

[0219] Y1, Y2, and Y3are each independently O, N(R6), or S; V1, V2, and V3are each independently a bond, N, NH, C, CH, or CH2 ;

[0220] R5and R6are each independently H, alkyl, aryl, or aralkyl;

[0221] L3, L4, and L5each independently comprise an alkylene;

[0222] T1, T2, and T3are each independently a bond, -O-, or a cleavage group;

[0223] D1, D2, and D3are each independently an active agent (e.g., a drug, a toxin), H, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, carboxylic acid, acyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, guanidinyl, amido, cyano, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, aryl, heteroaryl, or heterocyclyl, wherein at least one of D1, D2, and D3is a STING agonist, wherein the STING agonist is each independently a structure represented by structural formula (la); or

[0224] V1, T1and D1; V2, T2and D2; or V3, T3and D3together represent a branched moiety (e.g., a branched moiety substituted with one or more active agents); and ml, m2, and m3 are each independently 1, 2, or 3, preferably wherein ml, m2, and m3 are 1.

[0225] In certain embodiments, D1, D2or D3is each independently an active agent selected from:

[0226] (a) a microtubule targeting agent (e.g., maytansinoid, maytansine, DM1, DM4, maytansinol, auristatin, dolastatin 10, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), eribulin, Halichondrin B, tubulysin, cryptophycin, EG5 inhibitor, SB-715992 (ispinesib), or filanesib (ARRY-520));

[0227] (b) a DNA damaging agent (e.g., enediyne, calicheamicin, uncialamycin, topoisomerase inhibitors, topotecan, camptothecin, SN-38, irinotecan (CPT-11), exatecan, Dxd, pyrrolobenzodiazepine (PBD), PBD dimer, duocarmycin, Duocarmycin A, or CC-1065);

[0228] (c) an RNA targeting agent (e.g., thailanstatin, amatoxin, a-amanitin, or P-amanitin);

[0229] (d) an affinity ligand (e.g., the affinity ligand is a substrate, inhibitor, active agent, neurotransmitter, radioactive isotope, or mixtures thereof);

[0230] (e) a radioactive label (e.g., 32P or 35S), a fluorescent dye, an electron dense reagent, an enzyme, an immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or mixtures thereof;

[0231] (f) an immunomodulatory compound, an anti-cancer agent, an anti-viral agent, an antibacterial agent, an anti-fungal agent, an anti-parasitic agent, or mixtures thereof; (g) an estrogen receptor modulator (e.g., tamoxifen, raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, LY117018, onapristone or toremifene);

[0232] (h) an aromatase inhibitor(e.g., 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, letrozole or anastrozole);

[0233] (i) a nonsteroidal antiandrogen (NSAA) (e.g., flutamide, nilutamide, or bicalutamide);

[0234] (j) an aromatase inhibitor;

[0235] (k) a protein kinase inhibitor;

[0236] (l) a lipid kinase inhibitor;

[0237] (m) an antisense oligonucleotide;

[0238] (n) a ribozyme;

[0239] (o) a vaccine;

[0240] (p) an anti -angiogenic agent;

[0241] (q) a Bcl-xL inhibitor;

[0242] (r) a NAMPT inhibitor; and

[0243] (s) a Carmaphycin; and provided at least one of D1, D2, and D3is a STING agonist.

[0244] In certain embodiments, D1, D2or D3is each independently an active agent selected from MMAE, MMAF, exatecan, taltobulin, Genz-644282, dasatinib, and a STING agonist; wherein the STING agonist is independently a structure represented by formula (la).

[0245] In certain embodiments, V1is a bond and ml is 1; V2is a bond and m2 is 1; and / or V3is a bond and m3 is 1.

[0246] In certain embodiments, L3, L4, or L5each independently comprises a Ci-Cioo alkylene. In certain embodiments, L3, L4, or L5each independently comprises *-(CH2CH2)- (OCH2CH2)I -20-**, wherein * indicates the point of attachment to Y1, Y2or Y3, respectively; and ** indicates the point of attachment to V1, V2or V3, respectively.

[0247] In certain embodiments, L3, L4, or L5each independently comprises an oligoethylene glycol (e.g., oligoethylene glycol comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ethylene glycol moieties).

[0248] In certain embodiments, L3, L4, or L5each independently further comprises an amido moiety. In certain embodiments, L3, L4, or L5each independently comprises 1, 2, 3, 4, 5, or 6 amido moieties. In certain embodiments, L3, L4, or L5each independently further comprises a heteroaryl (e.g., pyrazolyl, triazolyl). In certain embodiments, L3, L4, or L5each independently comprises a structure represented by formula (Ill-a) or (Ill-b):

[0249] (Ill-a) (Ill-b) wherein: each Ay1represents a linkage to V1, V2or V3, respectively and each Ay2represents a linkage to Y1, Y2, or Y3,respectively; preferably each Ay1and Ay2are each independently Ci-io alkyl.

[0250] In certain embodiments, at least one of L3, L4, or L5each independently comprises a structure represented by formula (Ill-a) or (Ill-b).

[0251] In certain embodiments, ; * indicates the point of attachment to V1; and ** indicates the point of attachment to Y1.

[0252] In certain embodiments, L4comprises *-(CH2CH2)-(OCH2CH2)I-2O-**, wherein * indicates the point of attachment to the V2; and ** indicates the point of attachment to the Y2.

[0253] In certain embodiments, L5is *-(CH2CH2)-(OCH2CH2)s-**, wherein * indicates the point of attachment to the V3; and ** indicates the point of attachment to the Y3.

[0254] In certain embodiments, T1, T2, and T3each independently comprises a structure represented by formula (Ill-d) wherein:

[0255] Y is selected from - NHC(O)-, -#C(O)NH-, -#(CH2)tNHC(O)-, and -#COO-, preferably -#C(O)NH-;

[0256] R1is -CH2OR1A, or -CO2R1B; R1Ais H or a hydroxyl protecting group, preferably H;

[0257] R1Bis H or a carboxyl protecting group, preferably H; each R2is independently H or a hydroxyl protecting group, preferably H; t is 1, 2, or 3, preferably 1; indicates the point of attachment to D1, D2, or D3of formula (III-TAB), respectively;

[0258] * indicates the point of attachment to V1, V2, and V3of formula (III-TAB), respectively; and

[0259] # indicates the point of attachment to the phenyl ring of formula (Ill-d).

[0260] In certain embodiments, T1, T2, or T3comprises a structure represented by formula (III-d-1): wherein: indicates the point of attachment to D1, D2, or D3of formula (III-TAB); and

[0261] * indicates the point of attachment to V1, V2, or V3of formula (III-TAB).

[0262] In certain embodiments, D1, D2, and / or D3is a STING agonist, wherein the STING agonist has a structure represented by formula (la): wherein:

[0263] V is a moiety coupled to T1, T2or T3. In certain embodiments, D1, D2, and / or D3, is a STING agonist, wherein the STING agonist has a structure represented by formula (la): wherein:

[0264] L2is a bond, or a moiety coupled to T1, T2or T3respectively.

[0265] In certain embodiments, D1and D3are exatecan (e.g., wherein D1and D3are both exatecan), and D2is a STING agonist, wherein the STING agonist is independently selected from a structure represented by formula (la).

[0266] In certain embodiments, D1, D2and / or D3is H, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, carboxylic acid, acyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, guanidinyl, amido, cyano, azido, alkylthio, cycloalkyl, alkyl sulfonyl, sulfonamido, aryl, heteroaryl, or heterocyclyl; provided at least one of D1, D2, and D3is a STING agonist.

[0267] In certain embodiments, D2is H, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, amino, amido, aryl, heteroaryl, or heterocyclyl.

[0268] In certain embodiments, D2is selected from - In certain embodiments, D3is an active agent selected from MMAE, MMAF, exatecan, taltobulin, Genz-644282, dasatinib, and a STING agonist; wherein the STING agonist is independently selected from a structure represented by formula (la).

[0269] In certain embodiments, V1is N and V1, T1and D1together represent a branched moiety having a structure represented by formula (III-e-1) or a pharmaceutically acceptable salt thereof: wherein:

[0270] Ax3represents a linkage to L3;

[0271] Lx1and Lx2each independently comprise an alkylene;

[0272] Tx1and Tx2are each independently a bond or a cleavage group; and

[0273] Bx1and Bx2are each independently an active agent (e.g., a drug or a toxin);

[0274] In certain embodiments, V1is CH and V1, T1, and D1together represent a branched moiety having a structure represented by formula (III-e-2) or a pharmaceutically acceptable salt thereof: (lll-e-2) wherein:

[0275] Ax3represents a linkage to L3;

[0276] Lx1and Lx2each independently comprise an alkylene;

[0277] Tx1and Tx2are each independently a bond or a self-immolative moiety; and

[0278] Bx1and Bx2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

[0279] In certain embodiments, V1is CH and V1, T1, and D1together represent a branched moiety having a structure represented by formula (III-e-3) or a pharmaceutically acceptable salt thereof: wherein:

[0280] Ax3represents a linkage to L3;

[0281] Lx1and Lx2each independently comprise an alkylene;

[0282] Gx1, Gx2, and Gx3are each independently an alkylene, each Rx1is independently H, alkyl, or aralkyl;

[0283] Tx1and Tx2are each independently a bond or a self-immolative moiety; and

[0284] Bx1and Bx2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

[0285] In certain embodiments, V1is C and V1, T1and B1together represent a branched moiety having a structure represented by formula (III-e-4) or a pharmaceutically acceptable salt thereof: wherein:

[0286] Ax3represents a linkage to L3;

[0287] Lx1, Lx2, and Lx3each independently comprise an alkylene;

[0288] Tx1, Tx2, and Tx3are each independently a bond or a self-immolative moiety; and

[0289] Bx1, Bx2, and Bx3are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

[0290] In certain embodiments, wherein V2is N and V2, T2, and B2together represent a branched moiety having a structure represented by formula (IILe-5) or a pharmaceutically acceptable salt thereof: wherein:

[0291] Ay3represents a linkage to L3;

[0292] Ly1and Ly2each independently comprise an alkylene;

[0293] Ty1and Ty2are each independently a bond, or a self-immolative moiety; and

[0294] By1and By2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

[0295] In certain embodiments, V2is CH and V2, T2, and B2together represent a branched moiety having a structure represented by formula (III-e-6) or a pharmaceutically acceptable salt thereof: wherein:

[0296] Ay3represents a linkage to L3;

[0297] Ly1and Ly2each independently comprise an alkylene;

[0298] Ty1and Ty2are each independently a bond or a self-immolative moiety; and

[0299] By1and By2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

[0300] In certain embodiments, V2is CH and V2, T2, and B2together represent a branched moiety having a structure represented by formula (III-e-7) or a pharmaceutically acceptable salt thereof: wherein:

[0301] Ay3represents a linkage to L3; and

[0302] Ly1and Ly2each independently comprise an alkylene; Gy1, Gy2, and Gy3are each independently an alkylene, each Ry1is independently H, alkyl, or aralkyl;

[0303] Ty1and Ty2are each independently a bond or a self-immolative moiety; and

[0304] By1and By2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

[0305] In certain embodiments, V2is C and V2, T2and B2together represent a branched moiety having a structure represented by formula (III-e-8) or a pharmaceutically acceptable salt thereof: wherein:

[0306] Ay3represents a linkage to L3;

[0307] Ly1, Ly2, and Ly3each independently comprise an alkylene;

[0308] Ty1, Ty2, and Ty3are each independently a bond or a self-immolative moiety; and

[0309] By1, By2, and By3are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

[0310] In certain embodiments, V3is N and V3, T3and D3together represent a branched moiety having a structure represented by formula (III-e-9) or a pharmaceutically acceptable salt thereof: wherein:

[0311] Az3represents a linkage to L5;

[0312] Lz1and Lz2each independently comprise an alkylene;

[0313] Tz1and Tz2are each independently a bond or a cleavage group; and Bz1and Bz2are each independently an active agent (e.g., a drug or a toxin).

[0314] In certain embodiments, V3is CH and V3, T3, and D3together represent a branched moiety having a structure represented by formula (III-e-10) or a pharmaceutically acceptable salt thereof: (iii-e-10) wherein:

[0315] Az3represents a linkage to L5;

[0316] Lz1and Lz2each independently comprise an alkylene;

[0317] Tz1and Tz2are each independently a bond or a self-immolative moiety; and

[0318] Bz1and Bz2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

[0319] In certain embodiments, V3is CH and V3, T3, and D3together represent a branched moiety having a structure represented by formula (III-e-7) or a pharmaceutically acceptable salt thereof: wherein:

[0320] Az3represents a linkage to L5;

[0321] Lz1and Lz2each independently comprise an alkylene;

[0322] Gz1, Gz2, and Gz3are each independently an alkylene, each Rz1is independently H, alkyl, or aralkyl;

[0323] Lz1and Lz2each independently comprise an alkylene;

[0324] Tz1and Tz2are each independently a bond or a self-immolative moiety; and

[0325] Bz1and Bz2are each independently an active agent (e.g., a drug or a toxin). In certain embodiments, V3is CH and V3, T3, and D3together represent a branched moiety having a structure represented by formula (III-e-12) or a pharmaceutically acceptable salt thereof: wherein:

[0326] Az3represents a linkage to L5;

[0327] Lz1, Lz2, and Lz3each independently comprise an alkylene;

[0328] Tz1, Tz2, and Tz3are each independently a bond or a self-immolative moiety; and

[0329] Bz1, Bz2, and Bz3are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

[0330] In certain embodiments, Ax3is a bond or C1-20 alkylene; Lx1and Lx2each independently comprises C1-20 alkylene and / or an oligoethylene glycol; Tx1and Tx2are each independently a bond or a cleavage group represented by structural formula (Ill-d); and Bx1and Bx2are each independently an active agent (e.g., a drug or a toxin).; wherein formula (Ill-d) is represented by:

[0331] Y is selected from - NHC(O)-, -#C(O)NH-, -#(CH2)tNHC(O)-, and -#COO-, R1is -CH2OR1A, or -CO2R1B;

[0332] R1Ais H or a hydroxyl protecting group;

[0333] R1Bis H or a carboxyl protecting group; each R2is independently H or a hydroxyl protecting group; t is 1, 2, or 3, preferably 1; indicates the point of attachment to Bx1or Bx2of formula (III-e-1, III-e-2, Ill-e-

[0334] 3, and III-e-4), respectively;

[0335] * indicates the point of attachment to the Lx1or Lx2of formula (III-e-1, III-e-2, III- e-3, and III-e-4) respectively; and

[0336] # indicates the point of attachment to the phenyl ring of formula (Ill-d).

[0337] In certain embodiments, wherein Lx1and Lx2are each independently Ci-6 alkylene and / or an oligoethylene glycol (e.g., oligoethylene glycol comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ethylene glycol moieties). In certain embodiments, Lx1and Lx2each independently further comprises an amido moiety. In certain embodiments, Lx1and Lx2each independently comprises 1, 2, 3, 4, 5, or 6 amido moieties. In certain embodiments, Lx1and Lx2each independently further comprises a heteroaryl (e.g., pyrazolyl, triazolyl).

[0338] In certain embodiments, Ay3is a bond or C1-20 alkylene; Ly1andLy2each independently comprises C1-20 alkylene and / or an oligoethylene glycol; Ty1and Ty2are each independently a bond or a cleavage group represented by structural formula (Ill-d); and By1and By2are each independently an active agent (e.g., a drug or a toxin).; wherein formula (Ill-d) is represented by:

[0339] Y is selected from - NHC(O)-, -#C(O)NH-, -#(CH2)tNHC(O)-, and -#COO-, R1is -CH2OR1A, or -CO2R1B;

[0340] R1Ais H or a hydroxyl protecting group;

[0341] R1Bis H or a carboxyl protecting group; each R2is independently H or a hydroxyl protecting group; t is 1, 2, or 3, preferably 1; indicates the point of attachment to By1or By2of formula (III-e-5, III-e-6, Ill-e- 7, and III-e-8), respectively;

[0342] * indicates the point of attachment to the Ly1or Ly2of formula ((III-e-5, III-e-6, III- e-7, and III-e-8) respectively; and # indicates the point of attachment to the phenyl ring of formula (III-d).

[0343] In certain embodiments, wherein Ly1and Ly2are each independently Ci-6 alkylene and / or an oligoethylene glycol (e.g., oligoethylene glycol comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ethylene glycol moieties). In certain embodiments, Ly1and Ly2each independently further comprises an amido moiety. In certain embodiments, Ly1and Ly2each independently comprises 1, 2, 3, 4, 5, or 6 amido moieties. In certain embodiments, Ly1and Ly2each independently further comprises a heteroaryl (e.g., pyrazolyl, triazolyl).

[0344] In certain embodiments, Az3is a bond or C1-20 alkylene; Lz1and Lz2each independently comprises C1-20 alkylene and / or an oligoethylene glycol; Tz1and Tz2are each independently a bond or a cleavage group represented by structural formula (III-d); and BXz1and BXz2are each independently an active agent (e.g., a drug or a toxin).; wherein formula (III-d) is represented by:

[0345] Y is selected from - NHC(O)-, -#C(O)NH-, -#(CH2)tNHC(O)-, and -#COO-, R1is -CH2OR1A, or -CO2R1B;

[0346] R1Ais H or a hydroxyl protecting group;

[0347] R1Bis H or a carboxyl protecting group; each R2is independently H or a hydroxyl protecting group; t is 1, 2, or 3, preferably 1; indicates the point of attachment to Bz1or Bz2of formula (III-e-9, III-e-10, III- e-11, and III-e-12), respectively;

[0348] * indicates the point of attachment to the Lz1or Lz2of formula (III-e-9, III-e-10, III- e-11, and III-e-12) respectively; and

[0349] # indicates the point of attachment to the phenyl ring of formula (III-d).

[0350] In certain embodiments, wherein Lz1and Lz2are each independently Ci-6 alkylene and / or an oligoethylene glycol (e.g., oligoethylene glycol comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ethylene glycol moieties). In certain embodiments, Lz1and Lz2each independently further comprises an amido moiety. In certain embodiments, Lz1and Lz2each independently comprises 1, 2, 3, 4, 5, or 6 amido moieties. In certain embodiments, Lz1and Lz2each independently further comprises a heteroaryl (e.g., pyrazolyl, triazolyl).

[0351] In certain embodiments, L1Acomprises *-(CH2CH2)-(OCH2CH2)I-2O-* *, wherein * indicates the point of attachment to the X3; and ** indicates the point of attachment to formula (II-OXMI) or (II-0XM2). In certain embodiments, L1Acomprises a moiety represented wherein * indicates the point of attachment to the X3of formula (III-TAB) and ** indicates the point of attachment to the remainder of LAB.

[0352] In certain such preferred embodiments, LABcomprises a moiety represented by structural formula (II): wherein:

[0353] Y is selected from - NHC(O)-, -#C(O)NH-, -#(CH2)tNHC(O)-, and -#COO-;

[0354] G is represented by one of the following structural formulas: wherein

[0355] R3is H, alkyl, CH2OR3A, or CO2R3B; each R4is independently H or a hydroxyl protecting group; R3Ais H or a hydroxyl protecting group; and

[0356] R3Bis H or a carboxyl protecting group; each Z is independently C1-5 alkyl, halogen, cyano, or nitro; nzis 0, 1, 2 or 3;

[0357] * indicates the point of attachment to the remainder of LAB; indicates the point of attachment to L2or V; and

[0358] # indicates the point of attachment to the phenyl ring.

[0359] In certain preferred embodiments, LABcomprises a moiety represented by structural formula (Ila): wherein:

[0360] Y is selected from - NHC(O)-, -#C(O)NH-, -#(CH2)tNHC(O)-, and -#COO-, R1is -CH2OR1A, or -CO2R1B;

[0361] R1Ais H or a hydroxyl protecting group;

[0362] R1Bis H or a carboxyl protecting group; each R2is independently H or a hydroxyl protecting group; t is 1, 2, or 3, preferably 1; indicates the point of attachment to L2or V;

[0363] * indicates the point of attachment to the remainder of LAB; and

[0364] # indicates the point of attachment to the phenyl ring.

[0365] In certain preferred embodiments, R1is -CH20R1A. In certain such preferred embodiments, R1Ais H. In certain preferred embodiments, R1is -COOR1B. In certain such preferred embodiments, R1Bis H.

[0366] In certain embodiments, LABcomprises a peptide.

[0367] In certain such embodiments, the peptide comprises at least one hydrophilic amino acid. In certain embodiments, the peptide comprises an amino acid having a side chain having a moiety that bears a charge at neutral pH in aqueous solution (e.g., an amine, guanidine, or carboxyl moiety).

[0368] In certain embodiments, the peptide comprises an amino acid selected from alanine, aspartate, asparagine, glutamate, glutamine, glycine, lysine, ornithine, proline, serine, histidine, arginine and threonine.

[0369] In certain embodiments, LABcomprises from 1 to 20 -OCH2CH2- moieties. In certain such embodiments, LABcomprises from 2 to 6 -OCH2CH2- moieties.

[0370] In certain preferred embodiments, LABcomprises a moiety represented by structural formula (lie): wherein:

[0371] L6is a linker,

[0372] Y is selected from - NHC(O)-, -#C(O)NH-, -#(CH2)tNHC(O)-, and -#COO-,

[0373] R3is -CH2OR1A, or -CO2R1B;

[0374] R1Ais H or a hydroxyl protecting group;

[0375] R1Bis H or a carboxyl protecting group; each R4is independently H or a hydroxyl protecting group; t is 1, 2, or 3, preferably 1;

[0376] ## indicates the point of attachment to L2or V, and

[0377] * indicates the point of attachment to the remainder of LAB.

[0378] In certain preferred embodiments, Y is - NHC(O)-, wherein # indicates the point of attachment to the phenyl ring. In other embodiments, Y is -#C(O)NH-, wherein # indicates the point of attachment to the phenyl ring.

[0379] In certain preferred embodiments, LABcomprises a moiety represented by structural formula (IV): wherein

[0380] Y is selected from - NHC(O)-, -#c(O)NH-, -#(CH2)tNHC(O)-, and -#COO-, wherein # indicates the point of connection to the phenyl;

[0381] D is an active agent, e.g., selected from a STING agonist, wherein the STING agonist is independently a structure represented by formula (la)), MMAE, ProMMAE, MMAF, taltobulin, Genz-644282, dasatinib and exatecan;

[0382] * indicates the point of attachment to the remainder of LABand

[0383] # indicates the point of attachment to L2or V.

[0384] In certain embodiments, wherein L6comprises: a C1-50 alkylene or C1-50 heteroalkylene wherein the C1-50 alkylene or C1-50 heteroalkylene comprises one or more of:

[0385] (i) one or more unsaturated bonds;

[0386] (ii) a heteroarylene (e.g., a heteroarylene in the alkylene or heteroalkylene chain);

[0387] (iii) at least one C1-20 alkyl substituent; and

[0388] (iv) at least one isoprenyl group having a structure represented by Formula (V):

[0389] In certain such embodiments, L6comprises a C1-50 alkylene. In other embodiments, L6comprises a C1-50 heteroalkylene. In certain embodiments, L6comprises an unsaturated bond (e.g., 1, 2, 3, 4 or 5 unsaturated bonds). In certain embodiments, L6is substituted with a C1-20 alkyl.

[0390] In certain embodiments, L6comprises an isoprenyl group having a structure represented by formula below: wherein nv is an integer of 1-20.

[0391] In certain embodiments, L6comprises a peptide comprising at least one hydrophilic amino acid and the nitrogen of Y forms a peptide bond with a carbonyl of a hydrophilic amino acid. In certain such embodiments, the hydrophilic amino acid comprises a side chain having a moiety which has electric charge in aqueous solution at a neutral pH in aqueous solution (e.g., an amine, guanidine, or carboxyl moiety).

[0392] In certain such embodiments, the hydrophilic amino acid is selected from arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine and threonine.

[0393] In certain embodiments, L6comprises a unit represented by structural formula (VI) or (VII)

[0394] -(CH2)r(L7(CH2)o)s- (VI),

[0395] -(CH2CH2L8)W- (VII); wherein:

[0396] L7is a single bond, -O-, -S-, -NR21-, -C(O)NR22-, -NR23C(O)-, -NR24SO2-, or - SO2NR25-, preferably -O-;

[0397] L8is -O-, Ci-8 alkylene, or -NR21-, preferably -O-;

[0398] R21to R25are each independently H, Ci-6 alkyl, Ci-6 alkyl(Ce-2o aryl), or Ci-6 alkyl(C3-2o heteroaryl); r is an integer of 0 to 10, preferably 2; o is an integer of 0 to 12, preferably 2; s is an integer of 1 to 20, preferably 2, 5, or 11; and w is an integer of 1 to 20, preferably 2 to 5.

[0399] In certain such embodiments, L7is -O-. In certain embodiments, L8is -O-. In certain embodiments, R21is H. In certain embodiments, R22is H. In certain embodiments, R23is H. In certain embodiments, R24is H. In certain embodiments, R25is H. In certain embodiments, r is 1 or 2. In certain embodiments, o is 1 or 2. In certain embodiments, s is 1 to 12, preferably 2, 5, or 11. In certain embodiments, w is 1 to 12, preferably 2 to 5. In certain embodiments, L6comprises at least one polyethylene glycol unit represented

[0400] In certain embodiments, L6comprises a unit represented by structural formula (Va), (Vb), (Vc), (Vd), or (Ve): wherein:

[0401] L9is a single bond or C1-30 alkylene; and

[0402] R11is H or Ci-10 alkyl.

[0403] In certain such embodiments, L9is a single bond. In other embodiments, L9is C1-30 alkylene. In certain embodiments, R11is H. In other embodiments, R11is C1-10 alkyl (e.g., methyl).

[0404] In certain embodiments, L6comprises: i) a branching unit covalently coupled to AB by a primary linker; ii) a first branch which couples a first D to the branching unit; and iiia) a second branch which couples a second D to the branching unit; or iiib) a second branch comprising an alkyl or heteroalkyl (e.g., a polyethylene glycol unit or a polyethylene glycol oligomer) is covalently coupled the branching unit.

[0405] In certain preferred embodiments, L6comprises a second branch which couples a second D, via a second cleavage group, to the branching unit. In certain such embodiments, L6comprises a second branch comprising an alkyl or heteroalkyl (e.g., a polyethylene glycol unit or a polyethylene glycol oligomer) coupled the branching unit.

[0406] In certain embodiments, the branching unit has a structure represented by formula (Via), (VIb), (Vic), or (Vid): wherein

[0407] G1, G2, G3are each independently a bond,

[0408] R30is H or alkyl;

[0409] R40is H, alkyl or L5’-CO2R50;

[0410] R50is H or alkyl; and

[0411] L2, L3, L4, and L5are each independently a bond or alkylene.

[0412] In certain embodiments, the branching unit has a structure represented by formula Vie: wherein R30is H or alkyl.

[0413] In certain embodiments, the branching unit has a structure represented by formula (Vif): wherein R30is H or alkyl. In certain embodiments, the conjugate comprises 1, 2, 3, or 4 branched linkers. In certain such embodiments, each branched linker comprises at least two active agents. In certain such embodiments, each branched linker comprises two active agents.

[0414] In certain embodiments, the branching unit comprises a lysine residue and the primary linker is bound to a C-terminus of lysine.

[0415] In certain embodiments, the conjugate is cleavable in a target cell (e.g., the conjugate cleaves to release one or more active agents).

[0416] In certain preferred embodiments, L6comprises a moiety represented by structural formula (Vf), (Vg), (Vh), (Vi) or (Vj):

[0417] wherein

[0418] D is an active agent independently selected from a STING agonist wherein the STING agonist is independently a structure represented by formula (la), MMAE, ProMMAE, MMAF, exatecan, taltobulin, Genz-644282, and dasatinib,

[0419] ** indicates the point of connection to Y, and

[0420] * indicates the point of connection to the remainder of LAB.

[0421] In certain preferred embodiments, D is a moiety represented by one of the following structural formulas:

[0422]

[0423]

[0424]

[0425]

[0426] wherein indicates the point of attachment to the remainder of LAB.

[0427] In certain embodiments, D is a moiety represented by one of the following structural formulas:

[0428]

[0429] , indicates the point of attachment to the remainder of LAB

[0430] In certain embodiments, D is a moiety represented by one of the following structural formulas: remainder of LAB.

[0431] In certain preferred embodiments, the conjugate comprises a structure selected from:

[0432] wherein indicates the point of attachment to the remainder of LAB.

[0433] In certain embodiments, the conjugate comprises a structure selected from:

[0434] wherein indicates the point of attachment to the remainder of LAB.

[0435] In certain embodiments, the conjugate comprises a structure selected from:

[0436] wherein indicates the point of attachment to the remainder of LAB.

[0437] In certain embodiments, the conjugate comprises a structure selected from:

[0438]

[0439] wherein indicates the point of attachment to the remainder of LAB.

[0440] In certain embodiments, the conjugate comprises a structure selected from:

[0441] wherein indicates the point of attachment to the remainder of LAB.

[0442] In certain embodiments, the conjugate comprises a structure selected from:

[0443] wherein ' indicates the point of attachment to the remainder of LAB.

[0444] In certain embodiments, the conjugate comprises a structure selected from:

[0445] wherein indicates the point of attachment to the remainder of LAB.

[0446] In certain embodiments, the conjugate comprises a structure selected from:

[0447] wherein indicates the point of attachment to the remainder of LAB.

[0448] In certain embodiments, the conjugate comprises a structure selected from:

[0449] wherein indicates the point of attachment to the remainder of LAB.

[0450] In certain embodiments, AB comprises a cysteine residue and LABis covalently connected to AB by a sulfur atom in the cysteine residue (e.g., by a sulfur atom in the side chain of the cysteine residue) via a thioether bond.

[0451] In certain embodiments, a C-terminus of AB comprises an amino acid motif that is recognized by an isoprenoid transferase.

[0452] In certain embodiments, the amino acid motif comprises a sequence of CY’Y’X’; wherein C is cysteine; each Y’ is independently an aliphatic amino acid; and X’ is selected from glutamine, glutamate, serine, cysteine, methionine, alanine and leucin. In certain embodiments, each Y’ is independently selected from alanine, isoleucine, leucine, methionine and valine. In certain embodiments, the amino acid motif comprises a sequence of CAAX’.

[0453] In certain embodiments, AB specifically binds to a target selected from:

[0454] (a) cell surface proteins or transmembrane proteins (e.g., receptors (e.g., growth factor receptors, cytokine receptors), cluster of differentiation (CD) markers, ion channels, and transporters);

[0455] (b) cytokines and chemokines (e.g., tumor necrosis factors, interferons, and growth factors);

[0456] (c) enzymes (e.g., proteases, kinases, phosphatases, and polymerases);

[0457] (d) hormones and hormone receptors (e.g., peptide hormones and steroid hormone receptors);

[0458] (e) pathogen-associated antigens (e.g., viral proteins, bacterial proteins, fungal antigens, and parasitic antigens);

[0459] (f) tumor-associated antigens (e.g., cancer / testis antigens, oncofetal antigens, and overexpressed or mutated proteins in cancer);

[0460] (g) extracellular matrix proteins (e.g., collagens, fibronectin, and laminins);

[0461] (h) intracellular proteins (e.g., transcription factors, signaling molecules, and structural proteins);

[0462] (i) toxins and venoms, (e.g., bacterial toxins and animal venoms);

[0463] (j) blood group antigens (e.g., ABO antigens and Rh antigens);

[0464] (k) autoantigens (e.g., nuclear antigens and cytoplasmic antigens);

[0465] (l) allergens (e.g., environmental allergens and food allergens);

[0466] (m) metabolites and small molecules (e.g., drugs and haptens);

[0467] (n) viral vectors and gene therapy components (e.g., capsid proteins and transgene products); and

[0468] (o) synthetic or engineered proteins (e.g., fusion proteins and chimeric proteins).

[0469] In certain embodiments, AB specifically binds to a cell surface protein or transmembrane protein, wherein the surface protein or transmembrane protein is selected from CD3, CD4, CD8, CD19, CD20, CD28, CD30, CD45, CD56, CD133, CD44, CD47, CD79b, CD80, CD86, DLK1, PD-1, PD-L1, CTLA-4, EGFR, HER2, Nectin-4, TR0P2, LI CAM, CCR5, CCR8, TIM-3 Siglec-15, B7-H7 (HHLA2) and CXCR4.

[0470] In certain embodiments, AB specifically binds to a cytokine or chemokine, wherein the cytokine or chemokine is selected from IL-ip, IL-2, IL-4, IL-6, IL-8 (CXCL8), IL- 10, IL-12, IL-17A, TNF-a, IFN-y, IFN-a, TGF-P, GM-CSF, MCP-1 (CCL2), MIP-la (CCL3), MIP-ip (CCL4), RANTES (CCL5), SDF-1 (CXCL12), CXCL10 (IP- 10), and Eotaxin (CCL11). In certain embodiments, AB specifically binds to a tumor-associated antigen, wherein the tumor-associated antigen is selected from B7-H4, B7-H7 (HHLA2), HER2, EGFR, MUC1, CEA (Carcinoembryonic Antigen), PSA (Prostate-Specific Antigen), CA19- 9, CA125, NY-ESO-1, WT1 (Wilms Tumor 1), MAGE-A1, MAGE-A3, Survivin (BIRC5), p53, MART-1 (Melan-A), gplOO (PMEL), Tyrosinase, GD2, CD20, CD19, PSMA (Prostate-Specific Membrane Antigen), CLDN18.2, Mesothelin, SSEA-4 (Stage-Specific Embryonic Antigen-4), BCMA (B-cell Maturation Antigen), CD22, CD33, CD138 (Syndecan-1), R0R1 (Receptor tyrosine kinase-like Orphan Receptor 1), GPC3 (Glypican- 3), TF (Tissue Factor), Lewis-Y and AFP (Alpha-fetoprotein).

[0471] In certain embodiments, AB is an anti-Lewis-Y antibody (e.g., hu3S193, or BR96). In certain embodiments, AB is an anti-Lewis-Y antibody in Table 1.

[0472] In certain embodiments, AB is an anti-EGFR antibody (e.g., cetuximab, panitumumab, necitumumab, or nimotuzumab). In certain embodiments, AB is an anti- EGFR antibody in Table 2.

[0473] In certain embodiments, AB is an anti-PD-1 antibody (e.g., pembrolizumab, nivolumab, pembrolizumab, cemiplimab, cemiplimab, nivolumab, dostarlimab, retifanlimab, toripalimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, MGA012, AMP -224, or AMP-514) In certain embodiments, AB is an anti-PD-1 antibody in Table 3.

[0474] In certain preferred embodiments, AB is an anti-PD-Ll antibody (e.g., atezolizumab, avelumab, durvalumab, or cosibelimab) In certain embodiments, AB is an anti-PD-Ll antibody in Table 4.

[0475] In certain embodiments, AB is an anti-TIM-3 antibody (e.g., LY3321367, MBG453, TSR-022, Sym023, BGBA425, R07121661, ICAGN02390, BMS-986258, or Sabatolimab). In certain embodiments, AB is an anti-TIM-3 antibody in Table 5.

[0476] In certain embodiments, AB is an anti-Siglec-15 antibody (e.g., NC318, or PYX- 106).

[0477] In certain embodiments, AB is an anti-B7-H7 antibody (e.g., NPX267, or HBM1020).

[0478] In certain embodiments, AB is an anti-HER2 antibody (e.g., trastuzumab, pertuzumab, sacituzumab, patritumab, or margetuximab). In certain embodiments, AB is an anti-HER2 antibody in Table 6. In certain embodiments, AB is an anti-RORl antibody (e.g., cirmtuzumab or zilovertamab). In certain embodiments, AB is an anti-RORl antibody in Table 7.

[0479] In certain embodiments, AB is an anti-CD19 antibody (e.g., tafasitamab, coltuximab, loncastuximab, MOR208, MEDI-551, denintuzumab mafodotin, taplitumomab paptox, XmAb 5871, MDX-1342, AFM11, or blinatumomab). In certain embodiments, AB is an anti-CD19 antibody in Table 8.

[0480] In certain embodiments, AB is an anti-LlCAM antibody (e.g., Ab417, or chCE7).

[0481] In certain embodiments, AB is an anti-CLDN18.2 antibody (e.g., claudiximab, zolbetuximab, ASKB589, or osemitamab). In certain embodiments, AB is an anti- CLDN18.2 antibody in Table 9.

[0482] In certain embodiments, AB is an anti-B7-H4 antibody (e.g., FPA150).

[0483] In certain embodiments, AB is an anti-DLKl antibody (e.g., CBA-1205).

[0484] In certain embodiments, AB is an anti-CCR8 antibody (e.g., BMS-986340, S- 531011, BAY3375968, or GS-1811).

[0485] In certain embodiments, AB is an anti-TROP2 antibody (e.g., datopotamab or sacituzumab). In certain embodiments, AB is an anti-TROP2 antibody in Table 10. Methods of Treatment

[0486] In certain aspects, the present disclosure provides methods of treating a disease in a subject in need thereof, comprising administering a conjugate of formula (I) or a pharmaceutical composition , wherein the disease is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease, and allergic disease.

[0487] In certain embodiments, the disease is an infectious disease.

[0488] In other embodiments, the disease is cancer. In certain such embodiments, the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi’s sarcoma, and melanoma. In certain aspects, the present disclosure provides a method of inducing an immune response in a subject in need thereof, comprising administering to the subject a conjugate of formula (I) or a pharmaceutical composition.

[0489] In certain such embodiments, the inducing of the immune response is effective to prevent or treat a disease in the subject.

[0490] In certain embodiments, the disease is cancer. In certain such embodiments, the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi’s sarcoma, and melanoma.

[0491] In certain aspects, the present disclosure provides pharmaceutical compositions comprising the antibody-drug conjugates disclosed herein or a pharmaceutically acceptable salt thereof.

[0492] In certain embodiments, the antibody is an anti-Lewis-Y antibody, an anti-EGFR antibody, an anti-PD-1 antibody, an anti-PD-Ll antibody, an anti-TIM-3 antibody, an anti- Siglec-15 antibody, an anti-B7-H7 antibody, an anti-HER2 antibody, an anti-RORl antibody, an anti-CD19 antibody, an anti-LlCAM antibody, an anti-CLDN18.2 antibody, an anti-TROP2 antibody, an anti-B7-H4 antibody, an anti-DLKl antibody, or an anti-CCR8 antibody, or an antigen-binding fragment thereof. In certain embodiments, the antibody is an antibody selected from the antibodies in Tables 1-10.

[0493] In certain embodiments, the antibody is a humanized, human, or chimeric antibody.

[0494] In certain embodiments, the antibody is a humanized antibody.

[0495] In certain embodiments, the humanized antibody comprises: (a) (i) a variable heavy chain framework region from a heavy chain of a human antibody or from a human consensus framework; and (ii) a variable light chain framework region from a light chain of a human antibody or from a human consensus framework. In some embodiments, at least one amino acid in the variable domain framework region from the heavy chain is substituted with the corresponding amino acid from a heavy chain of a mouse antibody or mouse consensus framework; or the variable domain framework region from the light chain is substituted with the corresponding amino acid from a light chain of a mouse antibody or mouse consensus framework. In certain embodiments, the humanized antibody comprises: (a) (i) a variable heavy chain framework region from a heavy chain of a human antibody or from a human consensus framework; and (ii) a variable light chain framework region from a light chain of a human antibody or from a human consensus framework..

[0496] In certain embodiments, the antibody or antigen-binding fragment thereof may be selected from the group consisting of a monoclonal antibody, a domain antibody (dAb), a single chain antibody (scAb), a Fab fragment, a Fab' fragment, a F(ab')2 fragment, an scFab fragment, an Fv fragment, a dsFv fragment, a single chain variable fragment (scFv), an scFv- Fc fragment, a single domain heavy chain antibody, a single domain light chain antibody, a variant antibody, a multimeric antibody, a minibody, a diabody, a bispecific antibody, and a multispecific antibody. In certain embodiments, the antibody or antigen-binding fragment thereof may be a monoclonal antibody, a single chain antibody (scAb), a Fab fragment, a F(ab’)2 fragment, a single chain variable fragment (scFv), a scFv-Fc fragment, a multimeric antibody, or a bispecific antibody. In certain embodiments, the antibody or antigen-binding fragment thereof may be a chimeric, humanized or fully human monoclonal antibody. In certain embodiments, the antibody is an IgG isotype. In certain embodiments, the antibody is an IgGl isotype. In certain embodiments, the antibody comprises a N297A substitution according to EU numbering convention. In certain embodiments, the antibody comprises L234A and L235A substitutions according to EU numbering convention. In certain embodiments, the antibody comprises a P329G substitution or a P329A substitution according to EU numbering convention. In certain embodiments, the antibody is an IgG4 isotype. In certain embodiments, the antibody comprises a S228P substitution according to EU numbering convention.

[0497] Linker

[0498] The linkers LABdescribed herein may be cleavable, non-cleavable and hydrophilic or hydrophobic.

[0499] In certain embodiments, the cleavable linker is cleavable under intracellular or extracellular conditions, by which an active agent is released from an antibody constructactive agent conjugate in the intracellular environment.

[0500] The cleavable linker can be cleaved by a cleaving agent present in an intracellular environment (e.g., lysosomes, endosomes, or caveolea). The cleavable linker may be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not being limited to, a lysosomal or endosomal protease. Generally, the peptidyl linker has a length of at least two amino acids or a length of at least three amino acids. Cleaving agents may include cathepsin B, cathepsin D, and plasmin, all of which are known to hydrolyze dipeptide drug derivatives to release an active drug in target cells (e.g., see Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123). The most common are peptidyl linkers cleavable by enzymes present in antigen-expressing cells. For example, peptidyl linkers cleavable by thiol-dependent protease cathepsin-B, which is highly expressed in cancer tissue, may be used (e.g., a Phe-Leu or Gly-Phe-Leu-Gly linker). Other examples of these linkers are described in, for example, U.S. Patent No. 6,214,345. In addition, the peptidyl linker cleavable by an intracellular protease may be, for example, a Val-Cit linker, a Phe-Lys linker (e.g., see U.S. Patent No. 6,214,345, which describes the synthesis of doxorubicin using a Val-Cit linker), or a Vai-Ala linker. The Val-Cit linker or the Vai-Ala linker may contain a pentafluorophenyl group, and may contain a succinimide group or a maleimide group. Alternatively, the Val-Cit linker or the Vai-Ala linker may contain a pentafluorophenyl group, may contain a 4-aminobenzoic acid (PABA) group and a maleimide group, and may contain a PABA group and a succinimide group.

[0501] In addition, a cleavable linker may be easily hydrolyzed in a pH-sensitive manner, i.e., at certain pH values. Generally, the pH-sensitive linker may be hydrolyzed under acidic conditions. For example, acid-labile linkers that can be hydrolyzed in lysosomes (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconic amides, orthoesters, acetals, and ketals) may be used (e.g., see: U.S. Patent NOs. 5,122,368, 5,824,805, and 5,622,929; and Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; and Neville et al., 1989, Biol. Chem. 264: 14653-14661). These linkers are relatively stable under neutral pH conditions, such as in blood, but are unstable at pH 5.5, which is the approximate pH of lysosomes, or less than pH 5.0. Examples of hydrolysable linkers include thioether linkers (e.g., thioethers attached to a therapeutic agent via an acylhydrazone bond) (e.g., see U.S. Patent No. 5,622,929).

[0502] Also, the linker is cleavable under reducing conditions (e.g., a disulfide linker). For example, various disulfide linkers including N-succinimidyl-5-acetylthioacetate (SATA), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl-3-(2- pyridyldithio)butyrate (SPDB), and N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2- pyridyl-thio)toluene)- (SMPT), and those that can be formed using SPDB and SMPT (e.g., see: Thorpe et al., 1987, Cancer Res. 47:5924-5931; and U.S. Patent No. 4,880,935).

[0503] In addition, the linker may be a malonate linker (Johnson et al., 1995, Anticancer Res. 15: 1387-93), a maleimidobenzoyl linker (Lau et al., 1995, Bioorg-Med-Chem. 3(10): 1299-1304), a 3'-N-amide analogue (Lau et al., 1995, Bioorg-Med-Chem. 3(10): 1305- 12), a P-glucuronide linker (Jeffery et al., 2006, Bioconjug Chem. 17(3):832-40), or a P- galactoside linker (Kolodych et al., 2017, Eur J Med Chem. Dec 15;142:376-382).

[0504] The non-cleavable linker may be a maleimidocaproyl linker. The maleimidocaproyl linker may include N-maleimidomethylcyclohexane-1 -carboxylate. The maleimidocaproyl linker may contain a succinimide group. The maleimidocaproyl linker may contain a pentafluorophenyl group. The linker may be a combination of a maleimide group and one or more polyethylene glycol molecules. The linker may be a combination of a maleimidocaproyl group and one or more polyethylene glycol molecules. The linker may be a maleimide-PEG4 linker. The linker may be a combination of a maleimidocaproyl linker containing a succinimide group and one or more polyethylene glycol molecules. The linker may be a combination of a pentafluorophenyl group and a maleimidocaproyl linker containing one or more polyethylene glycol molecules. The linker may contain a maleimide linked to a polyethylene glycol molecule, wherein the polyethylene glycol allows for more linker flexibility or allows longer linkers to be used. The linker may be a (maleimidocaproyl)-(valine-citrulline)-(para-aminobenzyloxycarbonyl) linker.

[0505] In certain embodiments, the linker may be a cleavable linker.

[0506] In certain embodiments, the linker may be a protease cleavable linker, an acid- cleavable linker, a disulfide linker, a self-immolative linker or a self-stabilizing linker, a malonate linker, a maleimidobenzoyl linker, a 3'-N-amide analogue, a P-glucuronide linker, or a P-galactoside linker.

[0507] In certain embodiments, the protease cleavable linker may include a thiol -reactive spacer or a dipeptide, and more specifically, the protease cleavable linker may include a thiol -reactive maleimidocaproyl spacer, a valine-citrulline dipeptide, or a p-amino- benzyloxycarbonyl spacer.

[0508] In certain embodiments, the acid-cleavable linker may be a hydrazine linker or a quaternary ammonium linker.

[0509] In certain embodiments, the linker LABmay have a structure of General Formula Ila’ . [General Formula Ila’] wherein: in General Formula Ila’, a wave symbol is a site that is linked to an antibody, and * is a site that is linked to an active agent;

[0510] G is a glucuronic acid moiety

[0511] R3is H, alkyl, CH2OR3A, or CO2R3B;

[0512] R3Ais H or a hydroxyl protecting group; and

[0513] R3Bis H or a carboxyl protecting group; each of R4is independently hydrogen or a hydroxyl-protecting group ;Rrand R2are each independently hydrogen, Ci-8 alkyl, or C3-8 cycloalkyl;

[0514] Ywis -C(O)-, -C(O)NRW'-, -C(O)O-, -S02NRw'-, -P(O)RW"NRW', -SONRW'-, or - P02NRWl-, wherein C, S, or P is directly bonded to a phenyl ring, and RWland Rw" are each independently hydrogen, C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C1-8 alkylthio, mono- or di-Ci-8 alkylamino, C3-2o heteroaryl, or Ce-2o aryl;

[0515] Z is independently hydrogen, C1-8 alkyl, halogen, cyano, or nitro; nzis 0 to 3; and

[0516] YLis any one selected from A) or B) below:

[0517] A) Ci-50 alkylene or 1- to 50-membered heteroalkylene, satisfying at least one of the following:

[0518] (i) YLincludes one or more unsaturated bonds;

[0519] (ii) two atoms in YLare substituted with a divalent substituent, which completes a heteroarylene; (iii) YLis a 1- to 50-membered heteroalkylene;

[0520] (iv) the alkylene is substituted with at least one C1-20 alkyl; and

[0521] B) comprises at least one isoprenyl derivative unit of General Formula Illa’ below which can be recognized by an isoprenoid transferase:

[0522] [Formula Illa’]

[0523] In certain embodiments, the conjugate may have a structure of General Formula Ila”.

[0524] [General Formula Ila”]

[0525] [General Formula Ila”] wherein each X is an active agent; each G is independently a glucuronic acid moiety

[0526] R3is H, alkyl, CH2OR3A, or CO2R3B;

[0527] R3Ais H or a hydroxyl protecting group; and

[0528] R3Bis H or a carboxyl protecting group; each R4is independently hydrogen or a hydroxyl-protecting group;

[0529] R1and R2are each independently hydrogen, Ci-s alkyl, or C3-8 cycloalkyl; Ywis -C(O)-, -C(O)NRW'-, -C(O)O-, -SO2NRW'-, -P(O)RW"NRW', -SONRW'-, or -

[0530] PC>2NRW'-, wherein the C, S, or P is directly bonded to the phenyl ring of Formula Ila"; and Rwand Rware each independently hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C1-8 alkylthio, mono- or di-Ci-8 alkylamino, C3-20 heteroaryl, or C6-20 aryl; each Z is independently hydrogen, C1-8 alkyl, halogen, cyano, or nitro; nzis 0, 1, 2, or 3;

[0531] YLcomprises:

[0532] A) Ci-50 alkylene or C1-50 heteroalkylene and comprises

[0533] (i) one or more unsaturated bonds

[0534] (ii) a heteroarylene; or

[0535] (iii) is substituted with at least one C1-20 alkyl; or

[0536] B) at least one isoprenyl group having a structure represented by General Formula

[0537] Illa’ :

[0538] [General Formula Illa’]

[0539] 1 and nDLare each independently 1 to 20.

[0540] The present disclosure also provides a conjugate represented by General Formula Ila” below or a pharmaceutically acceptable salt or solvate thereof:

[0541] [General Formula Ila”] wherein

[0542] AB is an antibody or antigen-binding fragment thereof; each X is an active agent; each G is independently a glucuronic acid moiety

[0543] R3is H, alkyl, CH2OR3A, or CO2R3B;

[0544] R3Ais H or a hydroxyl protecting group; and

[0545] R3Bis H or a carboxyl protecting group; each R4is independently hydrogen or a hydroxyl-protecting group;

[0546] R1and R2are each independently hydrogen, Ci-s alkyl, or C3-8 cycloalkyl;

[0547] Ywis -C(O)-, -C(O)NRW'-, -C(O)O-, -SO2NRW'-, -P(O)RW"NRW', -SONRW'-, or - PO2NRWl-, wherein the C, S, or P is directly bonded to the phenyl ring of Formula Ila"; RWland Rw" are each independently hydrogen, C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C1-8 alkylthio, mono- or di-Ci-8 alkylamino, C3-2o heteroaryl, or Ce-2o aryl; each Z is independently hydrogen, C1-8 alkyl, halogen, cyano, or nitro; nzis 0, 1, 2, or 3;

[0548] YLcomprises:

[0549] A) Ci-50 alkylene or C1-50 heteroalkylene and comprises

[0550] (i) one or more unsaturated bonds

[0551] (ii) a heteroarylene; or

[0552] (iii) is substituted with at least one C1-20 alkyl; or

[0553] B) at least one isoprenyl group having a structure represented by General Formula Illa’ :

[0554] [General Formula Illa’]

[0555] 1 and nDLare each independently 1 to 20.

[0556] In certain embodiments, the antibody or antigen-binding fragment thereof is selected from a monoclonal antibody, a domain antibody (dAb), a single chain antibody (scAb), a Fab fragment, a Fab' fragment, a F(ab')2 fragment, an scFab fragment, an Fv fragment, a dsFv fragment, a single chain variable fragment (scFv), an scFv-Fc fragment, a single domain heavy chain antibody, a single domain light chain antibody, a variant antibody, a multimeric antibody, a minibody, a diabody, a bispecific antibody, and a multispecific antibody.

[0557] In certain preferred embodiments, each .

[0558] In certain embodiments, R1and R2are each hydrogen.

[0559] In certain embodiments, R3is hydrogen, alkyl, CH2OR3A, or CChR38

[0560] R3Ais H or a hydroxyl protecting group; and

[0561] R3Bis H or a carboxyl protecting group;

[0562] In certain embodiments, each R4is a hydroxyl-protecting group.

[0563] In certain preferred embodiments, nzis 0.

[0564] In certain preferred embodiments, each Ywis -C(O)NRW’-, further wherein the C is directly bonded to the phenyl ring of Formula Ila”, and NRW’ is bonded to YL.

[0565] In certain preferred embodiments, each R4is independently hydrogen.

[0566] In certain preferred embodiments, R1and R2are each hydrogen; nzis 0; and each Ywis -C(O)NRW’-, C is directly bonded to the phenyl ring of Formula Ila”, and Rw’ is hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C1-8 alkylthio, mono- or di-Ci-8 alkylamino, C3-20 heteroaryl, or C6-20 aryl, wherein NR’ is bonded to YL.

[0567] In certain embodiments, YLcomprises a nitrogen-containing 1- to 50-membered heteroalkylene. In certain embodiments, YLcomprises a hydrophilic amino acid. In certain embodiments, Ywcomprises two or more atoms of the hydrophilic amino acid, and the nitrogen of Ywforms a peptide bond with a carbonyl of the hydrophilic amino acid.

[0568] In certain embodiments, YLis covalently bonded to the antibody or antigen-binding fragment thereof by a thioether bond and the thioether bond comprises a sulfur atom of a cysteine of the antibody or antigen-binding fragment thereof .

[0569] In certain embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid motif recognizable by an isoprenoid transferase at the C-terminus of the antibody or antigen-binding fragment thereof, and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.

[0570] In certain preferred embodiments, the amino acid motif has a CYYX sequence, further wherein:

[0571] C is cysteine;

[0572] Y is an aliphatic amino acid;

[0573] X is selected from glutamine, glutamate, serine, cysteine, methionine, alanine, and leucine; and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.

[0574] In certain preferred embodiments, the amino acid motif has a CYYX sequence further wherein:

[0575] Y is selected from alanine, isoleucine, leucine, methionine, and valine.

[0576] In certain preferred embodiments, the amino acid motif has a CVIM (SEQ ID NO: 208) or CVLL sequence (SEQ ID NO: 209).

[0577] In certain embodiments, at least one of 1 to 20 amino acids preceding the amino acid motif is glycine.

[0578] In certain preferred embodiments, YLcomprises the amino acid sequence of GGGGGGGCVIM at the C-terminus (SEQ ID NO: 210).

[0579] In certain preferred embodiments, YLcomprises an oxime. In certain embodiments, the oxygen atom of the oxime is on the side of YLlinked to W and the carbon atom of the oxime is on the side of YLlinked to AB. In certain embodiments, the carbon atom of the oxime is on the side of YLlinked to W and the oxygen atom of the oxime is on the side of YLlinked to AB.

[0580] In certain embodiments, YLis a C1-50 heteroalkylene containing an oxime, the oxygen atom of the oxime is on the side of YLlinked to W, the carbon atom of the oxime is on the side of YLlinked to AB, or the carbon atom of the oxime is on the side of YLlinked to W, and the oxygen atom of the oxime is on the side of YLlinked to AB.

[0581] In certain preferred embodiments, YLcomprises an oxime, and at least one isoprenyl unit covalently bonds the oxime to AB (e.g., at least one isoprenyl unit directly or indirectly bonds the oxime to AB). In certain preferred embodiments, YLcomprises or , wherein n40 is 1 - 10, preferably at least 2.

[0582] In certain embodiments, YLcomprises an oxime, and at least one polyethylene glycol unit covalently bonds the oxime to an active agent.

[0583] In certain embodiments, the oxygen atom of the oxime is on the side of YLlinked to Ywand the carbon atom of the oxime is on the side of YLlinked to AB. In certain embodiments, the carbon atom of the oxime is on the side of YLlinked to Ywand the oxygen atom of the oxime is on the side of YLlinked to AB.

[0584] In certain preferred embodiments, YLis a C1-50 heteroalkylene containing an oxime, the oxygen atom of the oxime is on the side of YLlinked to Yw, the carbon atom of the oxime is on the side of YLlinked to AB, or the carbon atom of the oxime is on the side of YLlinked to Yw, and the oxygen atom of the oxime is on the side of YLlinked to AB.

[0585] In certain preferred embodiments, YLcomprises an oxime, and at least one isoprenyl unit covalently bonds the oxime to AB (e.g., at least one isoprenyl unit directly or indirectly bonds the oxime to AB).

[0586] In certain embodiments, YLcomprises a binding unit formed by a reaction between an alkyne and an azide or between an aldehyde or ketone group and hydrazine or hydroxylamine.

[0587] In some embodiments, the linker YLis covalently bound to AB by a thioether bond. In some preferred embodiments, AB comprises a C-terminal amino acid motif that is recognized by an isoprenoid transferase; and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.

[0588] In some preferred embodiments, AB comprises an amino acid motif recognizable by an isoprenoid transferase. In some embodiments, AB further comprises a spacer unit comprising an amino acid, an oligopeptide, or a polypeptide between AB and the amino acid motif. In some embodiments, AB is covalently bonded to the linker YLthrough the amino acid motif.

[0589] In some embodiments, AB of the conjugate is modified to have a point of attachment which enables AB to react with the linker moiety. In certain embodiments, the linker YLcomprises a linking moiety formed by a 1,3- dipolar cycloaddition reaction, hetero-Di els- Alder reaction, nucleophilic substitution reaction, non-aldol type carbonyl reaction, addition to carbon-carbon multiple bond, oxidation reaction, or click reaction.

[0590] In certain preferred embodiments, the cleavage group is cleavable in a target cell and is capable of releasing one or more active agents.

[0591] In certain embodiments, at least one branched linker is covalently coupled to AB; and at least two active agents are covalently coupled to the branched linker. In certain embodiments, one branched linker is coupled to AB. In certain embodiments, two branched linkers are coupled to AB. In certain embodiments, three branched linkers are coupled to AB. In certain embodiments, four branched linkers are coupled to AB. In certain embodiments, each branched linker is coupled to two active agents. In certain embodiments, the conjugate comprises at least two different active agents. In certain embodiments, at least one branched linker is coupled to two different active agents.

[0592] In certain embodiments, the branching unit is a nitrogen atom. In other embodiments, the branching unit is an amide and the primary linker comprises the carbonyl of the amide. In yet other embodiments, the branching unit is an amide and the secondary linker comprises the carbonyl of the amide. In certain preferred embodiments, the branching unit is lysine.

[0593] In certain embodiments, AA refers to an amino acid group. In certain embodiments, AA refers to an amino acid group in which one or more amino acids are bonded.

[0594] In certain embodiments, i) the linker includes a peptide sequence of multiple amino acids; and ii) at least two active agents are covalently bonded to the side chain of an amino acid.

[0595] In certain embodiments, the amino acid group is a group by main-chain linkage or side-chain linkage of 1 to 20 amino acids.

[0596] In certain embodiments, the amino acid group is a group by main-chain linkage or side-chain linkage of 1 to 20 arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine or threonine residue(s).

[0597] In certain embodiments the amino acid group is a group by main-chain linkage or side-chain linkage of 1 to 20 arginine, aspartate, glutamate, lysine or ornithine residue(s).

[0598] In certain embodiments, the amino acid group includes 1 to 20 amino acids, e.g., at least one lysine. In certain embodiments, the amino acid group comprises main-chain or side-chain linkage of lysine.

[0599] Exemplary antibody drug conjugates, which contain certain linkers and antibodies, are disclosed in US 10,583,197, US 9,993,568, US 9,951,072, US 9,919,057, US 9,669,107, US 11,413,353, US 11,173,214, US 11,167,040, US 10,980,890, US 10,583,197, US 10,383,949, US 10,273,235, US 10,183,997, and US 10,118,965, the contents of each of which is fully incorporated by reference herein. Additional conjugates related to this structure, which contain certain linkers and antibodies as well as detailed preparation methods, are disclosed in US 9,919,057, US 9,993,568, US 10,980,890 and US 11,413,353; the contents of each of which is fully incorporated by reference herein.

[0600] Additional conjugates related to this structure, as well as detailed preparation methods, are disclosed in US 11,173,214 and US 11,167,040; the contents of each of which is fully incorporated by reference herein.

[0601] In certain embodiments, the term "active agent moiety" as used herein refers to a compound that comprises an active agent and covalent bonds which bond the active agent to a linker or a part thereof.

[0602] In the present disclosure, the active agent moiety may be directly bonded to the linker, and one or more, particularly, two or more, three or more, or four or more active agent moieties may be directly bonded to the linker.

[0603] In certain embodiments, active agents are each independently selected from a chemotherapeutic agent and a toxin.

[0604] In addition, the active agent may be an immunomodulatory compound, an anticancer agent, an anti-viral agent, an antibacterial agent, an antifungal agent, an antiparasitic agent, or a combination thereof, and may be selected for use from active agents listed below: (a) erlotinib, bortezomib, fulvestrant, sunitinib, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodepa, carboquone, meturedepa, uredepa, ethylenimine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, bullatacin, bullatacinone, topotecan, bryostatin, callystatin, CC-1065, adozelesin, carzelesin, bizelesin, cryptophy cin 1, cryptophy cin 8, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancrati statin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A, clodronate, neocarzinostatin chromophore, aclacinomysins, actinomycin, antimycin, azaserine, bleomycins, cactinomycin, carabicin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubucin, 6-diazo-5- oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin, liposomal doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, , denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6- mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone, propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, folinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfornithine, elliptinium acetate, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, 2-ethylhydrazide, procarbazine, polysaccharide-k, razoxane, sizofiran, spirogermanium, tenuazonic acid, triaziquone, 2, 2', 2"-tri chlorotri ethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, arabinoside, albumin-engineered nanoparticle formulation of paclitaxel, docetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin , vinblastine, platinum, etoposide, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, ibandronate, CPT-11, topoisomerase inhibitor RFS 2000, difluoromethylornithine, retinoic acid, capecitabine, or a pharmaceutically acceptable salt, solvate or acid thereof;

[0605] (b) monokines, lymphokines, traditional polypeptide hormones, parathyroid hormones, thyroxine, relaxin, prorelaxin, glycoprotein hormone, follicle stimulating hormone, thyroid stimulating hormone, luteinizing hormone, hepatic growth factor fibroblast growth factor, prolactin, placental lactogen, tumor necrosis factor, tumor necrosis factor-a, tumor necrosis factor-P, mullerian inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, thrombopoietin, erythropoietin, osteoinductive factor, interferon, interferon- a, interferon-P, interferon-y, colony stimulating factor (CSF), macrophage-CSF, granulocyte-macrophage-CSF, granulocyte-CSF, interleukin (IL), IL-1, IL-la, IL- 2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL- 11, IL-12, polypeptide factor, LIF, kit ligand, or a combination thereof;

[0606] (c) diphtheria toxin, botulinum toxin, tetanus toxin, decentretoxin, cholera toxin, amanitin, a-amanitin, pyrrolobenzodiazepine, pyrrolobenzodiazepine derivative, indolinobenzodiazepine, pyridinobenzodiazepine, tetrodotoxin, brevetoxin, ciguatoxin, ricin, AM toxin, auristatin, tubulysin, geldanamycin, maytansinoid, calicheamycin, daunomycin, doxorubicin, methotrexate, vindesine, SG2285, dolastatin, dolastatin analog, auristatin, cryptophycin, camptothecin, rhizoxin, rhizoxin derivatives, CC-1065, CC-1065 analogs or derivatives, enediyne antibiotics, esperamicin, epothilone, toxoid, or a combination thereof;

[0607] (d) an affinity ligand, wherein the affinity ligand is a substrate, an inhibitor, an active agent, a neurotransmitter, a radioisotope, or a combination thereof;

[0608] (e) a radioactive label,32P,35S, a fluorescent dye, an electron dense reagent, an enzyme, biotin, streptavidin, digoxigenin, hapten, an immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or a combination thereof;

[0609] (f) an immunomodulatory compound, an anticancer agent, an anti-viral agent, an antibacterial agent, an anti-fungal agent, an anti-parasitic agent, or a combination thereof;

[0610] (g) tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, LY117018, onapri stone, or toremifene;

[0611] (h) 4(5)-imidazole, megestrol acetate, exemestane, letrozole, or anastrozole; (i) flutamide, nilutamide, bicalutamide, leuprolide, goserelin, or troxacitabine;

[0612] (j) an aromatase inhibitor;

[0613] (k) a protein kinase inhibitor;

[0614] (l) a lipid kinase inhibitors

[0615] (m) an antisense oligonucleotide;

[0616] (n) a ribozyme;

[0617] (o) a vaccine; and

[0618] (p) an anti -angiogenic agent.

[0619] In certain embodiments, the active agent is the wavy line is a connection point to the conjugate.

[0620] In certain aspects, the present disclosure also provides pharmaceutical compositions for the prevention or treatment of hyperproliferation, cancer, or an angiogenic disease, including the conjugate. In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically effective amount of a chemotherapeutic agent.

[0621] In certain embodiments, the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi’s sarcoma, and melanoma.

[0622] The present disclosure also provides a pharmaceutical preparation comprises the conjugate.

[0623] Antibody or Antigen-Binding Fragment thereof

[0624] The present disclosure provides conjugates having a structure represented by Formula I: wherein:

[0625] AB is an antibody or antigen-binding fragment thereof;

[0626] LABis an antibody linker; nDis an integer selected from 1-10; nDLis an integer selected from 1-10; and each D is independently an active agent (e.g., a drug, a toxin, an immune modulator), wherein at least one D is a STING agonist, each such STING agonist independently selected from a moiety represented by structural formula (la).

[0627] As described herein, the antibody according to the present disclosure is a polypeptide comprising one or more complementarity-determining areas or regions (CDRs).

[0628] In some embodiments, the CDR is included in a “framework” region, and the framework orients the CDR(s) so that the CDR(s) can have appropriate antigen-binding properties.

[0629] AB may be an anti-Lewis-Y antibody or antigen-binding fragment thereof.

[0630] The Lewis-Y antigen is a member of a family of blood-related antigens, and its expression is restricted to granulocytes and epithelial surfaces in adults. It is expressed on the surface of 60%-90% of carcinomas. The Lewis-Y antigen is expressed in 44%-90% of

[0631] Ill breast cancer (BC) cases. In addition, its expression in cases of BC is correlated with a worse prognosis and a more advanced disease stage.

[0632] Although the Lewis-Y antigen is expressed in both normal and neoplastic cells, its expression distribution differs between the two tissue types. Expression in normal epithelial tissue is restricted to the secretory borders of epithelial surfaces, making it less accessible to the circulation. In contrast, the expression of the antigen is very high on all surfaces of carcinoma cells, including luminal surfaces. This differentiated expression pattern is the target for treatment with monoclonal antibodies.

[0633] The anti -Lewis-Y antibody may be hu3S193, or BR96. The murine monoclonal antibody 3S193 was developed to recognize the Lewis-Y antigen of the MCF-7 breast carcinoma cell line (Laura Testa, et al., Clinics (Sao Paulo). 2021; 76: e3146). The murine 3S193 antibody was specific to the Lewis-Y antigen and reactive against cells expressing the antigen. Therefore, a humanized immunoglobulin G monoclonal antibody, hu3S193, was developed for in-human studies. Studies in nude mice bearing human lung carcinoma xenografts of BR96, demonstrated that murine and chimeric BR96 were able to prevent or slow growth when administered soon after cell implantation (Scheiber G., et al., Cancer Res., 52: 3262-3266, 1992.).

[0634] In some embodiments, the anti-Lewis-Y antibody or antigen-binding fragment thereof comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,

[0635] (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 211;

[0636] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 212;

[0637] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 213;

[0638] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 214;

[0639] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 215; and

[0640] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 216.

[0641] In some embodiments, the anti-Lewis Y antibody or antigen-binding fragment thereof comprises a combination of a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 217, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 218.

[0642] Table 1. Anti-Lewis- Y antibody sequences

[0643] AB may be an anti-EGFR antibody or antigen-binding fragment thereof.

[0644] The human epidermal growth factor receptor is a 170 kDa transmembrane receptor encoded by the c-erbB protooncogene, and exhibits intrinsic tyrosine kinase activity (Modjtahedi et al., Br. J. Cancer 73:228-235 (1996); Herbst and Shin, Cancer 94: 1593-1611 (2002)). SwissProt database entry P00533 provides the sequence of human EGFR. EGFR regulates numerous cellular processes via tyrosine-kinase mediated signal transduction pathways, including, but not limited to, activation of signal transduction pathways that control cell proliferation, differentiation, cell survival, apoptosis, angiogenesis, mitogenesis, and metastasis (Atalay et al., Ann. Oncology 14: 1346-1363 (2003); Tsao and Herbst, Signal 4:4-9 (2003); Herbst and Shin, Cancer 94: 1593-1611 (2002); Modjtahedi et al., Br. J. Cancer 73:228-235 (1996)).

[0645] Known ligands of EGFR include EGF, TGFA / TGF-alpha, amphiregulin, epigen / EPGN, BTC / betacellulin, epiregulin / EREG and HBEGF / heparin-binding EGF. Ligand binding by EGFR triggers receptor homo- and / or heterodimerization and autophosphorylation of key cytoplasmic residues. The phosphorylated EGFR recruits adapter proteins like GRB2 which in turn activate complex downstream signaling cascades, including at least the following major downstream signaling cascades: the RAS-RAF-MEK- ERK, PI3 kinase-AKT, PLCgamma-PKC, and STATs modules. This autophosphorylation also elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signal transduction cascades, principally the MAPK, Akt and JNK pathways, leading to cell proliferation. Ligand binding by EGFR may also activate the NF-kappa-B signaling cascade. Ligand binding also directly phosphorylates other proteins like RGS16, activating its GTPase activity and potentially coupling the EGF receptor signaling to G protein-coupled receptor signaling. Ligand binding also phosphorylates MUC1 and increases its interaction with SRC and CTNNB 1 / beta-catenin.

[0646] Overexpression of EGFR has been reported in numerous human malignant conditions, including cancers of the bladder, brain, head and neck, pancreas, lung, breast, ovary, colon, prostate, and kidney. (Atalay et al., Ann. Oncology 14: 1346-1363 (2003); Herbst and Shin, Cancer 94: 1593-1611 (2002); and Modjtahedi et al., Br. J. Cancer 73:228- 235 (1996)). In many of these conditions, the overexpression of EGFR correlates or is associated with poor prognosis of the patients. (Herbst and Shin, Cancer 94: 1593-1611 (2002); and Modjtahedi et al., Br. J. Cancer 73:228-235 (1996)). EGFR is also expressed in the cells of normal tissues, particularly the epithelial tissues of the skin, liver, and gastrointestinal tract, although at generally lower levels than in malignant cells (Herbst and Shin, Cancer 94: 1593-1611 (2002)).

[0647] In some embodiments, the anti-EGFR antibody or antigen-binding fragment thereof may be cetuximab, panitumumab, necitumumab, or nimotuzumab.

[0648] In some embodiments, the anti-EGFR antibody or antigen-binding fragment thereof comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,

[0649] (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 221;

[0650] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 222;

[0651] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 223;

[0652] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 224;

[0653] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 225; and

[0654] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 226.

[0655] In some embodiments, the anti-EGFR antibody or antigen-binding fragment thereof comprises a combination of a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 227, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 228.

[0656] Table 2. Anti-EGFR antibody sequences

[0657]

[0658] AB may be an anti-PD-1 antibody or antigen-binding fragment thereof.

[0659] Programmed cell death protein 1 (PD-1), (CD279 cluster of differentiation 279) is a protein encoded in humans by the PDCD1 gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system’s response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells. PD-1 is an immune checkpoint and guards against autoimmunity through two mechanisms. First, it promotes apoptosis (programmed cell death) of antigen-specific T-cells in lymph nodes. Second, it reduces apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells).

[0660] PD-1 inhibitors, a class of drugs that block PD-1, activate the immune system to attack tumors and are used to treat certain types of cancer. PD-1 binds two ligands, PD-L1 and PD-L2.

[0661] PD-L1, the ligand for PD1, is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established. Monoclonal antibodies targeting PD- 1 that boost the immune system are developed for the treatment of cancer. Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumor activity. This is known as immune checkpoint blockade.

[0662] A number of cancer immunotherapy agents that target the PD-1 receptor have been developed. One such anti-PD-1 antibody drug, nivolumab, (Opdivo - Bristol Myers Squibb), produced complete or partial responses in non-small-cell lung cancer, melanoma, and renalcell cancer. Pembrolizumab (Keytruda, MK-3475, Merck), which also targets PD-1 receptors, was approved to treat metastatic melanoma. It is being used in clinical trials in the US for lung cancer, lymphoma, and mesothelioma. Toripalimab is a humanized IgG4 monoclonal antibody against PD-1. Moreover, atezolizumab (MPDL3280A, Roche) and avelumab (Merck KGaA, Darmstadt, Germany and Pfizer) target the similar PD-L1 receptor.

[0663] The anti-PD-1 antibody may be nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, MGA012, AMP-224, or AMP-514).

[0664] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,

[0665] (a) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 1; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 2;

[0666] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 3;

[0667] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 4;

[0668] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 5; and

[0669] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 6; or

[0670] (b) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 11;

[0671] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 12;

[0672] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 13;

[0673] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 14;

[0674] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 15; and

[0675] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 16; or

[0676] (c) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 19;

[0677] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 20;

[0678] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 21;

[0679] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 22;

[0680] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 23; and

[0681] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 24; or

[0682] (d) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 27;

[0683] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 28;

[0684] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 29;

[0685] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 30;

[0686] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 31; and

[0687] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 32; or

[0688] (e) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 37;

[0689] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 38; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 39;

[0690] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 40;

[0691] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 41; and

[0692] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 42; or

[0693] (f) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 45;

[0694] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 46;

[0695] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 47;

[0696] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 48;

[0697] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 49; and

[0698] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 50; or

[0699] (g) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 53;

[0700] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 54;

[0701] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 55;

[0702] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 56;

[0703] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 57; and

[0704] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 58; or

[0705] (h) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 61;

[0706] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 62;

[0707] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 63;

[0708] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 64;

[0709] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 65; and

[0710] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 66; or

[0711] (i) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 69;

[0712] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 70; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 71;

[0713] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 72;

[0714] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 73; and

[0715] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 74; or

[0716] (j) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 239;

[0717] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 240;

[0718] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 241;

[0719] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 242;

[0720] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 243; and

[0721] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 244.

[0722] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 1; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 2; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 3; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 4; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 5; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 6.

[0723] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 11; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 12; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 13; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 14; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 15; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 16.

[0724] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 19; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 20; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 21; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 22; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 23; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 24.

[0725] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 27; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 28; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 29; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 30; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 31; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 32.

[0726] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 239; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 240; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 241; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 242; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 243; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 244.

[0727] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 37; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 38; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 39; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 40; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 41; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 42.

[0728] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 45; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 46; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 47; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 48; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 49; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 50.

[0729] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 53; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 54; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 55; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 56; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 57; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 58.

[0730] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 61; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 62; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 63; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 64; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 65; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 66.

[0731] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 69; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 70; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 71; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 72; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 73; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 74.

[0732] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a combination of:

[0733] (a) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 7; and a variable light chain comprising the amino acid sequence of SEQ ID NO: 8; or

[0734] (b) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 10, or

[0735] (c) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 25, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 26, or

[0736] (d) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 33, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 34, or

[0737] (e) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 35, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 36, or

[0738] (f) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 43, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 44, or

[0739] (g) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 51, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 52, or (h) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 60, or

[0740] (i) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 67, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 68, or

[0741] (j) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 75, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 76.

[0742] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 7, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 8.

[0743] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0744] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 25, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 26.

[0745] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 33, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 34.

[0746] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 35, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 36.

[0747] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 43, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 44.

[0748] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 51, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 52.

[0749] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 60.

[0750] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 67, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 68.

[0751] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 75, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 76.

[0752] Table 3. Anti-PD-1 antibody sequences

[0753] AB may be an anti-PD-Ll antibody or antigen-binding fragment thereof.

[0754] Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene. Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the adaptive arm of immune systems during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis.

[0755] The anti-PD-Ll antibody may be atezolizumab, avelumab, durvalumab, or cosibelimab.

[0756] In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,

[0757] (a) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 77;

[0758] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 78;

[0759] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 79;

[0760] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 80; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 81; and

[0761] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 82; or

[0762] (b) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 87;

[0763] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 88;

[0764] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 89;

[0765] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 90;

[0766] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 91; and

[0767] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 92; or

[0768] (c) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 95;

[0769] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 96;

[0770] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 97;

[0771] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 98;

[0772] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 99; and

[0773] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 100 ; or

[0774] (d) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 259;

[0775] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 260;

[0776] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 261;

[0777] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 262;

[0778] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 263; and

[0779] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 264;

[0780] (e) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 267;

[0781] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 268;

[0782] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 269;

[0783] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 270;

[0784] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 271; (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 272.

[0785] In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 77; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 78; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 79; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 80; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 81; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 82.

[0786] In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 87; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 88; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 89; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 90; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 91; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 92.

[0787] In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 95; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 96; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 97; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 98; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 99; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 100.

[0788] In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 259; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 260; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 261; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 262; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 263; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 264.

[0789] In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 267; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 268; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 269; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 270; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 271; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 272. In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises a combination of:

[0790] (a) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 83, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 84, or

[0791] (b) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 93, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 94, or

[0792] (c) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 101, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 102, or

[0793] (d) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 103, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 104; or

[0794] (e) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 273, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 274.

[0795] In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 83, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 84.

[0796] In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 93, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 94.

[0797] In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 101, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 102.

[0798] In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 103, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 104.

[0799] In some embodiments, the anti-PD-Ll antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 273, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 274.

[0800] Table 4. Anti-PD-Ll antibody sequences

[0801]

[0802]

[0803] AB may be an anti- TIM-3 antibody or antigen-binding fragment thereof.

[0804] Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3) gene. HAVCR2 was first described as a cell surface molecule expressed on IFNy producing CD4+ Thl and CD8+ Tel cells. The expression was also detected in Thl7 cells, regulatory T-cells, and innate immune cells (dendritic cells, NK cells, monocytes). HAVCR2 receptor is a regulator of the immune response.

[0805] HAVCR2 expression is up regulated in tumor-infiltrating lymphocytes in lung, gastric, head and neck cancer, schwannoma, melanoma and follicular B-cell non-Hodgkin lymphoma. The anti-TIM-3 antibody may be LY3321367, MBG453, TSR-022, Sym023, BGBA425, R07121661, ICAGN02390, BMS-986258, or Sabatolimab.

[0806] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,

[0807] (a) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 105;

[0808] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 106;

[0809] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 107;

[0810] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 108;

[0811] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 109; and

[0812] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 110.

[0813] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a combination of:

[0814] (a) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 111, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 112.

[0815] Table 5. Anti-TIM-3 antibody sequences

[0816] *CDR sequences are identified according to Chothia numbering scheme.

[0817] AB may be an anti-Siglec-15 antibody or antigen-binding fragment thereof.

[0818] Sialic acid binding Ig-like lectin 15 (Siglec-15) is a protein that in humans is encoded by the SIGLEC15 gene. Siglec-15 is predominately expressed on osteoclasts, elevated levels of Siglec-15 in the bone metastatic niche can promote tumor-induced osteoclastogenesis as well as suppress antigen-specific T cell responses. Researchers demonstrated that antibody blockade of the Siglec-15 / sialic acid glycol-immune checkpoint axis acts as a treatment for breast cancer bone metastasis.

[0819] Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) can promote osteoclast differentiation and increase bone resorption during bone remodeling. Protein analysis showed that the extracellular domain encoded by the Siglec-15 gene shared more than 30% sequence homology with the B7 gene family encoding PD-L1, indicating that its potential immunoregulatory function was similar to that of B7 family members. Siglec-15 inhibited the immune response of antigen-specific T cells by affecting the expansion of T cells. In vivo, Siglec-15 gene ablation inhibited the tumor growth rate, and the number of infiltrating CD8+T cells and NK cells and the production of IFN-y and other cytokines were also significantly increased in the meantime.

[0820] The anti- Siglec-15 antibody may be NC318, or PYX-106.

[0821] AB may be an anti-B7-H7 antibody or antigen-binding fragment thereof.

[0822] T cells express different costimulatory (i.e., CD28 and ICOS) and coinhibitory molecules (i.e., PD-1, CTLA-4, Tim-3, and LAG-3) on their surface, which generally belong to the B7 or TNF family. One of the B7 family ligands is B7-H7 (HHLA2) along with its receptor CD28H (TMIGD2 or IGPR1). B7-H7 is expressed on macrophages and activated dendritic cells, whereas CD28H is expressed on naive T cells, a subset of memory T cells, natural killer cells, Innate Lymphoid cells (ILCs) and plasmacytoid dendritic cells (pDCs).

[0823] The anti-B7-H7 antibody may be NPX267 (Keywan Mortezaee, Biomedicine & Pharmacotherapy Volume 162, June 2023, 114639) or HBM1020 (Xiaodong Wu, et al., Journal for ImmunoTherapy of Cancer. Volume 10, Issue Suppl 2).

[0824] AB may be an anti-B7-H4 antibody or antigen-binding fragment thereof.

[0825] B7-H4 (B7S1, B7x, VTCN1), a B7-family member expressed on antigen- presenting cells and / or tumors, can inhibit T cell-mediated inflammatory responses. B7-H4 expression in renal cell carcinoma, melanoma, breast, lung, gastric, colorectal, pancreatic, prostate, endometrial, and ovarian cancer is associated with increased tumor size, cancer stage, metastasis, progression, poor disease prognosis, decreased survival, and / or decreased infiltration of T cells. Inhibition of B7-H4 may be an alternative strategy to reinvigorate tumor-specific T cell responses.

[0826] The anti-B7-H4 antibody may be FPA150 (Jasgit C. Sachdev, et al., Journal of Clinical Oncology Volume 37, Number 15_suppl). AB may be an anti-HER2 antibody or antigen-binding fragment thereof.

[0827] Anti-HER2 therapies (also called HER2 inhibitors or HER2 -targeted therapies) are a class of medicines used to treat all stages of HER2-positive cancer, such as breast cancer.

[0828] Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. The human protein is also frequently referred to as HER2 (human epidermal growth factor receptor 2) or CD340 (cluster of differentiation 340). Amplification or over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer.

[0829] The anti-HER2 antibody may be trastuzumab, pertuzumab, or margetuximab. HER2 is the target of the monoclonal antibody trastuzumab. Trastuzumab is effective in cancers where HER2 is over-expressed. Pertuzumab is a fully humanized monoclonal antibody that binds to a different epitope of the HER2 extracellular domain (subdomain II) than trastuzumab (subdomain IV), thereby preventing HER2 from dimerizing with other members of the HER family (EGFR, HER3 and HER4), most notably HER3.

[0830] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,

[0831] (a) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 113;

[0832] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 114;

[0833] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 115;

[0834] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 116,

[0835] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 117; and

[0836] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 118, or

[0837] (b) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 123;

[0838] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 124; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 125;

[0839] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 126,

[0840] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 127; and

[0841] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 128, or

[0842] (c) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 132;

[0843] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 133;

[0844] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 134;

[0845] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 135,

[0846] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 136; and

[0847] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 137.

[0848] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 113; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 114; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 115; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 116; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 117; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 118.

[0849] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 123; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 124; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 125; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 126; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 127; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 128

[0850] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 132; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 133; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 134; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 135; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 136; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 137.

[0851] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises a combination of:

[0852] (a) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 119, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 120, or

[0853] (b) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 129, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 130, or

[0854] (c) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 138, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 139.

[0855] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 119, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 120.

[0856] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 129, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 130.

[0857] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 138, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 139.

[0858] Table 6. Anti-HER2 antibody sequences

[0859] AB may be an anti-RORl antibody or antigen-binding fragment thereof.

[0860] Receptor tyrosine kinase-like orphan receptor (R0R1) is a member of the receptor tyrosine kinases (RTK) family. OMIM entry 602336. Receptor tyrosine kinases function as cell surface receptors, and they have been postulated to play roles in the control of cell proliferation, differentiation, migration, and metabolism. The R0R1 gene encodes a type I glycosylated membrane protein with a predicted length of 937 amino acids. Expression of R0R1 has been observed in human heart, lung, and kidney, and also weakly in the central nervous system. Reddy et al. Truncated expression was observed in a variety of human cancers, including those originating from CNS or PNS neuroectoderm.

[0861] ROR1 has been shown to be expressed on cancer cells, including ovarian cancer cells, and on cancer stem cells. Treatment with a monoclonal antibody specific for ROR1 inhibited development of ovarian cancer cells, and ROR1 has been postulated as a target for cancer therapeutics.

[0862] The anti-RORl antibody may be cirmtuzumab, or zilovertamab.

[0863] In some embodiments, the anti-RORl antibody or antigen-binding fragment thereof comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,

[0864] (a) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 140;

[0865] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 141;

[0866] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 142;

[0867] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 143;

[0868] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 144; and

[0869] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 145.

[0870] In some embodiments, the anti-RORl antibody or antigen-binding fragment thereof comprises a combination of:

[0871] (a) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 146, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 147.

[0872] Table 7. Anti-RORl antibody sequences AB may be an anti-CD19 antibody or antigen-binding fragment thereof.

[0873] B-lymphocyte antigen CD 19, also known as CD 19 molecule (Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD 19. In humans, CD 19 is expressed in all B lineage cells. CD 19 plays two major roles in human B cells: on the one hand, it acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane; on the other, it works within the CD19 / CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.

[0874] The anti-CD19 antibody may be tafasitamab (MOR208), coltuximab ravtansine (SAR3419), loncastuximab tesirine, inebilizumab (MEDI-551), denintuzumab mafodotin, taplitumomab paptox, XmAb 5871, MDX-1342, or blinatumomab.

[0875] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,

[0876] (a) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 148;

[0877] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 149;

[0878] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 150;

[0879] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 151;

[0880] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 152; and

[0881] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 153; or

[0882] (b) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 156;

[0883] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 157;

[0884] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 158;

[0885] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 159; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 160; and

[0886] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 161; or

[0887] (c) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 164;

[0888] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 165;

[0889] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 166;

[0890] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 167;

[0891] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 168; and

[0892] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 169; or

[0893] (d) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 172;

[0894] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 173;

[0895] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 174;

[0896] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 175,

[0897] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 176; and

[0898] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 177; or

[0899] (e) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 291;

[0900] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 292;

[0901] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 293;

[0902] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 294,

[0903] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 295; and

[0904] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 296.

[0905] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 148; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 149; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 150; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 151; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 152; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 153.

[0906] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 156; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 157; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 158; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 159; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 160; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 161.

[0907] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 164; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 165; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 166; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 167; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 168; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 169.

[0908] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 172; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 173; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 174; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 175; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 176; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 177.

[0909] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 291; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 292; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 293; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 294, (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 295; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 296.

[0910] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises a combination of:

[0911] (a) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 154, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 155, or

[0912] (b) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 162, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 163, or

[0913] (c) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 170, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 171, or

[0914] (d) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 178, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 179, or

[0915] (e) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 180, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 181.

[0916] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 154, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 155.

[0917] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 162, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 163.

[0918] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 170, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 171.

[0919] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 178, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 179.

[0920] In some embodiments, the anti-CD19 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 180, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 181. Table 8. Anti-CD19 antibody sequences

[0921]

[0922]

[0923] AB may be an anti-LlCAM antibody or antigen-binding fragment thereof.

[0924] LI, also known as LI CAM, is a transmembrane protein member of the LI protein family, encoded by the LI CAM gene. This protein, of 200-220 kDa, is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation. It also plays a key role in treatmentresistant cancers due to its function.

[0925] The anti-LlCAM antibody may be Ab417 (Seulki Cho, et al., MAbs. 2016;8(2):414-25), or chCE7 (Chopra A. Molecular Imaging and Contrast Agent Database (MICAD) [Internet], Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013).

[0926] AB may be an anti-CLDN18.2 antibody or antigen-binding fragment thereof.

[0927] Claudins are a family of proteins, which form the important components of the tight cell junctions. They establish a paracellular barrier which controls the flow of molecules between the cells. The transmembrane domains of claudins include a N- terminus and a C-terminus in the cytoplasm. Different claudins are expressed on different tissues, their altered function has linked to formation of cancers of respective tissues.

[0928] Isoform 2 of the tight junction molecule claudin-18 (CLDN18.2) was identified as a highly selective cell lineage marker. They observed its expression in normal tissues is strictly confined to differentiated epithelial cells of the gastric mucosa, but it was absent from the gastric stem cell zone. Claudin 18.2 was retained on malignant transformation and was expressed in a significant proportion of primary gastric cancers and its metastases. Frequently ectopic activation of claudin 18.2 was also found in pancreatic, esophageal, ovarian, and lung tumors. CLDN18.2 has highly restricted expression pattern in normal tissues, with frequent ectopic activation in a diversity of human cancers.

[0929] Claudin 18.2 is involved in tumor development and progression and located in the outer cell membrane. It has exposed extracellular loops and is available for monoclonal antibody binding. These biological characteristics suggested that it is an ideal molecule for targeted therapy and led to the further development of monoclonal antibodies against claudin 18.2, such as claudiximab (IMAB362).

[0930] The anti-CLDN18.2 antibody may be claudiximab, zolbetuximab, ASKB589, or osemitamab.

[0931] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,

[0932] (a) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 182;

[0933] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 183; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 184;

[0934] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 185;

[0935] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 186; and

[0936] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 187; or

[0937] (b) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 192;

[0938] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 193;

[0939] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 194;

[0940] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 195;

[0941] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 196; and

[0942] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 197; or

[0943] (c) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 200;

[0944] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 201;

[0945] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 202;

[0946] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 203;

[0947] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 204; and

[0948] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 205.

[0949] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 182; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 183; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 184; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 185; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 186; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 187.

[0950] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 192; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 193; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 194; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 195; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 196; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 197.

[0951] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 200; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 201; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 202; (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 203; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 204; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 205.

[0952] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a combination of:

[0953] (a) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 188, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 189, or

[0954] (b) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 198, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 199, or

[0955] (c) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 200, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 201.

[0956] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 188, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 189.

[0957] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 198, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 199.

[0958] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 200, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 201.

[0959] Table 9. Anti-CLDN18.2 antibody sequences

[0960]

[0961]

[0962] AB may be an anti-TROP2 antibody or antigen-binding fragment thereof.

[0963] Human TR0P2 (tumor-associated calcium signal transducer 2, TACSTD2) is a 35- 46 kDa transmembrane calcium signal transducer glycoprotein having 323 amino acids (274 extracellular domains, 23 transmembrane domains, and 26 intracellular domains), and belongs to the epithelial cell adhesion molecule (EpCAM) family, which is an important component in cell signaling, proliferation, and differentiation. The expression of TROP2 is associated with tumor induction or tumor suppression in various carcinomas, but TROP2 is known to generally act as a tumor inducer.

[0964] The cleavage of the region between R87 and T88 from among 274 extracellular regions induces the rearrangement of the TR0P2 structure, resulting in changes in biological activity. Although this cleavage does not occur in normal tissues, TROP2 cleavage occurs in most carcinomas, including skin cancer, ovarian cancer, colon cancer, and breast cancer, and thus, TROP2 acts as a tumor inducer.

[0965] In certain embodiments, the anti-TROP2 antibody or antigen-binding fragment thereof may be datopotamab or sacituzumab.

[0966] In certain embodiments, the anti-TROP2 antibody or antigen-binding fragment thereof comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein

[0967] (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 303;

[0968] (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 304;

[0969] (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 305;

[0970] (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 306;

[0971] (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 307; and

[0972] (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 308.

[0973] In certain embodiments, the anti-TROP2 antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 309, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 310.

[0974] Table 10. Anti-TROP2 antibody sequences

[0975] AB may be an anti-DLKl antibody or antigen-binding fragment thereof.

[0976] Humanized anti-delta-like 1 homolog (DLK-1) antibody is a membrane protein with 6 tandem EGF-like motifs in extracellular region. Overexpression of DLK-1 has been reported in variety of cancer types including hepatocellular carcinoma (HCC).

[0977] The anti -DLK-1 antibody may be CBA-1205.

[0978] AB may be an anti-CCR8 antibody or antigen-binding fragment thereof.

[0979] C-C chemokine receptor type 8 (CCR8) is a cell surface receptor that belongs to the G protein-coupled receptor (GPCR) family. It is a protein expressed on the surface of various immune cells, including regulatory T cells (Tregs). Tregs have the ability to suppress the activity of other immune cells, including cytotoxic T cells and natural killer cells, which are responsible for recognizing and attacking tumor cells. In peripheral tissues, Resting conventional T cells (T conv cells) can differentiate into inducible regulatory T cells (iTreg) in the presence of specific cytokines such as TGF-P and IL-2. The CCR8 receptor on the surface of Tregs is then upregulated by local cytokine and chemokine signaling within the tumor site. This immunosuppressive effect of Tregs at the tumor site can indeed weaken the anti-tumor immune response, making them an important target for therapeutic intervention in cancer immunotherapy. However, such Treg-targeting cancer immunotherapies occasionally induce immunopathology and autoimmunity as adverse effects. CCR8 is known to play a crucial role in recruiting Tregs to the tumor site, fostering an immunosuppressive environment that aids tumor escape. By inhibiting CCR8, it is possible to disrupt this recruitment process, potentially enhancing anti-tumor immune responses and suppressing tumor growth.

[0980] The anti-CCR8 antibody may be BMS-986340, S-531011, BAY3375968, or GS- 1811.

[0981] In certain embodiments, the antibody drug conjugates disclosed herein have improved stability as compared to antibody drug conjugates known in the art.

[0982] In certain embodiments, the antibody comprises, but is not limited to, a monoclonal antibody, a bispecific antibody, a diabody, a multispecific antibody, a polyantibody, a minibody, a domain antibody, an antibody mimetic (or synthetic antibody), a chimeric antibody, a humanized antibody, a human antibody or an antibody fusion (or antibody conjugate), and a fragment thereof, and includes various forms of antibodies disclosed herein.

[0983] In certain embodiments, an antibody fragment of the antibody according to the present disclosure includes Fab, Fab', F(ab')2, scFab, Fv, dsFv, scFV, scFV-Fc, a minibody, a diabody, scAb, or dAb.

[0984] An antibody according to the present disclosure shares certain regions or sequences with other antibodies disclosed herein. In certain embodiments, the constant region of the antibody or antigen-binding fragment thereof may be shared. In certain embodiments, Fc regions may be shared. In certain embodiment, the frame of a variable region may be shared. The heavy chain variable region and the light chain variable region according to the present disclosure may be linked to at least a part of a human constant region. The selection of a constant region may be determined partially by whether or not antibody-dependent cell- mediated cytotoxicity, antibody-dependent cellular phagocytosis, and / or complementdependent cytotoxicity is required. For example, human isotypes IgGl and IgG3 have complement-dependent cytotoxicity, and human isotypes IgG2 and IgG4 do not have such cytotoxicity. In addition, human IgG land IgG3 induce a cell-mediated effector function stronger than that of human IgG2 and IgG4. The light chain constant region may be lambda or kappa.

[0985] A variable region of an immunoglobulin chain generally has the same overall structure and includes a comparatively conserved framework region (FR) linked by three hypervariable regions called “complementarity determining areas or regions or domains” or complementarity determining regions (CDRs). The CDRs of a variable region derived from each chain including a heavy chain / light chain pair are typically aligned by a framework region to form a structure specifically binding to a specific epitope of a target protein. These factors of naturally occurring light chain and heavy chain variable regions are typically included from the N-terminus to the C-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The position of amino acid sequences corresponding to each variable region may be determined by Kabat (Kabat et al., (1983) U.S. Dept, of Health and Human Services, “Sequences of Proteins of Immunological Interest”), Chothia(Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)) or in a manner related to the OPAL library (Hye Young Yang et. al., 2009 Mol. Cells 27: 225). The CDRs determined by each definition, when compared to each other, may be subsets which overlap or where one includes another. Those of ordinary skill in the art will be readily able to easily select CDR sequences according to the definitions above, given a variable region sequence of an antibody.

[0986] In certain embodiments, the antibody according to the present disclosure is a humanized antibody. A humanized antibody refers to any antibody in which the constant region of a non-human antibody is completely substituted with a human form of the constant region, and at least a portion of the variable region of a non-human antibody, except for the three loops of an amino acid sequence outside each variable region that binds to a target structure, is completely or partially substituted with the corresponding portion of a human antibody. Certain mutations may be introduced to the framework region to enhance the stability of antibodies while maintaining their antigen binding activity. Stabilization of therapeutic antibodies can result in improved serum half-life, lower dosage requirements, reduced side-effects, improved shelf-life and reduced shipping and storage costs.

[0987] In certain embodiments, the humanized antibody according to the present disclosure comprises:

[0988] (a) (i) a variable heavy chain framework region from a heavy chain of a human antibody or from a human consensus framework; and (ii) a variable light chain framework region from a light chain of a human antibody or from a human consensus framework.

[0989] In certain embodiments, at least one amino acid of the variable domain framework region from the heavy chain is substituted with the corresponding amino acid from a heavy chain of a mouse antibody or mouse consensus framework; or the variable domain framework region from the light chain is substituted with the corresponding amino acid from the light chain of a mouse antibody or mouse consensus framework.

[0990] In certain embodiments, the present disclosure discloses one or more amino acid sequences having substantial sequence identity to one or more amino acid sequences disclosed herein. Substantial identity means that the effects disclosed herein are maintained in the presence of sequence variations. In certain embodiments, the amino acid sequence has about 90% identity, about 95% identity, or about 99% identity to the heavy chain variable regions shown in Tables 1 to 10. In another embodiment, the amino acid sequence has about 90% identity, about 95% identity, or about 99% identity to the light chain variable regions shown in Tables 1 to 10. For example, in the case of variants exhibiting 90% identity, 95% identity, or 99% identity to the sequence of the antibody or antigen-binding fragment thereof according to the present disclosure, any mutation occurs in the framework of the variable region rather than the CDRs.

[0991] In certain embodiments, a nucleic acid encoding the antibody or fragment thereof according to the present disclosure is a nucleic acid encoding a full-length antibody including the CDRs disclosed herein, the variable region including the CDRs, and the variable region, and the constant region. Once the amino acid sequence is determined, the nucleic acid sequence may be easily determined in consideration of a known reverse transcription program, codon usage, and the like. Provided is also a pharmaceutical composition including a therapeutically effective amount of the antibody-drug conjugate or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable diluent, a carrier, a solubilizer, an emulsifier, a preservative, and / or an adjuvant. Also, for example, a method of treating a cancer patient by administering such a pharmaceutical composition is provided. The term "patient" includes human patients.

[0992] The pharmaceutical composition may include a pharmaceutically acceptable carrier. The carrier is used as a meaning including an excipient, a diluent, or an adjuvant. The carrier may be selected from the group consisting of, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, saline, buffer such as PBS, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil. The composition may include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, or a combination thereof.

[0993] The pharmaceutical composition may be prepared as any formulation according to general methods. The composition may be formulated into formulations for oral administration (e.g., powders, tablets, capsules, syrups, pills or granules) or for parenteral administration (for example, injections). In addition, the composition may be prepared as a systemic or local formulation.

[0994] The pharmaceutical composition may include an effective amount of the antibody or antigen-binding fragment thereof, an anticancer agent, or a combination thereof. The term "effective amount" refers to an amount sufficient to exhibit preventive or therapeutic effects when administered to an individual requiring prevention or treatment. The effective amount may be appropriately selected depending on a cell or individual that is selected by those or ordinary skill in the art. The effective amount may be determined according to factors including the severity of the disease, the age, body weight, health and gender of a patient, sensitivity of a patient to the drug, administration time, administration routes, excretion rate, treatment period, and drugs used in combination or simultaneously with the used compostion, and other factors well known in the medical field.

[0995] The dosage of the pharmaceutical composition may range, for example, from 10 pg / kg to about 30 mg / kg, optionally from 0.1 mg / kg to about 30 mg / kg, or alternatively from 0.3 mg / kg to about 20 mg / kg per adult. The pharmaceutical composition may be administered once a day, multiple times a day, once every 1 to 4 weeks, or once to 12 times a year.

[0996] Hereinafter, the present disclosure will be described in more detail with reference to examples and experimental examples.

[0997] The following examples and experimental Examples are intended to aid in understanding of the present disclosure and are not intended to limit the scope of the present disclosure.

[0998] Definitions

[0999] Unless otherwise defined in the present disclosure, scientific and technical terms used herein have the meaning as commonly understood by those of ordinary skill in the art. Furthermore, unless the context specifically requires otherwise, the singular includes the plural and the plural includes the singular. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.

[1000] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).

[1001] Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[1002] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known.

[1003] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[1004] “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[1005] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[1006] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[1007] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.

[1008] It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[1009] As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CFfc-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.

[1010] The term “conjugates" as used herein refers to cell binding agents that are covalently bonded to one or more molecules of a cytotoxic compound. In this regard, "cell binding agent" is a molecule having affinity for a biological target, and may be, for example, an antibody, particularly a monoclonal antibody, or an antibody fragment, and the binding agent functions to direct a biologically active compound to a biological target. In certain embodiments, the conjugate may be designed to target tumor cells through cell surface antigens. The antigen may be a cell surface antigen that is overexpressed or expressed in an abnormal cell type. Specifically, the target antigen may be expressed only on proliferative cells (e.g., tumor cells). The target antigen may be selected on the basis of different expression, usually between proliferative tissues and normal tissues. In the present disclosure, the antibody is bonded to the linker.

[1011] In the present disclosure, a "variant" of a polypeptide, for example, an antigenbinding fragment, a protein, or an antibody, is a polypeptide in which insertion, deletion, addition, and / or substitution have occurred at one or more amino acid residues compared to other polypeptide sequences, and includes fusion polypeptides. Protein variants also include those modified by protein enzymatic cleavage, phosphorylation or other post-translational modifications, but retaining the biological activity of the antibody disclosed herein, such as binding and specificity to R0R1. Variants may have about 99% identity, about 98% identity, about 97% identity, about 96% identity, about 95% identity, about 94% identity, about 93% identity, about 92% identity, about 91% identity, about 90% identity, about 89% identity, about 88% identity, about 87% identity, about 86% identity, about 85% identity, about 84% identity, about 83% identity, about 82% identity, about 81% identity, or about 80% identity to the sequence of the antibody or antigen-binding fragment thereof according to the present disclosure. Percent identity (%) or homology may be calculated by methods known in the art.

[1012] In certain embodiments, the percent homology or identity can be calculated by 100X[(same position) / min(TGA, TGB)], wherein TGA and TGB are the sum of the number of residues and internal gap positions in sequences A and B to be compared (Russell et al., J. Mol Biol., 244: 332-350 (1994).

[1013] In the present disclosure, a conservative amino acid substitution refers to a substitution that does not substantially affect the activity or antigen line of a polypeptide. A polypeptide may include one or more conservative substitutions. Non-limiting examples thereof are shown in Table 3 below.

[1014] The term "derivative" of a polypeptide as used herein refers to a polypeptide that has chemical modification at one or more residues through conjugation with other chemical moieties, different from insertion, deletion, addition or substitution variants.

[1015] The term "naturally occurring" as used herein in relation to polypeptides, nucleic acids, host cells, and the like refers to substances that exist naturally.

[1016] The term "percent sequence identity" or "percent identity" between two polynucleotide or polypeptide sequences refers to the number of identical matched positions shared by the sequences over a comparison window, taking into account additions or deletions (i.e., gaps) that must be introduced for optimal alignment of the two sequences. A matched position is any position where an identical nucleotide or amino acid is presented in both the target and reference sequence. Gaps presented in the target sequence are not counted since gaps are not nucleotides or amino acids. Likewise, gaps presented in the reference sequence are not counted since target sequence nucleotides or amino acids are counted, not nucleotides or amino acids from the reference sequence. The percentage of sequence identity is calculated by determining the number of positions at which the identical amino-acid residue or nucleic acid base occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity. The comparison of sequences and determination of percent sequence identity between two sequences can be accomplished using readily available software programs. Suitable software programs are available from various sources, and for alignment of both protein and nucleotide sequences. One suitable program to determine percent sequence identity is bl2seq, part of the BLAST suite of program available from the U.S. government's National Center for Biotechnology Information BLAST web site (at world wide web at blast.ncbi.nlm.nih.gov). B12seq performs a comparison between two sequences using either the BLASTN or BLASTP algorithm. BLASTN is used to compare nucleic acid sequences, while BLASTP is used to compare amino acid sequences. Other suitable programs are, e.g., Needle, Stretcher, Water, or Matcher, part of the EMBOSS suite of bioinformatics programs and also available from the European Bioinformatics Institute (EBI) at world wide web at ebi.ac.uk / Tools / psa.

[1017] As used herein, “homology” with respect to a peptide, polypeptide or antibody sequence refers to the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms known in the art needed to achieve maximal alignment over the full length of the sequences being compared.

[1018] In the present disclosure, "affinity" is the strength of interactions between an antibody or antigen-binding fragment thereof and an antigen, and is determined by properties of the antigen such as size, shape and / or charge of the antigen, and CDR sequences of the antibody or antigen-binding fragment thereof. The methods for determining the affinity are known in the art, and the following may be used as references.

[1019] The antibody or antigen-binding fragment thereof is called “specifically binding” to its target such as an antigen, when a dissociation constant (KD) is <10'6M. The antibody specifically binds to a target with “high affinity” when KD is <lx 10'8M.

[1020] As used in the present disclosure, the “antigen-binding fragment” of a chain (heavy chain or light chain) of an antibody or immunoglobulin includes a part of an antibody which lacks some amino acids compared to a full-length chain, but can specifically bind to an antigen. This fragment can be considered as having biological activity, in that the fragment can specifically bind to a target antigen, or can compete with other antibodies or antigen binding fragments thereof to bind to a specific epitope. In certain embodiments, such a fragment includes at least one CDR present in a full-length light chain or heavy chain, and in some embodiments, includes a short-chain heavy chain and / or light chain, or part thereof. This biological active fragment may be produced by a recombinant DNA technique or may be produced, for example, by cleaving an intact antibody enzymatically or chemically. An immunologically functional immunoglobulin fragment includes, but is not limited to, Fab, Fab, F(ab)2, scFab, dsFv, Fv, scFV, scFV-Fc, diabody, minibody, scAb, and dAb, and may be derived from any mammal, including, but not being limited to, a human, a mouse, a rat, a camelid, or a rabbit. The functional parts of antibodies such as the one or more CDRs disclosed in the present disclosure may be linked with a secondary protein or a small compound by a covalent bond, and thereby used as a targeted therapeutic agent for a specific target.

[1021] In the present disclosure, the “Fc” region includes two heavy chain fragments including CH2 and CH3 domains of an antibody. These two heavy chain fragments are linked to each other by hydrophobic interaction of two or more of disulfide bonds and a CH3 domain. In the present disclosure, the “Fab fragment” consists of one light chain and one heavy chain including a variable region and CHI only. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule. In an scFab, two molecules of Fab are linked by a flexible linker.

[1022] In the present disclosure, the “Fab' fragment” includes a Fab fragment and additionally a region between CHI and CH2 domains of a heavy chain. A disulfide bond may form between two heavy chains of Fab' fragments of two molecules, forming a F(ab')2 molecule.

[1023] In the present disclosure, as described above, the “F(ab')2 fragment” includes two light chains and two heavy chains including a variable region CHI and part of a constant region between the CHI and CH2 domains, with an inter-chain disulfide bond formed between the two heavy chains. Accordingly, a F(ab')2 fragment consists of two Fab' fragments, and the two Fab' fragments are joined to each other by the disulfide bond therebetween.

[1024] In the present disclosure, the “Fv region” is a fragment of an antibody which includes each variable region of a heavy chain and a light chain, but does not include constant regions. In an sdFV, a heavy chain and a light chain are linked by a disulfide bond. In an scFc, the Fv is linked by a flexible linker. In an scFv-Fc, an Fc is linked to an scFV. In a minibody, CH3 is linked to an scFV. A diabody includes the scFVs of two molecules.

[1025] In the present disclosure, the “single chain Fv” or “scFv” antibody fragment includes the VH and VL domains of an antibody, and these domains are present within a single polypeptide chain. An Fv polypeptide may additionally include a polypeptide linker between a Vh domain which enables the scFv to form the target structure for antigen binding, and a VL domain.

[1026] In the present disclosure, the “single-chain antibody (scAb)” is a single polypeptide chain including one constant region of a heavy chain or a light chain constant region in which heavy chain and light chain variable regions are linked by a flexible linker. For a single-chain antibody, U.S. Pat. No. 5,260,203 may be referred to, and short-chain antibody is disclosed herein by reference.

[1027] In the present disclosure, the “domain antibody (dAb)” is an immunologically functional immunoglobulin fragment including only a variable region of a heavy chain or a variable region of a light chain. In certain embodiments, two or more VH regions are linked by a covalent bond via a peptide linker, to form a bivalent domain antibody. Two VH regions of this bivalent domain antibody may target the same or different antigens.

[1028] In the present disclosure, “complementarity determining region” (CDR; that is, CDR1, CDR2, and CDR3) denotes amino acid residues of the variable domain of an antibody, which are necessary for binding to antigen. Each variable domain typically has three CDR domains, identified as CDR1, CDR2, and CDR3.

[1029] In the present disclosure, the “framework region” (FR) is a variable domain residue other than the CDR residues. Each variable domain typically has four FRs, identified as FR1, FR2, FR3, and FR4.

[1030] In the present disclosure, the “bivalent antigen-binding protein” or “bivalent antibody” includes two antigen-binding sites. The two antigen-binding sites included in a bivalent antibody may have the same antigen specificity, or may be a bispecific antibody where the antigen-biding sites bind to different antigens.

[1031] In the present disclosure, the “multispecific antigen-binding protein” or “multispecific antibody” targets two or more antigens or epitopes.

[1032] In the present disclosure, “linker” refers to a compound which covalently bonds a cytotoxic compound to an antibody.

[1033] In the present disclosure, “unsubstituted or substituted” is used to refer to a parent group which may be unsubstituted or substituted, "substituted" refers to a parent group having at least one substituent, and a substituent refers to a chemical moiety covalently bonded to or fused with a parent group.

[1034] In the present disclosure, “halo” refers to fluorine, chlorine, bromine, iodine, and the like.

[1035] In the present disclosure, “alkyl” is a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic or alicyclic, saturated or unsaturated (unsaturated, fully unsaturated) hydrocarbon compound. As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C1-C10 branched-chain alkyl groups. Preferably, the “alkyl” group refers to Ci-Ce straight-chain alkyl groups or Ci-Ce branched-chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1 -propyl, 2- propyl, n-butyl, sec-butyl, tert-butyl, 1 -pentyl, 2-pentyl, 3 -pentyl, neo-pentyl, 1 -hexyl, 2- hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl and the like. The “alkyl” group may be optionally substituted. Furthermore, the term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-30 for straight chains, C3- 30 for branched chains), and more preferably 20 or fewer. Examples of saturated alkyls may include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and the like, examples of saturated linear alkyls may include methyl, ethyl, n-propyl, n-pentyl (amyl), n-hexyl, n-heptyl, and the like, examples of saturated branched cyclic alkyls may include isopropyl, isobutyl, secbutyl, tert-butyl, isopentyl, neopentyl, and the like.

[1036] The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[1037] The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[1038] The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[1039] The term “Cx-y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A Ci-ealkyl group, for example, contains from one to six carbon atoms in the chain.

[1040] The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

[1041] The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkyl S-.

[1042] The term “amido”, as used herein, refers to a group wherein R9and R10each independently represent a hydrogen or hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[1043] The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein R9, R10, and R10’ each independently represent a hydrogen or a hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[1044] The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.

[1045] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

[1046] The term "alkoxy" as used herein refers to -OR where R is an alkyl group, and examples thereof may include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secbutoxy, isobutoxy, tert-butoxy, and the like.

[1047] The term "alkoxy alkyl" as used herein refers to a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by an alkoxy group, as defined herein. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms ("Ci- 8 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms ("Ci-

[1048] 6 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms ("Ci-

[1049] 4 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms ("Ci-

[1050] 3 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms ("Ci-

[1051] 2 alkoxyalkyl").

[1052] The term "alkenyl" as used herein is an alkyl having at least one carbon-carbon double bond. Examples of unsaturated alkenyl groups may include ethenyl (vinyl, - CH=CH2), l-propenyl(-CH=CHCH3), 2-propenyl, isopropenyl, butenyl, pentenyl, and hexenyl.

[1053] In the present disclosure, the term "alkynyl" as used herein refers to an alkyl group having at least one carbon-carbon triple bond, and examples of unsaturated alkynyl group may include ethynyl and 2-propynyl. The term "carboxy" as used herein refers to -C(=O)OH.

[1054] The term "formyl" as used herein refers to -C(=O)H.

[1055] The term "aryl" as used herein refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound. For example, the term "C5-7 aryl" refers to a moiety having 5 to 7 ring atoms, which is a monovalent moiety obtained by removing a hydrogen atom from the aromatic ring atom of an aromatic compound, and the term "C5-10 aryl" refers to a moiety having 5 to 10 ring atoms, which is a monovalent moiety obtained by removing a hydrogen atom from the aromatic ring atom of an aromatic compound. In this regard, the prefixes (C5-7, C5-10, and the like) refer to the number of ring atoms or a range of the number of ring atoms, regardless of whether they are carbon atoms or hetero atoms. For example, the term "C5-6 aryl" refers to an aryl group having 5 or 6 ring atoms. In this regard, the ring atoms may be all carbon atoms as in a "carboaryl group." Examples of carboaryl groups include, but are not limited to, those derived from benzene, naphthalene, azulene, anthracene, phenanthrene, naphthacene, and pyrene. Examples of aryl groups containing fused rings wherein at least one is an aromatic ring include, but are not limited to, groups derived from indane, indene, isoindene, tetralin, acenaphthene, fluorene, phenalene, acephenanthrene, and aseantrene. Alternatively, the ring atoms may contain one or more heteroatoms as in a "heteroaryl group."

[1056] The term “carbamate” is art-recognized and refers to a group wherein R9and R10independently represent hydrogen or a hydrocarbyl group.

[1057] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[1058] The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4, 5,6,7- tetrahydro-lH-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

[1059] The term “carbonate” is art-recognized and refers to a group -OCO2-.

[1060] The term “carboxy”, as used herein, refers to a group represented by the formula -CO2H.

[1061] The term "cycloalkyl" as used herein refers to an alkyl group which is a cyclyl group, and relates to a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon compound. Examples of cycloalkyl groups include, but are not limited to, those derived from: saturated single ring hydrocarbon compounds, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, and methylcyclohexane; or unsaturated single ring hydrocarbon compounds, such as cyclopropene, cyclobutene, cyclopentene, cyclohexene, methylcyclopropene, dimethylcyclopropene, methylcyclobutene, dimethylcyclobutene, methylcyclopentene, dimethylcyclopentene, and methylcyclohexene; and saturated heterocyclic hydrocarbon compounds, such as norcaran, norphenen, and norbornene.

[1062] The term “ester”, as used herein, refers to a group -C(O)OR9wherein R9represents a hydrocarbyl group.

[1063] The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.

[1064] The term "halo" or "halogen" used herein refers to fluoro (-F), chloro (-C1), bromo (-Br), and iodo (-1). The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

[1065] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[1066] The terms “heteroalkyl”, as used herein, refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-20 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-18 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-16 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 tol4 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-14 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 tol2 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-12 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having Ito 10 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-10 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-8 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-6 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi-4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-2 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroCi alkyl"). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl.

[1067] The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

[1068] The term "heteroaryl" as used herein refers to aryl containing one or more heteroatoms, and examples thereof may include pyridine, pyrimidine, benzothiophene, furyl, dioxolanyl, pyrrolyl, oxazolyl, pyridyl, pyridazinyl, and pyrimidinyl. More specifically, examples thereof may include benzofuran, isobenzofuran, indole, isoindole, indolizine, indolin, isoindoline, purine (adenine or guanine), benzimidazole, indazole, benzoxazole, benzisoxazole, benzodi oxole, benzofuran, benzotri azole, benzothiofuran, benzothiazole, C9 having two fused rings derived from benzothiazole, chromene, isochromene, chroman, iso-chroman, benzodioxane, quinoline, isoquinoline, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, C10 having two fused rings derived from pteridin, Cn having two fused rings derived from benzodiazepine, carbazole, dibenzofuran, dibenzothiophene, carboline, pyrimidine, C13 having three fused rings derived from pyridoindole, acridine, xanthene, thioxanthene, oxanthrene, phenoxathiin, phenazine, phenoxazine, phenothiazine, thianthrene, phenanthridine, phenanthroline, and C14 having three fused rings derived from phenazine.

[1069] The term "heterocyclyl" as used herein refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound. Furthermore, the term "heterocyclyl" or "heterocycle" used herein refers to a monosaturated or partially unsaturated non-aromatic compound or non-aromatic multi-ring system in which at least one heteroatom (that is, at least one cyclic heteroatom selected from oxygen, nitrogen and sulfur) is included in the ring. Unless otherwise specified, heterocyclyl groups have 5 to about 20 ring atoms, such as 3 to 12 ring atoms, such as 5 to 10 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (for example, 3, 4, 5, 6 or 7- membered rings), having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from oxygen, nitrogen and sulfur, in the ring. The rings of a multiple condensed ring system may be linked to one another through fusion, spiro and cross-linking bonds as long as valency requirements are satisfied. Examples of heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N- bromopyrrolidine, N-chloropiperidine, and the like.

[1070] The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbonhydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[1071] The term “hydroxy alkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[1072] The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[1073] The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[1074] The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[1075] The term “sulfonamido” is art-recognized and refers to the group represented by the general formulae wherein R9and R10independently represents hydrogen or hydrocarbyl.

[1076] The term “sulfoxide” is art-recognized and refers to the group -S(O)-.

[1077] The term “sulfonate” is art-recognized and refers to the group -SO3H, or a pharmaceutically acceptable salt thereof.

[1078] The term “sulfone” is art-recognized and refers to the group -S(O)2-.

[1079] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[1080] The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.

[1081] The term “thioester”, as used herein, refers to a group -C(O)SR9or -SC(O)R9wherein R9represents a hydrocarbyl.

[1082] The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

[1083] The term “urea” is art-recognized and may be represented by the general formula wherein R9and R10independently represent hydrogen or a hydrocarbyl.

[1084] The term “guanidine” refers to the formula (R9R10N)(RnR12N)C=N-R13where R9, R10, R11, R12and R13may be the same or different and are each independently selected from H or an alkyl group. Preferably, the alkyl group is a Ci-Ce alkyl group, more preferably a C1-C3 alkyl group. More preferably, the term “guanidine” refers to the formula HN=C(NH2)2, which the skilled person will appreciate is non-derivatized guanidine, where R9, R10, R11, R12and R13are each H.

[1085] When a series of functional groups includes a guanidine group, the functional groups may comprise one or more of the following moi eties, with R9, R10, R11, R12and R13taking the same meaning and preferences as those stated above:

[1086] The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity. Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726.

[1087] Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers.

[1088] “Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the active agent of the present disclosure. Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of this disclosure are metabolized to produce a compound of Formula I. The present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[1089] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.

[1090] The term “Log of solubility”, “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol / liter.

[1091] In the present disclosure, the prefixes (e.g., C1-12, C3-8, and the like) refer to the number of ring atoms or a range for the number of ring atoms, regardless of whether they are carbon atoms or hetero atoms. For example, the term "C3-6 heterocyclyl" as used herein relates to a heterocyclyl group having 3 to 6 ring atoms.

[1092] The term "prodrug" as used herein refers to compounds which, under in vivo physiological conditions (e.g., enzymatic oxidation, reduction and / or hydrolysis), may be converted directly or indirectly into a pyrrolobenzodiazepine drug by action of an enzyme or gastric acid.

[1093] In the present disclosure, "pharmaceutically acceptable salt" may be an acid addition salt formed by pharmaceutically acceptable free acid, and an organic acid or an inorganic acid may be used as the free acid.

[1094] Examples of the organic acid include, but are not limited to, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, meta-sulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid, and aspartic acid. Also, examples of the inorganic acid include, but are not limited to, hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid.

[1095] For example, when the compound has a functional group which is an anion or may be an inion (e.g., -COOH may be -COO-), the compound may form a salt with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+and K+, alkali earth metal cations such as Ca2+and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, include ammonium ions (i.e., NH4+) and substituted ammonium ions (e.g., NEER , NEER? , NHR3+ and NR4+).

[1096] Examples of some suitable substituted ammonium ions are those derived from the following: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. Examples of typical quaternary ammonium ions include N(CH3)4+. When the compound has a functional group which is a cation or may be a cation (e.g., -NH2 may be -NHs+), the compound may form a salt with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.

[1097] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetioxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, gluteptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalene carboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methansulfonic acid, mucoic acid, oleic acid, oxalic acid, palmitic acid, palmic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid and carboxymethyl cellulose.

[1098] The term "solvate" as used herein refers to a molecular complex between a compound according to the present disclosure and solvent molecules, and examples thereof include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, ethanolamine, or the compound according to the present disclosure bonded to a mixed solvent thereof.

[1099] It may be convenient or desirable to prepare, purify and / or handle the equivalent solvate of an active compound. The term "solvate" is used herein in its conventional sense to refer to a complex of a solute (e.g., an active compound or a salt thereof) and a solvent. When the solvent is water, the solvate may conveniently be referred to as a hydrate, such as monohydrate, dihydrate or trihydrate.

[1100] The phrase "effective amount" or "therapeutically effective amount" as used herein refers to an amount required to achieve a target therapeutic result (for administration amount and administration period and means). An effective dose is a minimum amount of activating agent necessary to give an object a minimum therapeutic benefit, and is less than a toxic dose. For example, a dosage may be in a range of about 100 ng to about 100 mg / kg per patient, more typically in a range of about 1 pg / kg to about 10 mg / kg. When the active compound is a salt, an ester, an amide, a prodrug, or the like, the dosage is calculated on the basis of a parent compound, and thus the actual weight used increases proportionally. The pyrrolobenzodiazepine compound according to the present disclosure may be formulated to include 0.1 mg to 3000 mg, 1 mg to 2000 mg, or 10 mg to 1000 mg of an active ingredient per unit dosage form, but the present disclosure is not limited thereto. The active ingredient may be administered to obtain a peak plasma concentration of the active compound of about 0.05 pM to about 100 pM, about 1 pM to about 50 pM, or about 5 pM to about 30 pM. For example, a 0.1 w / v% to 5 w / v% solution of the active ingredient in saline may be administered via an intravenous injection.

[1101] The concentration of the active compound in the pharmaceutical composition may be determined by the absorption, inactivation and excretion rate of the drug, and other factors known to those of ordinary skill in the art. The dosage may vary depending on the severity of symptoms / diseases. In addition, the dosage and administration method for a specific patient may be adjusted according to the professional judgment of an administration supervisor, in consideration of the severity of symptoms / diseases of patients, necessity, age, drug response, and the like, and the concentration range described herein is only an example and is not intended to limit the embodiments of the claimed composition. In addition, the active ingredient may be administered once, or a much smaller dosage of the active ingredient may also be administered in multiple doses.

[1102] The term "linker" as used herein refers to a compound that covalently bonds a cytotoxic compound to an antibody.

[1103] The terms "intracellularly cleaved" and "intracellular cleavage" as used herein refer to a metabolic process or reaction inside a cell on an antibody construct-active agent conjugate, by which the covalent attachment, e.g., the linker, between an active agent (B) and an antibody construct (Ab) is broken, thus causing a free drug or other metabolites of the conjugate dissociated from the antibody inside the cell.

[1104] EXAMPLES

[1105] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention. Preparation of Compounds

[1106] Preparation Example 1> Preparation of Compound 2

[1107] Preparation of Compound 1

[1108] To a solution of l-ethyl-3-methyl-7J / -pyrazole-5-carboxylic acid (8.0 g, 51.9 mmol) in dichloromethane (50 mL), oxalyl chloride (4.97 mL, 57.1 mmol) and a catalytic amount of M -di methyl form am ide (0.1 mL) were added at 0 °C. After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure to afford Compound 1 as a crude product.

[1109] Preparation of Compound 2

[1110] To a solution of crude Compound 1 in acetone (100 mL), potassium thiocyanate (6.5 g, 67.5 mmol) was added at 0 °C. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with hexane (100 mL). The resulting solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 2 (9.7 g, 95%). 'H-NMR (400 MHz, CDC13), 8 7.78 (d, 1H), 7.41 (s, 1H), 7.38 (d, 1H), 3.88 (s, 3H), 2.57 (s, 3H). ELMS m / z : [M+H]+196.00.

[1111] Preparation Example 2> Preparation of Compound 5

[1112] Preparation of Compound 3

[1113] To a solution of methyl 4-chloro-3-m ethoxy-5 -nitrobenzoate (15.0 g, 61.1 mmol), aqueous ammonia solution (28-30% NH3, 200 mL) was added. After stirring at 50 °C for 6 hours and cooled to room temperature, the resulting precipitate was collected by filtration, washed with water, and lyophilized to afford Compound 3 (9.51 g, 68%).1H-NMR (400 MHz, CDCI3) 6 8.29 (s, 1H), 8.04 (d, 1H), 7.87 (d, 1H), 7.78 (s, 1H), 4.01 (s, 3H). Preparation of Compound 4

[1114] To a solution of Compound 3 (300 mg, 1.30 mmol) in dichloromethane (9 mL), aluminum chloride (1.04 g, 7.81 mmol) was added at 0 °C under N2. After stirring at room temperature for 21 hours, the mixture was poured into ice water, and the resulting solid was collected by filtration and lyophilized to afford Compound 4 (223 mg, 79%). 'H-NMR (400 MHz, CDCI3), 8 11.73 (s, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.66 (s, 1H).

[1115] Preparation of Compound 5

[1116] To a solution of Compound 4 (2.0 g, 9.23 mmol) and cesium carbonate (3.61 g, 11.08 mmol) in 7\(7V-dimethylformamide (15 mL), the mixture was cooled to 0 °C under N2. After stirring for 5 minutes, trans- l,4-dibromo-2 -butene (5.93 g, 27.70 mmol) was then added at room temperature under N2, and the reaction mixture was stirred for an additional 2 hours. The mixture was extracted with ethyl acetate (3 x 20 mL), washed with distilled water (2 x 15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was solidified using di chloromethane and hexane to afford Compound 5 (2.53 g, 78%).1H-NMR (400 MHz, CDCI3), 6 8.23 (s, 2H), 8.02 (d, J= 1.8 Hz, 2H), 7.84 (d, J= 1.8 Hz, 2H), 7.73 (s, 2H), 6.16- 5.98 (m, 4H), 5.70 (s, 1H), 4.83 (d, J= 3.5 Hz, 4H), 4.25 (d, J= 5.4 Hz, 1H), 4.20-4.14 (m, 3H). ELMS m / z : [M+H]+350.98.

[1117] Preparation Example 3> Preparation of Compound 9

[1118] Preparation of Compound 6

[1119] To a solution of tert-butyl (E)-(4-aminobut-2-en-l-yl)carbamate (11.4 g, 61.57 mmol) in ethanol (100 mL), Compound 3 (10.0 g, 43.4 mmol) and N,N- diisopropylethylamine (14.9 mL, 86.7 mmol) were added. After stirring at 120 °C for 12 hours, the solvent was removed under reduced pressure, and the resulting residue was diluted with diethyl ether (40 mL). The resulting solid was collected by filtration and dried to afford Compound 6 (12.6 g, 76%). 'H-NMR (400 MHz, DMSO-d6), 8 8.18 (d, 1H), 8.01(s, 1H), 7.73 (t, 1H), 7.55 (d, 1H), 7.31 (s, 1H), 6.92 (s, 1H), 5.53 (s, 2H), 4.08 (s, 2H), 3.47 (s, 2H), 1.35 (m, 9H).

[1120] Preparation of Compound 7

[1121] To a solution of Compound 6 (10.0 g, 26.28 mmol) in methanol (90 mL), aqueous ammonia solution (28-30% NHs, 90 mL) and sodium hydrosulfite (Na2S?O4, 45 g, 262.8 mmol) were sequentially added at 0 °C. After stirring at room temperature for 1 hour and 30 minutes, methanol (100 mL) was added, and the resulting solid was removed by filtration. The filtrate was concentrated under reduced pressure, diluted with di chloromethane (100 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Compound 7 (6.9 g, 75%).1H-NMR(400 MHz, DMSO-d6), 6 7.62 (br s, 1H), 6.98 (br s, 1H), 6.92 (t, 1H), 6.87 (d, 1H), 6.79 (d, 1H), 5.57 (q, 2H), 4.67 (br s, 2H), 3.82 (br s, 1H), 3.76 (s, 3H), 3.51 (dd, 4H), 1.37 (s, 9H).

[1122] Preparation of Compound 8

[1123] To a solution of Compound 7 (6.9 g, 19.7 mmol) in A A-di methyl form am ide (50 mL), Compound 2 (4.9 g, 25.59 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 30 minutes. Triethylamine (5.4 mL, 39.38 mmol) and N-(3- dimethylaminopropyl)-A'-ethylcarbodiimide (4.2 g, 27.56 mmol) were then added at 0 °C. After stirring at room temperature for 17 hours, the mixture was concentrated under reduced pressure, diluted with diethyl ether (20 mL), and the resulting solid was collected by filtration to afford Compound 8 (7.7 g, 76%). ’H-NMR (400 MHz, DMSO-d6), 8 12.86 (s, 1H), 8.02 (s, 1H), 7.67 (s, 1H), 7.40 (m, 2H), 6.93 (m, 1H), 6.65 (s, 1H), 5.67 (m, 2H), 4.93 (d, 2H), 4.61 (q, 2H), 3.98 (s, 3H), 3.51 (m, 2H), 2.55 (m, 2H), 2.18 (s, 3H), 1.35 (t, 3H),

[1124] 1.32 (s, 9H).

[1125] Preparation of Compound 9

[1126] To a solution of Compound 8 (7.7 g, 15.05 mmol) in dichloromethane (25 mL) and methanol (25 mL), hydrochloric acid (4 M in 1,4-di oxane, 27 mL) was added, and the mixture was stirred for 2 hours and 30 minutes at room temperature. After stirring, the reaction mixture was concentrated under reduced pressure, diluted with diethyl ether (20 mL), and the resulting solid was collected by filtration to afford Compound 9 (5.6 g, 76%). 'H-NMR (400 MHz, DMSO-d6) 6 8.02 (s, 1H), 8.67(d, 1H), 7.41 (d, 1H), 7.37 (s, 1H), 6.66 (s, 1H), 6.01 (m, 1H), 5.65 (m, 1H), 4.97 (d, 2H), 4.60 (q, 2H), 3.98 (s, 3H), 2.66 (m, 5H),

[1127] 2.33 (m, 3H), 1.35 (m, 3H). ELMS m / z : [M+H]+823.0.

[1128] Example 1 : Preparation of Compound 14

[1129] Preparation of Compound 10

[1130] To a solution of Compound 5 (265 mg, 0.76 mmol) in A A-di methyl form am ide (4 mL), tert-butyl piperidin-4-ylcarbamate (167 mg, 0.83 mmol) and cesium carbonate (296 mg, 0.91 mmol) were added under N2. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate (50 mL), washed with distilled water (2 x 50 mL), and dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the mixture was diluted with dichloromethane and hexane, and the resulting solid was collected by filtration and dried to afford Compound 10 (248 mg, 70%). ELMS m / z : [M+H]+469.06.

[1131] Preparation of Compound 11

[1132] To a solution of Compound 9 (628 mg, 1.30 mmol) and Compound 10 (304 mg, 0.65 mmol) in / / -butanol (5 mL), A,A-diisopropylethylamine (0.56 mL, 3.24 mmol) was added at room temperature. After stirring at 120 °C for 24 hours and cooled to room temperature, the mixture was diluted with di chloromethane (100 mL) and methanol (20 mL), then washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was diluted with dichloromethane and hexane, and the solid was collected by filtration and dried to afford Compound 11 (124 mg, 23%). ELMS m / z : [M+H]+844.02.

[1133] Preparation of Compound 12

[1134] To a solution of Compound 11 (124 mg, 0.15 mmol) in methanol (4 mL) and distilled water (0.5 mL), aqueous ammonia solution (28-30% NEL, 0.4 mL) and sodium hydrosulfite (Na2S?O4, 218 mg, 2.94 mmol) were added under N2. After stirring at room temperature for 1 hour, the reaction mixture was diluted with methanol (50 mL) and filtered. The filtrate was concentrated under reduced pressure, diluted with di chloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Compound 12 (119 mg, crude). ELMS m / z : [M+H]+814.81.

[1135] Preparation of Compound 13

[1136] To a solution of crude Compound 12 (119 mg, 0.15 mmol) in N,N- dimethylformamide (1 mL), a solution of Compound 2 (32 mg, 0.16 mmol) in N,N- dimethylformamide (1 mL) was added under N2. After stirring at room temperature for 1 hour, A-(3-dimethylaminopropyl)-A'-ethylcarbodiimide hydrochloride (35 mg, 0.18 mmol) and triethylamine (0.06 mL, 0.44 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to afford Compound 13 (36 mg, 25%). ELMS m / z : [M+H]+975.15.

[1137] Preparation of Compound 14

[1138] To a solution of Compound 13 (36 mg, 0.04 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) was added at 0 °C under N2. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford Compound 14 (15.2 mg, 47%). ELMS m / z : [M+H]+875.06. Example 2 : Preparation of Compound 14a

[1139] Preparation of Compound 489

[1140] After dissolving Compound 5 (580 mg, 1.66 mmol) in A A-dimethylformamide (5 mL), morpholine (0.13 mL, 1.01 mmol) and cesium carbonate (590 mg, 1.81 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL x 2), and dried with anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, diluted with dichloromethane and hexane, and the resulting solid was filtered and dried to afford Compound 489 (504 mg, 70%). 'H-NMR (400 MHz, CDC13), 8 7.73-7.66 (m,lH), 6.03-5.84 (m,lH), 4.75 (dd, J= 5.0, 1.2 Hz, 1H), 3.75-3.68 (m, 2H), 3.06 (dd, J = 6.0, 1.1 Hz, 1H), 2.46 (t, J= 4.7 Hz, 2H). ELMS m / z : [M+H]+356.09.

[1141] Preparation of Compound 490

[1142] After dissolving Compound 9 (818 mg, 1.68 mmol) and Compound 489 (300 mg, 0.84 mmol) in normal butyl alcohol (13 mL), AA-diisopropylethylamine (0.74 mL, 4.21 mmol) was added at room temperature, heated to 120 °C, and stirred for 24 hours. After cooling the reaction solution to room temperature, the reaction solution was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. After dilution with diethyl ether, the resulting solid was filtered and dried to afford Compound 490 (129 mg, 21%). EI-MS m / z : [M+H]+731.03.

[1143] Preparation of Compound 491

[1144] After dissolving Compound 490 (129 mg, 0.17 mmol) in methyl alcohol (2 mL) and distilled water (0.1 mL), aqueous ammonia solution (28-30% ammonia, 0.17 mL) and sodium hydrosulfite (Na2S2C>4, 321 mg, 1.84 mmol) were added to the reaction solution under nitrogen. After stirring at room temperature for 1 hour, methanol (50 mL) was added to the reaction solution, and the resulting solid was filtered, and the filtered solution was concentrated, and then diluted with dichloromethane (100 mL), washed with distilled water (50 mL), and then the organic layer was dried with anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to afford Compound 491 (126 mg, crude). EIMS m / z : [M+H]+701.08.

[1145] Preparation of Compound 14a

[1146] After dissolving Compound 491 (126 mg, 0.18 mmol, crude) in N,N- dimethylformamide (2 mL), Compound 2 (39 mg, 0.2 mmol) was dissolved in N,N- dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, / -(3 -di methyl ami nopropyl )- / C-ethyl carbodi imide hydrochloride (40 mg, 0.21 mmol) and triethylamine (0.04 mL, 0.27 mmol) were added, and stirred at room temperature for 16 hours. The resulting material was concentrated under reduced pressure and purified by HPLC to afford Compound 14a (5.6 mg, 4% for 2 steps). EI-MS m / z : [M+H]+862.03.

[1147] Example 3 : Preparation of Compound 14b

[1148] Preparation of Compound 492

[1149] Compound 4 (1.5 g, 6.93 mmol) and cesium carbonate (2.5 g, 7.62 mmol) were dissolved in A(A -di methyl form am ide (6 mL) at 0 °C under nitrogen, and then stirred for 5 minutes. Cis-l,4-dibromo-2-butene (3.7 g, 17.32 mmol) was added to the reaction solution at room temperature under nitrogen and stirred for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (20 mL x 2) and brine (20 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated. The solid obtained by diluting with dichloromethane and hexane was filtered and dried to afford Compound 492 (1.64 g, 67%). ELMS m / z : [M+H]+351.23.

[1150] Preparation of Compound 493

[1151] After dissolving Compound 492 (649 mg, 1.86 mmol) in N, A -di methyl form am ide (6 mL), Lbutyl piperidiw-4-ylcarbamate (338 mg, 1.69 mmol) and cesium carbonate (660 mg, 2.03 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL x 2), and then dried with anhydrous sodium sulfate. The obtained material was filtered and concentrated under reduced pressure, and the solid obtained by diluting with dichloromethane and hexane was filtered and dried to afford Compound 493 (628 mg, 79%). 'H-NMR (400 MHz, DMSO), 5 8.21 (s, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 6.16 - 6.01 (m, 2H), 4.82 (d, J= 3.5 Hz, 2H), 4.17 (d, J= 5.5 Hz, 2H). ELMS m / z : [M+H]+469.49.

[1152] Preparation of Compound 494

[1153] After dissolving Compound 9 (413 mg, 0.85 mmol) and Compound 493 (600 mg, 1.28 mmol) in normal butyl alcohol (8 mL), diisopropylethylamine (0.74 mL, 4.27 mmol) was added at room temperature and stirred for 24 hours while heating to 120 °C. The reaction solution was cooled to room temperature, and then diluted with di chloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The washed material was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to afford Compound 494 (147 mg, 20%). ELMS m / z : [M+H]+844.13.

[1154] Preparation of Compound 495

[1155] After dissolving Compound 494 (147 mg, 0.17 mmol) in methanol (3 mL) and distilled water (0.1 mL), an aqueous ammonia solution (28-30%, 0.25 mL) and sodium hydrosulfite (Na2S2C>4, 303 mg, 1.74 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour, diluted with methanol (50 mL), and then filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The washed material was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to afford Compound 495 (141 mg, crude). ELMS m / z : [M+H]+814.81.

[1156] Preparation of Compound 496

[1157] After dissolving Compound 495 (141 mg, 0.17 mmol, crude) in N,N- dimethylformamide (1 mL), Compound 2 (37 mg, 0.19 mmol) was dissolved in N,N- dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, A-(3-dimethylaminopropyl)-A-ethylcarbodiimide hydrochloride (50 mg, 0.09 mmol) and triethylamine (0.03 mL, 0.22 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to afford Compound 496 (48 mg, 28%). ELMS m / z : [M+H]+975.16.

[1158] Preparation of Compound 14b After dissolving Compound 496 (48 mg 0.05 mmol) in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added at 0 °C under nitrogen. The reaction solution was stirred at room temperature for 2 hours, concentrated, and then purified by HPLC to afford Compound 14b (6.4 mg, 14%). ELMS m / z : [M+H]+875.17.

[1159] Example 4 : Preparation of Compound 14c

[1160] Preparation of Compound 497

[1161] To a solution of di-t-butyl-iminodiacetate (684 mg, 3.15 mmol) in N,N- dimethylformamide (7 mL) was added cesium carbonate (1.12 mg, 3.43 mmol). After stirring at room temperature for 10 minutes, the reaction solution was added Compound 5 (1 g, 2.86 mmol) at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 497 (1.05 g, 71%). 'H-NMR (400 MHz, CDC13) 8 7.79 (d, J= 1.9 Hz, 1H), 7.63 (d, J= 1.9 Hz, 1H), 6.62 (s, 1H), 5.95 (dt, J= 16.0, 5.2 Hz, 1H), 5.81 (dt, J= 15.7, 5.6 Hz, 1H), 4.74 (d, J= 5.4 Hz, 2H), 4.24 (d, J= 5.1 Hz, 2H), 1.48 (s, 18H).

[1162] Preparation of Compound 498

[1163] To a solution of Compound 497 (423 mg, 0.87 mmol) in methanol (4 mL) and tetrahydrofuran (10 mL) were added sodium hydroxide (105 mg, 2.61 mmol) in water (0.5 mL). After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 498 (223 mg, 69%). 'H-NMR (400 MHz, DMSO) 6 8.24 (s, 1H), 8.04 (d, J= 2.2 Hz, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.04 (s, 1H), 5.95 - 5.72 (m, 2H), 4.80 (d, J= 5.5 Hz, 2H), 3.60 (d, J= 6.0 Hz, 2H), 1.37 (s, 9H).

[1164] Preparation of Compound 499

[1165] To a solution of Compound 498 (650 mg, 1.68 mmol) and Compound 9 (831 mg, 2.02 mmol) in n-butanol (8 mL) was added MA-diisopropylethylamine (1.2 mL, 8.42 mmol) at -0°C. After stirring for 5 minutes, the reaction mixture was heated to 120°C for 20 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 499 (297 mg, 23%). ELMS m / z : [M+H]+761.45.

[1166] Preparation of Compound 500

[1167] To a solution of Compound 499 (294 mg, 0.39 mmol) in methanol (6 mL) were added ammonia solution (28-30% ammonia, 0.7 mL, 9.5 mmol) and sodium hydrosulfite (Na2S2C>4, 672 mg, 3.86 mmol). After stirring at room temperature for 1 hour, the resulting solid was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure to afford Compound 500 (202 mg, crude), which was used without further purification. ELMS m / z : [M+H]+731.5. Preparation of Compound 501

[1168] To a solution of Compound 500 (202 mg, 0.28 mmol) in A, A-dimethylformamide (1 mL) was added Compound 2 (30 mg, 0.15 mmol) in AA-dimethylformamide (1 mL). After stirring at 0°C for 30 minutes, the reaction solution was added N-(3- dimethylaminopropyl)-A-ethylcarbodiimide (43.7 mg, 0.28 mmol). The reaction solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 501 (122 mg, 49%). ELMS m / z : [M+H]+892.5.

[1169] Preparation of Compound 502

[1170] To a solution of Compound 501 (50 mg, 0.05 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.2 mL) at -0 °C. After reaction mixture was raised to room temperature and stirred under nitrogen for 1 hour, the reaction mixture was concentrated under reduced pressure to afford Compound 502 (63 mg, crude), which was used without further purification. ELMS m / z : [M+H]+792.53.

[1171] Preparation of Compound 503

[1172] To a solution of Compound 502 (35.4 mg, 0.04 mmol) in N, A-dimethylformamide (1 mL) was added AA-diisopropylethylamine (0.04 mL, 0.22 mmol), carbonyldiimidazole (22 mg, 0.13 mmol), and L(t-butoxycarbonyl)piperazine (25 mg, 0.13 mmol). After stirring at room temperature for 20 hours, the reaction solution concentrated under reduced pressure to afford Compound 503 (45 mg, crude), which was used without further purification. EL MS m / z : [M+H]+1004.59.

[1173] Preparation of Compound 14c

[1174] To a solution of Compound 503 (45 mg, 0.04 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) at -0 °C. After stirring at room temperature under nitrogen for 1 hour, the reaction mixture was concentrated. The resulting residue was purified by HPLC to afford Compound 14c (5.4 mg, 9.5%). ELMS m / z : [M+H]+904.42.

[1175] Example 5 : Preparation of Compound 20

[1176] Preparation of Compound 15

[1177] To a solution of tert-butyl prop-2-en-l-ylcarbamate (1.0 g, 6.44 mmol) in N,N- dimethylformamide (9 mL) and methanol (1 mL), trimethylsilyl azide (1.27 mL, 9.66 mmol) and copper(I) iodide (613 mg, 3.22 mmol) were added. After stirring at 90 °C for 18 hours, the mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride solution (2 x 50 mL), and dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to afford Compound 15 (373 mg, 29%). 'H-NMR (400 MHz, CDC13) 8 7.65 (s, 1H), 5.09 (s, 1H), 4.43 (d, J= 6.0 Hz, 2H), 1.46 (s, 9H).

[1178] Preparation of Compound 16

[1179] To a solution of Compound 15 (122 mg, 0.62 mmol) and Compound 5 (315 mg, 0.68 mmol) in A A-dimethylformamide (5 mL) was added potassium carbonate (102 mg, 0.74 mmol) at room temperature under N2. After stirring for 16 hours, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with distilled water (2 x 15 mL) and brine (15 mL). The reaction mixture was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to afford Compound 16 (146 mg, 50%).1H-NMR (400 MHz, DMSO) 5 8.27 (s, 1H), 8.06 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.78 (s, 1H), 7.30 (s, 1H), 6.17 - 6.07 (m, 1H), 5.97 - 5.93 (m, 1H), 5.07 (d, J= 6.0 Hz, 2H), 4.84 (d, J= 5.2 Hz, 2H), 4.16 (d, J = 5.9 Hz, 2H), 1.38 (s, 9H).

[1180] Preparation of Compound 17

[1181] To a solution of Compound 16 (265 mg, 0.57 mmol) and Compound 9 (412 mg, 0.85 mmol) in / / -butanol (3 mL), A,A-diisopropylethylamine (0.49 mL, 2.84 mmol) was added at room temperature. After stirring at 100 °C for 21 hours and cooled to room temperature, the mixture was diluted with di chloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 17 (352 mg, 73%). ELMS m / z : [M+H]+842.42.

[1182] Preparation of Compound 18

[1183] To a solution of Compound 17 (352 mg, 0.42 mmol) in methanol (10 mL) and distilled water (2 mL), aqueous ammonia solution (28-30% NHs, 0.6 mL) and sodium hydrosulfite (Na2S?O4, 728 mg, 4.2 mmol) were added under N2. After stirring at room temperature for 2 hours, the mixture was diluted with methanol (50 mL) and filtered. The filtrate was concentrated under reduced pressure, diluted with di chloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Compound 18 (100 mg, 29%), which was used without further purification. ELMS m / z : [M+H]+ 812.47.

[1184] Preparation of Compound 19

[1185] To a solution of Compound 18 (100 mg, 0.12 mmol) in N, A -di methyl form am ide (3 mL), a solution of Compound 2 (29 mg, 0.15 mmol) in N, A -di methyl form am ide (1 mL) was added under N2. After stirring at room temperature for 1 hour, A-(3-dimethylaminopropyl)- A’-ethylcarbodiimide (0.03 mL, 0.17 mmol) and triethylamine (0.05 mL, 0.05 mmol) were added. The mixture was stirred at room temperature for 16 hours. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to afford Compound 19 (80 mg, 66%). ELMS m / z : [M+H]+973.54.

[1186] Preparation of Compound 20

[1187] To a solution of Compound 19 (80 mg, 0.08 mmol) in di chloromethane (3 mL), trifluoroacetic acid (1 mL) was added at -78 °C under N2. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC and lyophilized to afford Compound 20 (25 mg, 35%).1H- NMR (400 MHz, DMSO) 5 12.84 (s, 1H), 8.19 (s, 2H), 8.04 - 7.91 (m, 3H), 7.65 (s, 2H), 7.37 (s, 2H), 7.30 (s, 2H), 6.52 (d, J= 2.6 Hz, 2H), 5.96 - 5.79 (m, 3H), 4.95 - 4.87 (m, 6H), 4.58 - 4.48 (m, 6H), 4.10 (q, J= 5.7 Hz, 2H), 3.70 (s, 3H), 2.10 (d, J= 6.5 Hz, 6H), 1.26 (q, J= 7.1 Hz, 6H). ELMS m / z : [M+H]+873.55.

[1188] Example 6 : Preparation of Compound 30

[1189] Preparation of Compound 21

[1190] To a solution of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-l -carboxylate (2.2 g, 10.93 mmol) in dichloromethane (20 mL), dimethyl sulfoxide (5 mL), triethylamine (9.2 mL, 65.6 mmol), and sulfur tri oxide-pyridine complex (4.3 g, 27.33 mmol) were added at 0 °C. After stirring at room temperature for 17 hours, the mixture was diluted with dichloromethane (100 mL), washed with distilled water (50 mL) and 0.1 N hydrochloric acid (50 mL), and dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to afford Compound 21 (1.65 g, 75%). 'H-NMR (400 MHz, CDC13) 8 9.60 - 9.44 (m, 1H), 4.13 (d, J= 61.6 Hz, 1H), 3.62 - 3.40 (m, 2H), 2.23 - 1.82 (m, 4H), 1.46 (d, J= 19.7 Hz, 9H).

[1191] Preparation of Compound 22

[1192] To a solution of lithium chloride (421 mg, 9.94 mmol) and trimethyl phosphonoacetate (2.2 g, 12.42 mmol) in acetonitrile (8 mL), triethylamine (1.4 mL, 10.04 mmol) was added at 0 °C. After stirring at room temperature for 10 minutes, a solution of Compound 21 (1.6 g, 8.28 mmol) in acetonitrile (12 mL) was added. The reaction mixture was stirred at room temperature for 17 hours. After filtering and concentrating under reduced pressure, the mixture was diluted with diethyl ether (100 mL), washed with saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The resulting residue was purified by column chromatography to afford Compound 22 (1.43 g, 67%). 'H-NMR (400 MHz, CDCI3) 6 6.14 (t, J= 10.0 Hz, 1H), 5.74 (d, J= 11.4 Hz, 1H), 5.32 - 5.22 (m, 1H), 3.71 (s, 3H), 3.59 - 3.34 (m, 2H), 2.31 (d, J = 12.9 Hz, 1H), 1.84 (ddt, J= 12.5, 8.4, 6.0 Hz, 2H), 1.67 (dt, J= 13.2, 6.6 Hz, 1H), 1.42 (d, J= 22.5 Hz, 9H).

[1193] Preparation of Compound 23

[1194] To a solution of Compound 22 (700 mg, 2.74 mmol) in tetrahydrofuran (20 mL), a solution of sodium hydroxide (219 mg, 5.48 mmol) in distilled water (10 mL) was added at 0 °C. After stirring at room temperature for 17 hours, the mixture was diluted with ethyl acetate (200 mL) and washed with 1 N hydrochloric acid (100 mL). The organic layer was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was afforded as Compound 23 (660 mg, 99%), which was used without further purification. 'H-NMR (400 MHz, CDCI3) 6 6.91 (d, J= 13.0 Hz, 1H), 5.84 (d, J= 15.6 Hz, 1H), 4.46 (d, J= 56.8 Hz, 1H), 3.45 (s, 2H), 2.10 (s, 1H), 1.87 (q, J= 6.6 Hz, 5H), 1.49 - 1.40 (m, 9H).

[1195] Preparation of Compound 24

[1196] To a solution of Compound 23 (660 mg, 2.74 mmol) in tetrahydrofuran (10 mL), isobutyl chloroformate (0.37 mL, 2.87 mmol) and triethylamine (0.46 mL, 3.28 mmol) were added at -78 °C. After stirring at room temperature for 1 hour, methanol (5 mL) and sodium borohydride (310 mg, 8.21 mmol) were added. The mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 24 (494 mg, 79%). 'H-NMR (400 MHz, CDC13) 8 5.66 (s, 1H), 4.31 (d, J = 39.6 Hz, 1H), 4.14 (d, J= 5.0 Hz, 2H), 3.39 (s, 1H), 2.01 (s, 1H), 1.94 - 1.76 (m, 3H), 1.71 (ddd, J= 11.0, 6.7, 3.1 Hz, 4H), 1.45 (d, J = 6.8 Hz, 9H).

[1197] Preparation of Compound 25

[1198] To a solution of Compound 24 (494 mg, 2.17 mmol) in dichloromethane (20 mL), A-methylmorpholine (0.48 mL, 4.34 mmol) and methanesulfonyl anhydride (416 mg, 2.39 mmol) were added at -78 °C. After stirring at room temperature for 2 hours, the mixture was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Compound 25 (632 mg, 95%), which was used without further purification. 'H-NMR (400 MHz, CDCI3) 6 5.82 (s, 1H), 5.67 (s, 1H), 4.72 (d, J = 6.5 Hz, 2H), 4.32 (d, J = 39.2 Hz, 1H), 4.17 - 4.09 (m, 1H), 3.40 (s, 1H), 3.02 (s, 3H), 2.05 (s, 1H), 1.84 (p, J= 6.4 Hz, 2H), 1.58 (s, 2H), 1.44 (s, 9H).

[1199] Preparation of Compound 26

[1200] To a solution of Compound 25 (632 mg, 2.07 mmol) and Compound 5 (448 mg, 2.07 mmol) in N, A -di methyl form am ide (15 mL), potassium carbonate (314 mg, 2.27 mmol) was added at room temperature under N2. After stirring for 16 hours, the mixture was diluted with ethyl acetate (200 mL) and washed with distilled water (2 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 26 (563 mg, 63%). 'H-NMR (400 MHz, DMSO) 5 8.25 (s, 1H), 8.04 (d, J= 1.9 Hz, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 5.92 - 5.82 (m, 1H), 5.69 - 5.62 (m, 1H), 4.83 (d, J= 5.9 Hz, 2H), 4.21 (s, 1H), 3.29 - 3.19 (m, 2H), 1.77 (q, J= 6.7 Hz, 2H), 1.65 (s, 1H), 1.33 (d, = 27.7 Hz, 9H).

[1201] Preparation of Compound 27

[1202] To a solution of Compound 26 (300 mg, 0.70 mmol) and Compound 9 (511 mg, 0.98 mmol) in / / -butanol (4 mL), A,A-diisopropylethylamine (0.61 mL, 3.52 mmol) was added at room temperature. After stirring at 120 °C for 20 hours and cooled to room temperature, the mixture was diluted with di chloromethane (100 mL), methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 27 (263 mg, 46%). ELMS m / z : [M+H]+801.41.

[1203] Preparation of Compound 28

[1204] To a solution of Compound 27 (263 mg, 0.32 mmol) in methanol (10 mL) and distilled water (2 mL), aqueous ammonia solution (28-30% NIL, 0.5 mL) and sodium hydrosulfite (Na2S?O4, 572 mg, 3.28 mmol) were added under N2. After stirring at room temperature for 2 hours, methanol (50 mL) was added. The mixture was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Compound 28 (223 mg, 88%) without purification. ELMS m / z : [M+H]+771.43.

[1205] Preparation of Compound 29

[1206] To a solution of Compound 28 (223 mg, 0.29 mmol) in N, A -di methyl form am ide (2 mL), a solution of Compound 2 (47 mg, 0.24 mmol) in N, A -di methyl form am ide (1 mL) was added under N2. After stirring at room temperature for 1 hour, A-(3-dimethylaminopropyl)- A’-ethylcarbodiimide (0.07 mL, 0.43 mmol) and triethylamine (0.12 mL, 0.87 mmol) were added. The reaction was stirred at room temperature for 16 hours. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to afford Compound 29 (99 mg, 36%). ELMS m / z : [M+H]+932.48.

[1207] Preparation of Compound 30

[1208] To a solution of Compound 29 (99 mg, 0.11 mmol) in dichloromethane (1.6 mL), trifluoroacetic acid (0.4 mL) was added at -78 °C under N2. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC and lyophilized to afford Compound 30 (56 mg, 64%). Example 7 : Preparation of Compound 30a

[1209] Preparation of Compound 504

[1210] To a solution of Compound 502 (40 mg, 0.04 mmol; Compound 502 was prepared by the method described in International Patent Publication No. WO 2024 / 100452 A2) in A A -di methyl form am ide (1 mL) were added triethylamine (0.10 mL, 0.745 mmol) and N,N- bis(t-butoxycarbonyl)-U / -pyrazole-l-carboxamidine (17 mg, 0.06 mmol) After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure to afford Compound 504 (37 mg, crude), which was used without further purification. EIMS m / z : [M+H]+1035.01.

[1211] Preparation of Compound 30a

[1212] To a solution of Compound 504 (45 mg, 0.04 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) at -0 °C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The resulting residue was purified by HPLC to afford Compound 30a (23.8 mg, 46%). ELMS m / z : [M+H]+835.09.

[1213] Example 8 : Preparation of Compound 35

[1214] Preparation of Compound 31

[1215] To a solution of tert-butyl 3-oxopiperazine-l-carboxylate (300 mg, 0.86 mmol) in tetrahydrofuran (4 mL), potassium hydroxide (57.7 mg, 1.02 mmol) and tetrabutylammonium bromide (TBAB, 55.3 mg, 0.17 mmol) were sequentially added. After stirring at room temperature for 30 minutes, a solution of Compound 5 (300 mg, 0.858 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with distilled water (30 mL), and dried over anhydrous magnesium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to afford Compound 31 (213 mg, 52.9%). 'H-NMR (400 MHz, CDCh), 8 8.26 (br s, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 5.90-5.80 (m, 2H), 4.84 (d, J= 4.4 Hz, 1H), 4.00 (d, J= 4.8 Hz, 2H), 3.92 (s, 2H), 3.53-3.51 (m, 2H), 3.27-3.24 (m, 2H), 1.41 (s, 9H). ELMS m / z : [M+H]+469.07.

[1216] Preparation of Compound 32

[1217] To a solution of Compound 9 (440 mg, 0.91 mmol) and Compound 31 (213 mg, 0.45 mmol) in / / -butanol (4.5 mL), A,A-diisopropylethylamine (0.43 mL, 2.49 mmol) was added at room temperature. After stirring at 120 °C for 24 hours and cooled to room temperature, the mixture was diluted with di chloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was diluted with dichloromethane and diethyl ether, and the resulting solid was collected by filtration and dried to afford Compound 32 (213 mg, 55.5%). EI-MS m / z : [M+H]+844.04.

[1218] Preparation of Compound 33

[1219] To a solution of Compound 32 (210 mg, 0.25 mmol) in methanol (6 mL) and distilled water (1 mL), aqueous ammonia solution (28-30%, 0.44 mL) and sodium hydrosulfite (Na2S?O4, 433 mg, 2.48 mmol) were added under N2. After stirring at room temperature for 1 hour and 45 minutes, the mixture was diluted with methanol (50 mL) and filtered. The filtrate was concentrated under reduced pressure, diluted with di chloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude Compound 33 (234 mg, crude). EI-MS m / z : [M+H]+814.14.

[1220] Preparation of Compound 34

[1221] To a solution of crude Compound 33 (234 mg, 0.24 mmol) in N,N- dimethylformamide (2.5 mL), a solution of Compound 2 (50.9 mg, 0.26 mmol) in N,N- dimethylformamide (1 mL) was added under N2. After stirring at room temperature for 1 hour, A-(3-dimethylaminopropyl)-A’-ethylcarbodiimide hydrochloride (68.1 mg, 0.35 mmol) and triethylamine (0.1 mL, 0.71 mmol) were added. The mixture was stirred at room temperature for 18 hours and 30 minutes. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to afford Compound 34 (48 mg, 20% for 2 steps). EI-MS m / z : [M+H]+975.19.

[1222] Preparation of Compound 35

[1223] To a solution of Compound 34 (48 mg, 0.05 mmol) in dichloromethane (3.2 mL), trifluoroacetic acid (0.8 mL) was added at 0 °C under N2. After stirring at 0 °C for 40 minutes, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC and lyophilized to afford Compound 35 (10.2 mg, 17%). 'H-NMR (400 MHz, DMSO-d6), 8 1.28 (br s, 2H), 9.13 (br s, 1H), 7.96 (d, J= 14.7 Hz, 2H), 7.65 (s, 2H), 7.37 (br s, 2H), 7.30 (s, 2H), 6.53 (d, J= 6.3 Hz, 2H), 5.86-5.63 (m, 4H), 4.92-4.89 (m, 4H), 4.56-4.50 (m, 4H), 3.31 (s, 5H), 2.11 (d, J = 4.9 Hz, 6H) 1.29-1.25 (m, 6H). EI-MS m / z : [M+H]+875.11. Example 9 : Preparation of Compound 42

[1224] Preparation of Compound 36

[1225] To a solution of 4-nitropyrazole (1.0 g, 6.13 mmol) in methanol (20 mL), aqueous ammonia solution (28-30%, 2.2 mL) and sodium hydrosulfite (7.7 g) were added. After stirring at room temperature for 1 hour, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. To the resulting residue, methanol (15 mL) was added, followed by di- / c / 7-butyl dicarbonate (2.24 mL, 9.73 mmol) and triethylamine (1.86 mL, 13.27 mmol) at room temperature. The mixture was stirred for 16 hours, then diluted with ethyl acetate (50 mL) and washed with distilled water (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Compound 36 (0.7 g, 43%). 'H-NMR (400 MHz, DMSO-de) 8 9.05 (s, 1H), 7.44 (s, 1H), 1.42 (s, 9H).

[1226] Preparation of Compound 37

[1227] To a solution of Compound 36 (0.7 g, 3.82 mmol) in A A -di methyl form am ide (15 mL), cesium carbonate (3.7 g, 11.46 mmol) and trans- l,4-dibromo-2 -butene (2.45 g, 11.46 mmol) were added. After stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 37 (867 mg, 71%). 'H-NMR (400 MHz, CDCh) 6 7.66 (s, 1H), 7.33 (s, 1H), 6.24 (s, 1H), 6.00 - 5.90 (m, 1H), 5.87 (td, J = 13.2, 5.9 Hz, 1H), 4.69 (d, J = 5.6 Hz, 2H), 3.94 (d, J = 6.9 Hz, 2H), 1.50 (s, 9H). ELMS m / z : [M+H]+317.26.

[1228] Preparation of Compound 38

[1229] To a solution of Compound 4 (540 mg, 2.5 mmol) in A A-di methyl form am ide (15 mL), cesium carbonate (894 mg, 2.75 mmol) and Compound 37 (867 mg, 2.75 mmol) were added. After stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 38 (830 mg, 73%). 'H-NMR (400 MHz, DMSO-d6) 6 9.12 (s, 1H), 8.24 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.30 (s, 1H), 6.08 (d, J= 15.4 Hz, 1H), 5.86 (d, J= 15.8 Hz, 1H), 4.82 (d, J= 5.4 Hz, 2H), 4.74 (d, J= 5.9 Hz, 2H), 1.44 (d, J= 2.3 Hz, 9H). ELMS m / z : [M+H]+452.31.

[1230] Preparation of Compound 39

[1231] To a solution of Compound 38 (830 mg, 1.83 mmol) and Compound 9 (1.13 g, 2.76 mmol) in / / -butanol (11 mL), A / V-diisopropylethylamine (1.6 mL, 9.18 mmol) was added. After stirring at 0 °C for 5 minutes and heated to 120 °C, the reaction mixture was stirred for 24 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 39 (420 mg, 28%). ELMS m / z : [M+H]+827.39. Preparation of Compound 40

[1232] To a solution of Compound 39 (420 mg, 0.51 mmol) in methanol (5 mL), aqueous ammonia solution (28-30%, 1.8 mL, 12.66 mmol) and sodium hydrosulfite (882 mg, 5.06 mmol) were added. After stirring at room temperature for 2.5 hours, the mixture was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by reversed-phase column chromatography to afford Compound 40 (400 mg). ELMS m / z : [M+H]+797.48.

[1233] Preparation of Compound 41

[1234] To a solution of Compound 40 (400 mg, 0.51 mmol) in A A-di methyl form ami de (1.5 mL), a solution of Compound 2 (109 mg, 0.55 mmol) in AA -di methyl form am ide (1 mL) was added at 0 °C. After stirring for 30 minutes, A-(3-dimethylaminopropyl)-A’- ethylcarbodiimide (0.1 mL, 0.61 mmol) and triethylamine (0.35 mL, 2.53 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours, filtered, and concentrated under reduced pressure. The resulting residue was purified by reversed-phase column chromatography to afford Compound 41 (97 mg, 20%).

[1235] Preparation of Compound 42

[1236] To a solution of Compound 41 (30 mg, 0.03 mmol) in di chloromethane (1 mL), trifluoroacetic acid (0.2 mL) was added at 0 °C. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC and lyophilized to afford Compound 42 (10 mg, 27%).1H- NMR (400 MHz, CD3OD) 5 7.80 (s, 1H), 7.57 (d, J = 11.4 Hz, 3H), 7.29 (s, 1H), 7.23 (s, 1H), 6.62 (d, J= 1.7 Hz, 1H), 6.56 (s, 1H), 5.85 (d, J= 18.0 Hz, 3H), 5.70 (d, J= 15.6 Hz, 1H), 5.01 (s, 4H), 4.63 (s, 3H), 4.61 - 4.52 (m, 2H), 4.45 (s, 2H), 3.74 (s, 2H), 3.31 (m, 3H), 2.65 (s, 1H), 2.20 (d, J= 12.3 Hz, 6H), 1.34 (dt, J= 21.7, 6.9 Hz, 6H). ELMS m / z : [M+H]+858.54.

[1237] Example 10 : Preparation of Compound 42a

[1238] Preparation of Compound 505

[1239] To a solution of 5-nitroindole (1 g, 6.13 mmol) in methanol (15 mL) was added palladium / charcoal (85 mg). After stirring at room temperature under hydrogen balloon for 3 hours, the reaction solution was passed through Celite. The filtrate was concentrated under reduced pressure. The concentrated filtrate was dissolved in A,A-dimethylformamide (15 mL) at room temperature and then di-t-butyl dicarbonate (1.3 g, 6.13 mmol) and diisopropylethylamine (0.79 g, 6.13 mmol) were added. After stirring at room temperature for 5 hours, the reaction mixture diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 mL x 2) and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated under reduced pressure to afford Compound 505 (1.15 g, 80%), which was used without further purification.1H- NMR (400 MHz, DMSO-d6) 8 12.88 (s, 1H), 9.25 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.42 (d, J= 8.4 Hz, 1H), 7.35 (d, J= 8.8 Hz, 1H), 1.48 (s, 9H).

[1240] Preparation of Compound 506

[1241] To a solution of Compound 505 (1 g, 4.28 mmol) in A A-dimethylformamide (40 mL) were added potassium carbonate (711 mg, 5.14 mmol) and trans- l,4-dibromo-2 -butene (2.75 g, 12.86 mmol) at room temperature. After stirring at 60 °C for 18 hours for 6 hours. The reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL x 2) and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 506 (372 mg, 23%). 'H-NMR (400 MHz, DMSO) 5 9.21 (s, 1H), 8.19 (s, 1H), 7.85 (s, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.14 (dd, J = 15.1, 7.1 Hz, 1H), 5.88 (q, J = 7.5 Hz, 1H), 5.05 (d, J = 6.0 Hz, 2H), 4.23 (d, J = 6.8 Hz, 1H), 4.16 (d, J = 7.3 Hz, 2H), 1.48 (s, 9H).

[1242] Preparation of Compound 507

[1243] To a solution of Compound 506 (369 mg, 1.0 mmol) in N, A-dimethylformamide (4 mL) were added 4-chloro-3-hydroxy-5-nitrobenzamide (182 mg, 0.84 mmol) and potassium carbonate (174 mg, 1.26 mmol) under nitrogen. After stirring at 50 °C for 5 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 507 (312 mg, 74%). 'H-NMR (400 MHz, DMSO-de) 5 9.23 (s, 1H), 8.24 (d, J = 17.5 Hz, 2H), 8.06 (s, 1H), 7.87 (d, J = 13.6 Hz, 2H), 7.78 (s, 1H), 7.50 (d, J= 9.2 Hz, 1H), 7.22 (d, J= 9.2 Hz, 1H), 6.21 (dt, J= 15.8, 6.2 Hz, 1H), 6.01 - 5.90 (m, 1H), 5.10 (d, J= 6.1 Hz, 2H), 4.86 (d, J= 5.3 Hz, 2H), 1.48 (s, 9H). ELMS m / z : [M+H]+502.31.

[1244] Preparation of Compound 508

[1245] To a solution of Compound 507 (310 mg, 0.62 mmol) and Compound 9 (406 mg, 0.98 mmol) in n-butanol (6 mL) was added diisopropylethylamine (0.21 mL, 1.24 mmol) at room temperature. After heating to 120 °C and stirring for 20 hours, the reaction solution was cooled to room temperature. The reaction mixture diluted with dichloromethane(100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. After dilution with dichloromethane and diethyl ether, the obtained solid was filtered. The solid was dried to afford Compound 508 (179 mg, crude), which was used without further purification. ELMS m / z : [M+H]+877.59.

[1246] Preparation of Compound 509 To a solution of Compound 508 (179 mg, 0.20 mmol, crude) in methanol (7 mL) and distilled water (1 mL) were added ammonia solution (28-30% ammonia, 0.2 mL) and sodium hydrosulfite (Na2S2C>4, 355 mg, 2.04 mmol). After stirring at room temperature for 1 hour, The reaction mixture was diluted with methanol (50 mL) and filtered. The filtrate was concentrated and diluted with acetonitrile (10 mL), and the obtained solid was filtered. The solid was dried to afford Compound 509 (172 mg, crude), which was used without further purification. ELMS m / z : [M+H]+847.58.

[1247] Preparation of Compound 510

[1248] To a solution of Compound 509 (172 mg, 0.20 mmol, crude) in N,N- dimethylformamide (4 mL) was added Compound 2 (47 mg, 0.24 mmol) in N,N - dimethylformamide (1 mL) under nitrogen. After stirring at room temperature for 1 hour, the reaction solution was added A-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (47 mg, 0.30 mmol) and triethylamine (0.72 mL, 0.61 mmol) at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 510 (83 mg, 40%). ELMS m / z : [M+H]+1008.64.

[1249] Preparation of Compound 42a

[1250] To a solution of Compound 510 (33 mg, 0.03 mmol) in di chloromethane (1.6 mL) was added trifluoroacetic acid (0.4 mL) at -78 °C under nitrogen. After stirring at room temperature for 1 hour, the reaction solution concentrated under reduced pressure. The resulting residue was purified by HPLC to afford the Compound 42a (11 mg, 27%).1H- NMR (400 MHz, DMSO-d6) 8 12.84 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.68 - 7.60 (m, 3H), 7.45 (s, 1H), 7.37 - 7.28 (m, 3H), 7.06 (d, J= 9.2 Hz, 1H), 6.52 (s, 2H), 6.02 (dt, J= 14.1, 6.5 Hz, 1H), 5.79 (s, 2H), 4.90 (dd, J= 20.3, 7.7 Hz, 5H), 4.52 (dq, J= 14.1, 6.3 Hz, 5H), 3.69 (s, 3H), 2.10 (d, J= 10.6 Hz, 6H), 1.25 (q, J= 7.9 Hz, 6H). ELMS m / z : [M+H]+908.54.

[1251] Example 11 : Preparation of Compound 42b

[1252] Preparation of Compound 511

[1253] To a solution of Compound 37 (520 mg, 1.64 mmol) in A, A-dimethylformamide (5 mL) were added Potassium phthalimide (335 mg, 1.81 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous ammonium chloride solution (50 x 2 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to afford Compound 511 (592 mg, 94%), which was used without further purification. 'HNMR (400 MHz, CDC13) 8 7.85 - 7.81 (m, 2H), 7.72 - 7.69 (m, 2H), 7.59 (s, 1H), 7.30 (s, 1H), 6.39 (s, 1H), 5.94 - 5.85 (m, 1H), 5.73 - 5.64 (m, 1H), 4.63 (dd, J= 6.1, 1.3 Hz, 2H), 4.28 (dd, J= 5.9, 1.3 Hz, 2H), 1.47 (s, 9H).

[1254] Preparation of Compound 512

[1255] To a solution of Compound 511 (592 mg, 1.55 mmol) in methanol (10 mL) was added hydrazine monohydrate (0.2 mL, 4.64 mmol). After stirring at room temperature for

[1256] 1 hour, the reaction solution was added Dichloromethane and diethyl ether. The resulting solid was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 512 (352 mg, 90% for

[1257] 2 steps). 'HNMR (400 MHz, CDCI3) 6 7.67 (s, 1H), 7.31 (s, 1H), 6.22 (s, 1H), 5.84 - 5.72 (m, 2H), 4.69 - 4.63 (m, 2H), 3.33 (d, J= 3.6 Hz, 2H), 1.51 - 1.48 (m, 11H). Preparation of Compound 513

[1258] To a solution of Compound 512 (350 mg, 1.39 mmol) in dichloromethane (20 mL) were added A,7V’-diisopropylethylamine (1.2 mL, 6.93 mmol) and bis(pentafluorophenyl)carbonate (1.6 g, 4.16 mmol) at -0 °C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The reaction mixture was added dichloromethane and hexane. The resulting solid was filtered and dried to afford Compound 513 (310 mg, 24%), which was used without further purification. ELMS m / z : [M+H]+463.23.

[1259] Preparation of Compound 514

[1260] To a solution of Compound 513 (97 mg, 0.11 mmol) in N, A-dimethylformamide (2 mL) were added Compound 63 (50 mg, 0.05 mmol) and A,A-diisopropylethylamine (0.05 mL, 0.26 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The reaction mixture was added dichloromethane and hexane. The resulting solid was filtered and dried to afford Compound 514 (59 mg, crude), which was used without further purification. ELMS m / z : [M+H]+1001.54.

[1261] Preparation of Compound 42b

[1262] To a solution of Compound 514 (59 mg, crude) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL) at -0 °C. After stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford Compound 42b (30 mg, 45% for 2 steps). ELMS m / z : [M+H]+901.42.

[1263] Example 12 : Preparation of Compound 42c

[1264] Preparation of Compound 515

[1265] To a solution of methyl 4-nitro- IT / -pyrazole-3 -carboxylate (100 mg, 0.54 mmol) in MA-dimethylformamide (3 mL) were added cesium carbonate (285 mg, 0.88 mmol) and trans- l,4-dibromo-2 -butene (625 mg, 2.92 mmol) After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 x 2 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 515 (111 mg, 62%). ELMS m / z : [M+H]+304.11.

[1266] Preparation of Compound 516

[1267] To a solution of Compound 63 (50 mg, 0.07 mmol) in A,A-dimethylformamide (2 mL) were added cesium carbonate (34 mg, 0.1 mmol) and Compound 515 (23 mg, 0.08 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 516 (16 mg, 24%). ELMS m / z : [M+H]+946.27.

[1268] Preparation of Compound 517

[1269] To a solution of Compound 516 (67 mg, 0.07 mmol) in acetic acid (1 mL) was added zinc powder (46 mg). After stirring at room temperature for 2 hours, the reaction mixture was filtered through Celite then washed with methanol. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford Compound 517 (3.2 mg, 3.6%). ELMS m / z : [M+H]+916.03.

[1270] Preparation of Compound 42c

[1271] To a solution of Compound 517 (43 mg, 0.05 mmol) in methanol (1.5 mL) was added lithium hydroxide monohydrate (24 mg, 0.14 mmol) dissolved in water (0.5 mL) at - 50 °C. After stirring at 0 °C for 20 hours, the reaction mixture was adjusted to pH 4-5 with acetic acid. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford Compound 42c (1 mg, 1.7%). ELMS m / z : [M+H]+902.00.

[1272] Example 13 : Preparation of Compound 42d

[1273] 519

[1274] Preparation of Compound 518

[1275] To a solution of Compound 36 (300 mg, 1.64 mmol) in A A -di methyl form am ide (10 mL) were added cesium carbonate (693 mg, 2.13 mmol) and l,4-dibromo-2 -butene (1.04 g, 4.91 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous ammonium chloride solution (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 518 (320 mg, 62%).

[1276] Preparation of Compound 519

[1277] To a solution of Compound 63 (400 mg, 0.42 mmol) in A-dimethylformamide (5 mL) were added cesium carbonate (548 mg, 1.68 mmol) and Compound 518 (158 mg, 0.50 mmol) in N, -di methyl form am ide (2 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. The reaction mixture was added dichloromethane (50 mL) and methanol (10 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 519 (246 mg, 61%). ELMS m / z : [M+H]+956.52.

[1278] Preparation of Compound 42d

[1279] To a solution of Compound 519 (246 mg, 0.26 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at -0 °C. After stirring at room temperature under nitrogen for 1.5 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford Compound 42d (92 mg, 30%). ELMS m / z : [M+H]+856.48.

[1280] Example 14 : Preparation of Compound 48

[1281] Preparation of Compound 43

[1282] To a solution of tert-butyl carbazate (5.0 g, 37.83 mmol) in A( A -di methyl form am ide (30 mL), sodium hydride (60%, 3.8 g, 94.6 mmol) was added at 0 °C. After stirring at 0 °C for 30 minutes, 1,3 -dibromopropane (3.8 mL, 37.8 mmol) was added. The mixture was stirred at room temperature for 3 hours, then diluted with ethyl acetate (300 mL) and washed with distilled water (2 x 150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 43 (3.9 g, 57%). 'H-NMR (400 MHz, CDC13) 8 3.86 (s, 1H), 3.49 - 3.41 (m, 2H), 3.07 - 2.99 (m, 2H), 2.03 (p, J = 6.8 Hz, 2H), 1.52 - 1.44 (m, 9H).

[1283] Preparation of Compound 44

[1284] To a solution of Compound 43 (1.2 g, 6.86 mmol) and Compound 5 (2.0 g, 5.72 mmol) in A( A -di methyl form am ide (15 mL), potassium carbonate (1.1 g, 8.58 mmol) was added at room temperature under N2. After stirring for 18 hours, the mixture was diluted with ethyl acetate (200 mL) and washed with distilled water (2 x 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 44 (2.0 g, 80%). 'H-NMR (400 MHz, DMSO) 5 8.28 (s, 1H), 8.05 (d, J= 2.1 Hz, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 6.02 - 5.83 (m, 2H), 4.81 (d, J= 5.1 Hz, 2H), 3.26 (d, J= 6.0 Hz, 2H), 2.84 (t, J= 6.8 Hz, 2H), 2.00 (t, J= 7.3 Hz, 2H), 1.37 (s, 9H).

[1285] Preparation of Compound 45

[1286] To a solution of Compound 44 (2.0 g, 4.54 mmol) and Compound 9 (4.7 g, 9.07 mmol) in / / -butanol (35 mL), A,A-diisopropylethylamine (5.5 mL, 31.8 mmol) was added at room temperature. After stirring at 100 °C for 21 hours and cooled to room temperature, the mixture was diluted with dichloromethane and diethyl ether. The resulting solid was collected by filtration, washed with diethyl ether, and purified by column chromatography to afford Compound 45 (1.0 g, 28%). EI-MS m / z : [M+H]+816.52.

[1287] Preparation of Compound 46

[1288] To a solution of Compound 45 (1.0 g, 1.29 mmol) in methanol (20 mL) and water (4 mL), aqueous ammonia solution (28-30%, 1.4 mL) and sodium hydrosulfite (Na2S?O4, 2.2 g, 12.87 mmol) were added under N2. After stirring at room temperature for 2 hours, methanol (50 mL) was added and the resulting solid was collected by filtration. The filtrate was concentrated under reduced pressure, diluted with di chloromethane (100 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude Compound 46 (1.0 g), which was used without further purification. EI-MS m / z : [M+H]+786.58.

[1289] Preparation of Compound 47

[1290] To a solution of Compound 46 (1.0 g, 1.29 mmol) in A A -di methyl form am ide (6 mL), a solution of Compound 2 (301 mg, 1.54 mmol) in A(A -di methyl form am ide (3 mL) was added under N2 at room temperature. After stirring for 1 hour, N-(3- dimethylaminopropyl)-A’-ethylcarbodiimide hydrochloride (0.34 mL, 1.93 mmol) and triethylamine (0.36 mL, 2.57 mmol) were added. The mixture was stirred at room temperature for 17 hours, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 47 (545 mg, 44%). EI-MS m / z : [M+H]+947.62.

[1291] Preparation of Compound 48

[1292] To a solution of Compound 47 (63 mg, 0.07 mmol) in di chloromethane (2 mL), trifluoroacetic acid (0.2 mL) was added at 0 °C under N2. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC and lyophilized to afford Compound 48 (42 mg, 53%). EL MS m / z : [M+H]+847.55.

[1293] Example 15 : Preparation of Compound 58

[1294] Preparation of Compound 49

[1295] To a solution of Compound 4 (5.0 g, 23.08 mmol) in A A -di methyl form am ide (30 mL), cesium carbonate (11.2 g, 34.62 mmol) was added at 0 °C under N2. After 5 minutes, ethyl 4-bromobutyrate (5.4 g, 27.70 mmol) was added at room temperature under N2. After stirring for 2 hours, the mixture was diluted with ethyl acetate (60 mL) and washed with distilled water (2 x 15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was solidified using dichloromethane and hexane, and the resulting solid was collected by filtration and dried to afford Compound 49 (4.7 g, 61%), which was used without further purification. 'H-NMR (400 MHz, CDCI3) 8 8.29 (s,lH), 8.05 (s, 1H), 7.87 (s, 1H), 7.77 (s, 1H), 4.28 (m, 2H), 3.61 (s, 2H), 2.56-2.54 (m, 2H), 2.2L2.03(m, 2H). ELMS m / z : [M+H]+331.20.

[1296] Preparation of Compound 50

[1297] To a solution of Compound 49 (4.5 g, 13.60 mmol) in ethanol (30 mL) were added tert-butyl (£)-(4-aminobut-2-en-l-yl)carbamate (2.5 g, 13.60 mmol) and N,N- diisopropylethylamine (2.37 mL, 27.21 mmol) at 120 °C under N2. After stirring for 12 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (60 mL), and washed with distilled water (2 x 15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 50 (4.5 g, 68%).1H NMR (400 MHz, CDCI3) 6 8.15 (d, J= 1.9 Hz, 1H), 8.10 (s, 1H), 7.50 (d, J= 2.0 Hz, 1H), 5.71 (dt, J= 4.7, 2.8 Hz, 2H), 4.73 (s, 1H), 4.27 (ddd, J= 5.8, 4.1, 1.5 Hz, 2H), 4.09 (t, J= 6.4 Hz, 2H), 3.75 (s, 2H), 3.72 (s, 3H), 2.52 (t, J= 7.2 Hz, 2H), 2.18 (p, J= 6.8 Hz, 2H), 1.44 (s, 9H). ELMS m / z : [M+H]+467.79

[1298] Preparation of Compound 51

[1299] To a solution of Compound 50 (4.4 g, 9.156 mmol) in methanol (20 mL), aqueous ammonia solution (28-30%, 10 mL) and sodium hydrosulfite (Na2S2O4, 15 g, 91.6 mmol) were added at 0 °C. After stirring at room temperature for 1.5 hours, the mixture was filtered through Celite using methanol. The filtrate was concentrated under reduced pressure to afford Compound 51 (4 g, 96%). ELMS m / z : [M+H]+437.31.

[1300] Preparation of Compound 52

[1301] To a solution of Compound 51 (4.0 g, 8.87 mmol) in A A -di methyl form am ide (30 mL), Compound 2 (1.9 g, 9.76 mmol) was added at 0 °C. After stirring at room temperature for 30 minutes, triethylamine (3.7 mL, 26.63 mmol) and A-(3-dimethylaminopropyl)-A’- ethylcarbodiimide (2.7 g, 17.75 mmol) were added at 0 °C. The mixture was stirred at room temperature for 17 hours, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 52 (3.8 g, 71%).1H- NMR (400 MHz, DMSO-d6) 8 12.86 (s, 1H), 7.99 (s, 1H), 7.66 (s, 1H), 7.37-7.35 (m, 2H), 6.89 (m, 1H), 6.63 (s, 1H), 5.79-5.72 (d, J= 16 Hz, 1H), 5.58-5.54 (d, J= 16 Hz, 1H) 4.94 (s, 2H), 4.22 (s, 3H), 4.20 (m, 6H), 3.61 (s, 3H), 2.11 (s, 2H), 1.36 (m, 9H), 1.17 (m, 4H). ELMS m / z : [M+H]+598.31.

[1302] Preparation of Compound 53

[1303] To a solution of Compound 52 (3.8 g, 6.21 mmol) in dichloromethane (50 mL), hydrochloric acid (4 M solution in 1,4-dioxane, 11.5 mL) was added. After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure and diluted with diethyl ether (20 mL). The resulting solid was collected by filtration to afford Compound 53 (3.9 g, 99%). 'H-NMR (400 MHz, DMSO-d6) 6 8.04 (s, 1H), 7.88 (m, 2H), 7.68 (s, 1H), 7.39 (s, 2H), 6.67 (s, 1H), 6.08-6.04 (d, J= 16 Hz, 1H), 5.59-5.55 (d, J= 16 Hz, 1H), 5.00 (s, 2H), 4.22 (m, 2H), 3.65 (s, 3H), 1.37 (s, 3H), 2.19 (s, 3H), 2.11 (m, 2H). ELMS m / z : [M+H]+498.31.

[1304] Preparation of Compound 54

[1305] To a solution of Compound 53 (3.8 g, 6.63 mmol) and Compound 38 (2.0 g, 4.42 mmol) in / / -butanol (13 mL), / A-diisopropylethylamine (3.85 mL, 22.13 mmol) was added at room temperature. After stirring at 100 °C for 21 hours and cooled to room temperature, the mixture was diluted with di chloromethane (100 mL), methanol (20 mL) and washed with distilled water (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 54 (1.6 g, 38%). ELMS m / z : [M+H]+913.98.

[1306] Preparation of Compound 55

[1307] To a solution of Compound 54 (1.6 g, 1.83 mmol) in methanol (8 mL), aqueous ammonia solution (28-30%, 3.2 mL) and sodium hydrosulfite (Na2S?O4, 3.1 g, 18.3 mmol) were added under N2. After stirring at room temperature for 1 hour, methanol (50 mL) was added and the resulting solid was collected by filtration. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford Compound 55 (1.4 g, 85%). ELMS m / z : [M+H]+883.05. Preparation of Compound 56

[1308] To a solution of Compound 55 (1.35 g, 1.51 mmol) in A(A -di methyl form am ide (10 mL), a solution of Compound 2 (324 mg, 1.66 mmol) in A(A -di methyl form am ide (1 mL) was added under N2. After stirring at room temperature for 1 hour, N-(3- dimethylaminopropyl)-A’-ethylcarbodiimide hydrochloride (465 mg, 3.02 mmol) and triethylamine (0.63 mL, 4.53 mmol) were added. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 56 (560 mg, 35%). ELMS m / z : [M+H]+1045.96.

[1309] Preparation of Compound 57

[1310] To a solution of Compound 56 (100 mg, 0.094 mmol) in methanol (2 mL), lithium hydroxide monohydrate (13.8 mg, 0.28 mmol) in distilled water (1 mL) was added at -50 °C under N2. After stirring at 0 °C for 2 hours, the mixture was acidified to pH 4~5 with acetic acid. The mixture was concentrated and lyophilized to afford crude Compound 57 (100 mg), which was used without further purification. ELMS m / z : [M+H]+1031.95.

[1311] Preparation of Compound 58

[1312] To a solution of crude Compound 57 (100 mg, 0.097 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at 0 °C under N2. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC and lyophilized to afford Compound 58 (42 mg, 34%). 'H-NMR (400 MHz, DMSO-d6) 8 12.80 (s, 1H), 9.77 (s, 2H), 7.96 (s, 1H), 7.87 (m, 2H), 7.65 (s, 2H), 7.53 (s, 1H), 7.34 (s, 2H), 7.28 (s, 2H), 6.53 (s, 2H), 5.79 (m, 3H), 5.65 (m, 1H), 4.90 (s, 4H), 4.62 (m, 2H), 4.50 (m, 6H), 3.92 (m, 3H), 2.24 (s, 2H), 2.11 (m, 6H), 1.74 (m, 2H), 1.26 (m, 6H). ELMS m / z : [M+H]+929.98.

[1313] Example 16 : Preparation of Compound 66

[1314] Preparation of Compound 59

[1315] To a solution of 4-aminopyrazole (5.89 g, 70.8 mmol) in tetrahydrofuran (200 mL), triethylamine (15 mL, 106.13 mmol) and di- / c / 7-butyl dicarbonate (48.8 mL, 212.26 mmol) were added under N2. After stirring at room temperature for 20 hours, ethyl acetate (50 mL) was added and the mixture was washed with distilled water (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 59 (5.9 g, 29%). 'H-NMR (400 MHz, CDC13) 5 8.19 (s, 1H), 7.63 (s, 1H), 6.34 (s, 1H), 1.64 (d, J = 3.9 Hz, 9H), 1.52 (s, 9H).

[1316] Preparation of Compound 60

[1317] To a solution of Compound 59 (1.1 g, 3.88 mmol) in acetonitrile (30 mL), potassium carbonate (590 mg, 4.27 mmol), 18-crown-6 (513 mg, 1.94 mmol), and methyl acrylate (367 mg, 4.27 mmol) were added. After stirring at room temperature for 30 minutes, ethyl acetate (50 mL) was added and the mixture was washed with distilled water (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Compound 60 (1.38 g, 96%). 'H-NMR (400 MHz, CDC13) 5 7.77 (s, 1H), 7.27 (d, J = 3.1 Hz, 1H), 3...

Claims

We claim:

1. A conjugate represented by formula (I):wherein:AB is an antibody or antigen-binding fragment thereof;LABis an antibody linker; nDis an integer selected from 1-10; nDLis an integer selected from 1-10; and each D is independently an active agent (e.g., a drug (such as an immune modulator), a toxin), wherein at least one D is a STING agonist, each such STING agonist independently selected from a moiety represented by structural formula (la):wherein:V is selected from H, alkyl, alkenyl, alkynyl, aminoalkyl, amidoalkyl, alkylamido, carboxyl alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl and heteroarylalkyl, or V is a moiety coupled to LABand selected from alkylene, heteroalkylene and aminoalkylene; each instance of W1and W2is independently selected from alkyl, amino, amido, and hydrazido; n and m are each independently 0, 1, 2, or 3;Z is selected from alkylene, alkenylene, and alkynylene;A and B are each independently aryl or heteroaryl;Xaand Xbare each independently selected from CH2, NH, O, -NHC(O)-, -C(O)NH-, -C(0)0-, -0C(0)-, -OC(O)NH-, -NHC(O)O-, and S;L1is selected from alkenylene, alkynylene, alkenylene-J-, alkynylene-J-, -alkylene- , cycloalkylene, arylene, heteroarylene, heteroalkenylene, heteroalkynylene, *Y1-O-Y2**, and *Y3-NRY-Y4**,L2is a bond or a moiety coupled to LABand selected from -NH-, alkylamino, -N(RL) -, -N(H)RL-, -N(RL)C(=NH)NH-, -C(=NH)NH-, alkylene, heteroarylene, heterocyclylene, and arylene, or L2is -NH2, alkylamino, -N(RL)2, -N(H)RL, -N(RL)C(=NH)NH2, - C(=NH)NH2, alkyl, heteroaryl, heterocyclyl or aryl, wherein each can be optionally substituted;Y1and Y3are each independently selected from alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, heteroal kenylene, and heteroalkynylene,Y2and Y4are each independently selected from a single bond, alkylene, carbonyl, carbonyl-alkylene, carbonyl -arylene, carbonyl-arylene-alkylene, acylamide-alkylene, alkylene-heterocyclylene, heterocyclylene-alkylene, arylene, and heterocyclylene;* is the point of connection to Xa,** is the point of connection to L2;J is alkylene-heteroarylene, alkylene-heterocyclylene, heteroarylene-alkylene, heterocyclylene-alkylene, heteroarylene, or heterocyclylene, wherein each can be optionally substituted;;RYis H, alkyl, aminoalkyl, or C(=NH)NH2; andRLis H, alkyl (e.g., alkyl substituted with carboxylic acid), heteroalkyl, ester, heterocyclyl, aryl, heteroaryl, or cycloalkyl; and provided that either V or L2is a moiety coupled to LAB.

2. The conjugate of claim 1, wherein D is a moiety represented by structural formula (la):wherein:V is selected from H, alkyl, alkenyl, alkynyl, aminoalkyl, amidoalkyl, alkylamido, carboxyl alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heterocyclylalkyl, and cycloalkylalkyl; andL2is a bond or a moiety coupled to LABand selected from -NH-, alkylamino, -N(RL) -, -N(H)RL-, -N(RL)C(=NH)NH-, -C(=NH)NH-, alkylene, heteroarylene, heterocyclylene, and arylene.

3. The conjugate of claim 1, wherein D is a moiety represented by structural formula(la):wherein:V is a moiety coupled to LABand selected from alkylene (e.g., alkylene substituted with alkoxy and / or amino) heteroalkylene, and aminoalkylene;L2is selected from -NH2, alkylamino, -N(RL)2, -N(H)RL, -N(RL)C(=NH)NH2, - C(=NH)NH2, alkyl, heteroaryl, heterocyclyl, and aryl; preferably -NH(RL) and -N(RL)2, wherein each can be optionally substituted;RLis H, alkyl, (e.g., alkyl substituted with carboxylic acid), heteroalkyl, ester, heterocyclyl, aryl, heteroaryl, or cycloalkyl.

4. The conjugate of claim 3, wherein RLis a moiety represented by structural formula (Ia-RL)wherein:YRLis selected from -#NHC(O)-alkyl, -#C(O)NH- alkyl, and -#COO alkyl (e.g., alkyl substituted with alkoxy);R1is -CH2OR1A, or -CO2R1B;R1Ais H or a hydroxyl protecting group;R1Bis H or a carboxyl protecting group; each R2is independently H or a hydroxyl protecting group;# indicates the point of attachment to the phenyl ring and## indicates the point of attachment to the N to which RLis bonded.

5. The conjugate of claim 3 or 4, wherein:V iswherein * indicates the point of connection to Xb, and ** indicates the point of connection to LAB; and / or* indicates the point of connection to L1.

6. The conjugate of claim 2, whereinL1is selected from alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, heteroalkenylene, heteroalkynylene, *Y1-O-Y2**, and *Y3-NRY-Y4**;L2is a bond or a moiety coupled to LABand selected from -NH-, - N(RL)-, -N(RL)C(=NH)NH-, -C(=NH)NH-, alkylene, heteroarylene, heterocyclylene, and arylene;Y2and Y4are each independently selected from a single bond, alkylene, and heterocyclylene; andRYis H, alkyl, or C(=NH)NH2.

7. The conjugate of any one of claims 1-6, wherein Xbis O.

8. The conjugate of claim 2, wherein V is H.

9. The conjugate of claim 2, wherein V is alkyl.

10. The conjugate of claim 9, wherein V is methyl.

11. The conjugate of claim 2, wherein V is selected from -(alkylene)carboxylic acid, -(alkylene)guanidino, aminoalkyl, -(alkylene)NHC(O)CH2guanidino, - (alkylene)O(alkylene)guanidino, -(alkylene-O) nvaminoalkyl, -(alkylene-O-) nvalkoxylalkyl, and -(alkylene)amine; wherein each can be optionally substituted; wherein nv is an integer selected from 0 to 20.

12. The conjugate of claim 11, wherein V is C1-3 alkyl substituted with -COOH.

13. The conjugate of claim 11, wherein V is C1-6 alkyl substituted with five-membered heteroaryl, wherein the five-membered heteroaryl is optionally substituted one or more alkyl.

14. The conjugate of claim 11, wherein V is -(alkylene-O) nvaminoalkyl or -(alkylene- O) nvalkoxylalkyl, wherein nv is an integer selected from 0 to 10.

15. The conjugate of claim 14, wherein V is -(CH2CH2O)nv-aminoalkyl, wherein nv is an integer selected from 0 to 6.

16. The conjugate of claim 11, wherein V is Ci-6 aminoalkyl.

17. The conjugate of any one of claims 1-16, wherein W1is amido.

18. The conjugate of any one of claims 1-17, wherein W2is amido.The conjugate of any one of claims 1-18, wherein D is represented by structural formula (lb):

20. The conjugate of any one of claims 1-19, wherein A is heteroaryl.

21. The conjugate of claim 20, wherein A is 5-membered heteroaryl.

22. The conjugate of any one of claims 1-21, wherein B is heteroaryl.

23. The conjugate of claim 22, wherein B is 5-membered heteroaryl.

24. The conjugate of any one of claims 1-23, wherein A and B are each independently represented by one of the following structural formulas:wherein:Raand Rbare each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, halogen, OH, -OP(O)R’R”, -OR’, -NR’R”, -OCOR’, -CO2R’, -SOR’, -SO2R’, -CONR’R”, -SO2NR’R”, -OCONR’R”, -NR’ COR”, -NR’ SOR”, -NR’CO2R”, and -NR’SO2R”, and whereinR’ and R” are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, and a C2- 6 alkynyl.

25. The conjugate of any one of claims 1-24, wherein D is represented by structural formula (Ic):

26. The conjugate of any one of claims 1-25, wherein Z is alkenylene.

27. The conjugate of claim 26, wherein Z is -CH=CH-.

28. The conjugate of any one of claims 1-26, wherein Xais O.

29. The conjugate of any one of claims 1-28, wherein L1comprises a moiety represented by one of the following structural formulas:wherein:Q is phenyl or heteroarylene, and p and q are each independently 0, 1, 2, or 3, preferably 1 or 2.

30. The conjugate of claim 29, wherein p is 1 and q is 0 or 1.

31. The conjugate of claim 29, wherein L1is a moiety represented by one of the following structural formulas:wherein:G’ is CH or N,J is alkylene-heteroarylene, alkylene-heterocyclylene, heteroarylene-alkylene, heterocyclylene-alkylene, heteroarylene or heterocyclylene, wherein each can be optionally substituted;, k is 1, 2, or 3, preferably 1 or 2, and* indicates the point of attachment to Xa.

32. The conjugate of claim 31, wherein L1is a moiety represented by the following structural formula:

33. The conjugate of claim 31, wherein L1is a moiety represented by the following structural formula:

34. The conjugate of claim 31, wherein L1is a moiety represented by the following structural formula:

35. The conjugate of claim 34, wherein G’ is CH.

36. The conjugate of any one of claims 31-35, wherein J is a moiety represented by one of the following structural formulas:wherein: nJis an integer between 1-10 (e.g., 2, 3, 4, or 5), and** indicates the point of attachment to L2when L2is present, or LABwhen L2is a bond.

37. The conjugate of claim 31 or 36, wherein L1is a moiety represented by the following structural formula:wherein ** indicates the point of attachment to L2when L2is present, or LABwhen L2is a bond.

38. The conjugate of any one of claims 1-28, wherein L1is *Y1-O-Y2** or *Y3-NRY- Y4**; wherein * indicates the point of attachment to Xaand ** indicates the point of attachment to L2when L2is present, or LABwhen L2is a bond.

39. The conjugate of claim 38, wherein L1is *Y1-O-Y2** wherein * indicates the point of attachment to Xaand ** indicates the point of attachment to L2when L2is present, or LABwhen L2is a bond.

40. The conjugate of claim 39, wherein Y1is C2-6 alkenylene or C2-6 alkynylene.

41. The conjugate of claim 40, wherein Y1is unsubstituted C4 alkenylene or unsubstituted C4 alkynylene.

42. The conjugate of claim 41, wherein Y1is selected from43. The conjugate of any one of claims 38-42, wherein Y2is a single bond.

44. The conjugate of claim 38, wherein L1is *Y3-NRY-Y4**; wherein * indicates the point of attachment to Xaand ** indicates the point of attachment to L2when L2is present, or LABwhen L2is a bond.

45. The conjugate of claim 44, wherein Y3is C2-6 alkenylene or C2-6 alkynylene.

46. The conjugate of claim 45, wherein Y3is unsubstituted C4 alkenylene or unsubstituted C4 alkynylene.

47. The conjugate of claim 46, wherein Y3is selected from48. The conjugate of any one of claims 44-47, wherein Y4is C1-6 alkylene.

49. The conjugate of claim 48, wherein Y4is C1-3 alkylene optionally substituted with 1 to 3 substituents selected from C 1-5 alkyl, C1-5 haloalkyl, halogen, OH, oxo, -OR', - NR'R", -OCOR', -CO2R', -SOR', -SO2R', -CONR'R", -SO2NR'R", -OCONR'R", - NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", whereinR’ and R” are each independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl.

50. The conjugate of claim 49, wherein Y4is unsubstituted C1-3 alkylene.

51. The conjugate of any one of claims 44-50, wherein RYis selected from H, unsubstituted C1-3 alkyl, or -C(=NH)NH2.

52. The conjugate of claim 51, wherein RYis H.

53. The conjugate of claim 51, wherein RYis methyl or -C(=NH)NH2.

54. The conjugate of any one of claims 2 and 6-53, wherein L2is selected from a bond,-NH-, alkylamino, -N(RL)-, -N(H)RL-, -N(RL)C(=NH)NH-, 5- to 12-membered heteroarylene, 5- to 12-membered heterocyclylene, and C6-12 arylene.

55. The conjugate of claim 54, wherein L2is -N(RL)C(=NH)NH-.

56. The conjugate of claim 55, wherein RLis H.

57. The conjugate of claim 54, wherein L2is -N(RL)-.

58. The conjugate of claim 54, wherein RLis H, C1-6 alkyl, C1-6 alkyl carboxylic acid, or alkoxyl carboxylic acid.

59. The conjugate of claim 54, wherein RLis H, methyl, -CH2CH2COOH, - CH(CH2COOH)2, or -(CH2CH2O)2CH2COOH.

60. The conjugate of claim 54, wherein L2is selected from 5- to 7-membered heteroarylene, 5- to 7-membered heterocyclylene, and Ce arylene.

61. The conjugate of claim 57, wherein L2is 5- to 7-membered heteroarylene optionally independently substituted with 1 to 3 substituents selected from C1-5 alkyl, C1-5 haloalkyl, halogen, OH, C(=NH)NH2, -OR’, -NR’R”, -OCOR’, -CO2R’, -SOR’, -SO2R’, -CONR’R”, -CON(R’)R”N(R’”)2, -SO2NR’R ”, -OCONR’R ”, -NR’COR ”, -NR’SOR ”, -NR’CO2R ”, and -NR’ SO2R”, and whereineach instance of R’, R” and R’” is each independently selected from hydrogen, Ci- io alkyl, C2-10 alkenyl, and C2-10 alkynyl.

62. The conjugate of claim 57, wherein L2is unsubstituted 5- to 7-membered heterocyclylene.

63. The conjugate of any one of claims 2 and 6-54, wherein L2is a bond.

64. The conjugate of any one of claims 2 and 6-54, wherein L2is a moiety represented by one of the following structural formulas:wherein * indicates the point of attachment to LAB.

65. The conjugate of claim 38, wherein L1is *Y1-0-Y2** and wherein -O-Y2-L2is a moiety represented by one of the following structural formulas:formulas indicates the point of attachment to L2, or to LABwhen L2is a bond.

66. The conjugate of claim 38, wherein Li is *Y3-NRy-Y4**, and wherein -NRy-Y4-L2 is a moiety represented by one of the following structural formulas:wherein * in the structural formulas indicates the point of attachment to L2, or to LABwhen L2is a bond.

67. The conjugate of any one of claims 2 and 6-32, wherein D is represented by structural formula (Id):wherein:W3is selected from H, alkyl, amino, amido and carboxyl; and* indicates the point of attachment to LAB.

68. The conjugate of claim 67, wherein D is represented by structural formula (le):wherein:W3is selected from H, alkyl, amino, amido and carboxyl, and* indicates the point of attachment to LAB.

69. The conjugate of any one of claims 67 or 68, wherein W3is selected from H, alkyl, and carboxyl.

70. The conjugate of claim 69, wherein W3is H or COOH.

71. The conjugate of any one of claims 2 and 6-32, wherein D is represented by one of the following structural formula (If), (Ig) and (Ih):wherein * indicates the point of attachment to LAB.

72. The conjugate of any one of claims 1-71, wherein the active agent is selected from(a) a microtubule targeting agent (e.g., maytansinoid, maytansine, DM1, DM4, maytansinol, auristatin, dolastatin 10, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), eribulin, Halichondrin B, tubulysin, cryptophycin, EG5 inhibitor, SB-715992 (ispinesib), or filanesib (ARRY-520));(b) a DNA damaging agent (e.g., enediyne, calicheamicin, uncialamycin, topoisomerase inhibitor, topotecan, camptothecin, SN-38, irinotecan (CPT-11), exatecan, Dxd, pyrrolobenzodiazepine (PBD), PBD dimer, duocarmycins, Duocarmycin A, or CC-1065);(c) an RNA targeting agent (e.g., thailanstatin, amatoxin, a-amanitin, or P-amanitin);(d) an affinity ligand (e.g., the affinity ligand is a substrate, inhibitor, active agent, neurotransmitter, radioactive isotope, or mixtures thereof);(e) a radioactive label (e.g., 32P or 35S), a fluorescent dye, an electron dense reagent, a enzyme, an immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or mixtures thereof;(f) an immunomodulatory compound, an anti-cancer agent, an anti-viral agent, an antibacterial agent, an anti-fungal agent, an anti-parasitic agent, or mixtures thereof;(g) an estrogen receptor modulator (e.g., tamoxifen, raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, LY117018, onapristone or toremifene);(h) an aromatase inhibitor(e.g., 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, letrozole or anastrozole);(i) a nonsteroidal antiandrogen (NSAA) (e.g., flutamide, nilutamide, or bicalutamide);(j) an aromatase inhibitor;(k) a protein kinase inhibitor;(l) a lipid kinase inhibitor;(m) an antisense oligonucleotide;(n) a ribozyme;(o) a vaccine;(p) an anti -angiogenic agent;(q) a Bcl-xL inhibitor;(r) a NAMPT inhibitor; and(s) a Carmaphycin; and provided at least one D is a STING agonist.

73. The conjugate of any one of claims 1-72, wherein LABcomprises one or more moieties selected from a peptide moiety, an oxime moiety, a phenyl moiety, a branched moiety, a saccharide moiety, and a -OCH2CH2- moiety.

74. The conjugate of claim 73, wherein LABcomprises a moiety represented by structural formula (II-OXMI):wherein:Rloxmand R2oxmare each independently H, alkyl, or cycloalkyl, preferably alkyl; or Rloxmand R2oxmcombine to form a cycloalkyl.

75. The conjugate of claim 73, wherein LABcomprises a moiety represented by structural formula (II-0XM2):wherein:X1and X2are each independently N(R4oxm), O, or S, preferably X1is N(R4oxm) and X2is O; andR4oxmp[ alkyl, aryl, or aralkyl, preferably H;Rloxmand R2oxmare each independently H, alkyl, or cycloalkyl, preferably alkyl; or Rloxmand R2oxmcombine to form a cycloalkyl.

76. The conjugate of claim 74 or 75, wherein LABcomprises a moiety represented by:

77. The conjugate of any one of claims 1-76, wherein the conjugate comprises a moiety represented by structural formula (III-TAB):wherein:L1Ais a linkage to the remainder of LAB, wherein L1Acomprises a C1-C100 alkylene; X3and X4are each independently N(R5), O, or S;Y1, Y2, and Y3are each independently O, N(R6), or S;V1, V2, and V3are each independently a bond, N, NH, C, CH, or CH2 ;R5and R6are each independently H, alkyl, aryl, or aralkyl;L3, L4, and L5each independently comprise an alkylene;T1, T2, and T3are each independently a bond, -O-, or a cleavage group;D1, D2, and D3are each independently an active agent (e.g., a drug, a toxin), H, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, carboxylic acid, acyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, guanidinyl, amido, cyano, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, aryl, heteroaryl, or heterocyclyl, wherein at least one of D1, D2, and D3is a STING agonist, wherein the STING agonist is each independently a structure represented by structural formula (la),; orV1, T1and D1; V2, T2and D2; or V3, T3and D3together represent a branched moiety (e.g., a branched moiety substituted with one or more active agents); and ml, m2, and m3 are each independently 1, 2, or 3, preferably wherein ml, m2, and m3 are 1.

78. The conjugate of claim 77, wherein D1, D2or D3is each independently an active agent selected from:(a) a microtubule targeting agent (e.g., maytansinoid, maytansine, DM1, DM4, maytansinol, auristatin, dolastatin 10, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), eribulin, Halichondrin B, tubulysin, cryptophycin, EG5 inhibitor, SB-715992 (ispinesib), or filanesib (ARRY-520));(b) a DNA damaging agent (e.g., enediyne, calicheamicin, uncialamycin, topoisomerase inhibitors, topotecan, camptothecin, SN-38, irinotecan (CPT-11), exatecan, Dxd, pyrrolobenzodiazepine (PBD), PBD dimer, duocarmycin, Duocarmycin A, or CC-1065);(c) an RNA targeting agent (e.g., thailanstatin, amatoxin, a-amanitin, or P-amanitin);(d) an affinity ligand (e.g., the affinity ligand is a substrate, inhibitor, active agent, neurotransmitter, radioactive isotope, or mixtures thereof);(e) a radioactive label (e.g., 32P or 35S), a fluorescent dye, an electron dense reagent, an enzyme, an immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or mixtures thereof;(f) an immunomodulatory compound, an anti-cancer agent, an anti-viral agent, an antibacterial agent, an anti-fungal agent, an anti-parasitic agent, or mixtures thereof;(g) an estrogen receptor modulator (e.g., tamoxifen, raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, LY117018, onapristone or toremifene);(h) an aromatase inhibitor(e.g., 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, letrozole or anastrozole);(i) a nonsteroidal antiandrogen (NSAA) (e.g., flutamide, nilutamide, or bicalutamide);(j) an aromatase inhibitor;(k) a protein kinase inhibitor;(l) a lipid kinase inhibitor;(m) an antisense oligonucleotide;(n) a ribozyme;(o) a vaccine;(p) an anti -angiogenic agent;(q) a Bcl-xL inhibitor;(r) a NAMPT inhibitor; and(s) a Carmaphycin; and provided at least one of D1, D2, and D3is a STING agonist.

79. The conjugate of claim 77 or 78, wherein D1, D2or D3is each independently an active agent selected from MMAE, MMAF, exatecan, taltobulin, Genz-644282, dasatinib, and a STING agonist; wherein the STING agonist is independently a structure represented by formula (la).

80. The conjugate of any one of claims 77-79, wherein V1is a bond and ml is 1; V2is a bond and m2 is 1; and / or V3is a bond and m3 is 1.

81. The conjugate of any one of claims 77-80, wherein L3, L4, or L5each independently comprises a Ci-Cioo alkylene.

82. The conjugate of any one of claims 77-80, wherein L3, L4, or L5each independently comprises *-(CH2CH2)-(OCH2CH2)I -20-**, wherein * indicates the point of attachment to Y1, Y2or Y3, respectively; and ** indicates the point of attachment to V1, V2or V3, respectively.

83. The conjugate of any one of claims 77-80, wherein L3, L4, or L5each independently comprises an oligoethylene glycol (e.g., oligoethylene glycol comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ethylene glycol moieties).

84. The conjugate of any one of claims 77-83, wherein L3, L4, or L5each independently further comprises an amido moiety.

85. The conjugate of claim 84, wherein L3, L4, or L5each independently comprises 1, 2, 3, 4, 5, or 6 amido moieties.

86. The conjugate of any one of claims 77-85, wherein L3, L4, or L5each independently further comprises a heteroaryl (e.g., pyrazolyl, triazolyl).

87. The conjugate of any one of claims 77-86, wherein L3, L4, or L5each independently comprises a structure represented by formula (Ill-a) or (Ill-b):(IILa) (IILb) wherein: each Ay1represents a linkage to V1, V2or V3, respectively and each Ay2represents a linkage to Y1, Y2or Y3,respectively; preferably each Ay1and Ay2are each independently Ci-io alkyl.

88. The conjugate of claim 77, wherein at least one of L3, L4, or L5each independently comprises a structure represented by formula (Ill-a) or (Ill-b).

89. The conjugate of claim 81, wherein:indicates the point of attachment to V1; and ** indicates the point of attachment to Y1;L4comprises *-(CH2CH2)-(OCH2CH2)I-2O-* *, wherein * indicates the point of attachment to V2; and ** indicates the point of attachment to Y2; and / orL5is *-(CH2CH2)-(OCH2CH2)5-**, wherein * indicates the point of attachment to V3; and ** indicates the point of attachment to Y3.

90. The conjugate of any one of claims 77-89, wherein T1, T2, and T3each independently comprises a structure represented by formula (Ill-d)wherein:Y is selected from - NHC(O)-, -#C(0)NH-, -#(CH2)tNHC(O)-, and -#COO-, preferably -#C(0)NH-;R1is -CH2OR1A, or -CO2R1B;R1Ais H or a hydroxyl protecting group, preferably H;R1Bis H or a carboxyl protecting group, preferably H; each R2is independently H or a hydroxyl protecting group, preferably H; t is 1, 2, or 3, preferably 1; indicates the point of attachment to D1, D2, or D3of formula (III-TAB), respectively;* indicates the point of attachment to V1, V2, and V3of formula (III-TAB), respectively; and# indicates the point of attachment to the phenyl ring of formula (Ill-d).

91. The conjugate of 90, wherein T1, T2, or T3comprises a structure represented by formula (III-d-1):wherein: indicates the point of attachment to D1, D2, or D3of formula (III-TAB); and * indicates the point of attachment to V1, V2, or V3of formula (III-TAB).

92. The conjugate of any one of claims 77-91, wherein D1, D2, and / or D3is a STING agonist, wherein the STING agonist has a structure represented by formula (la):wherein:V is a moiety coupled to T1, T2or T3.

93. The conjugate of any one of claims 77-91, wherein D1, D2, and / or D3, is a STING agonist, wherein the STING agonist has a structure represented by formula (la):wherein:L2is a bond, or a moiety coupled to T1, T2or T3respectively.

94. The conjugate of any one of claims 77-93, wherein D1, D2and / or D3is H, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, carboxylic acid, acyl, ester, thioester, alkoxy, phosphoryl, amino, alkylamino, guanidinyl, amido, cyano, azido, alkylthio, cycloalkyl, alkylsulfonyl, sulfonamido, aryl, heteroaryl, or heterocyclyl; provided at least one of D1, D2, and D3is a STING agonist.

95. The conjugate of claim 94, wherein D2is H, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, amino, amido, aryl, heteroaryl, or heterocyclyl.

96. The conjugate of claims 94 or 95, wherein D2is selected from -97. The conjugate of any one of claims 77-96, wherein: V1is N and V1, T1and D1together represent a branched moiety having a structure represented by formula (III-e-1) or a pharmaceutically acceptable salt thereof:wherein:Ax3represents a linkage to L3;Lx1and Lx2each independently comprise an alkylene;Tx1and Tx2are each independently a bond or a cleavage group; andBx1and Bx2are each independently an active agent (e.g., a drug or a toxin);98. The conjugate of any one of claims 77-96, wherein: V1is CH and V1, T1, and D1together represent a branched moiety having a structure represented by formula (III-e-2) or a pharmaceutically acceptable salt thereof:wherein:Ax3represents a linkage to L3;Lx1and Lx2each independently comprise an alkylene;Tx1and Tx2are each independently a bond or a self-immolative moiety; andBx1and Bx2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

99. The conjugate of any one of claims 77-96, V1is CH and V1, T1, and D1together represent a branched moiety having a structure represented by formula (III-e-3) or a pharmaceutically acceptable salt thereof:wherein:Ax3represents a linkage to L3;Lx1and Lx2each independently comprise an alkylene;Gx1, Gx2, and Gx3are each independently an alkylene,each Rx1is independently H, alkyl, or aralkyl;Tx1and Tx2are each independently a bond or a self-immolative moiety; andBx1and Bx2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

100. The conjugate of any one of claims 77-96, V1is C and V1, T1and B1together represent a branched moiety having a structure represented by formula (III-e-4) or a pharmaceutically acceptable salt thereof:wherein:Ax3represents a linkage to L3;Lx1, Lx2, and Lx3each independently comprise an alkylene;Tx1, Tx2, and Tx3are each independently a bond or a self-immolative moiety; andBx1, Bx2, and Bx3are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

101. The conjugate of any one of claims 77-100, (A) wherein V2is N and V2, T2, and B2together represent a branched moiety having a structure represented by formula (IILe-5) or a pharmaceutically acceptable salt thereof:wherein:Ay3represents a linkage to L3;Ly1and Ly2each independently comprise an alkylene;Ty1and Ty2are each independently a bond, or a self-immolative moiety; andBy1and By2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl; or(B) wherein V2is CH and V2, T2, and B2together represent a branched moiety having a structure represented by formula (III-e-6) or a pharmaceutically acceptable salt thereof:wherein:Ay3represents a linkage to L3;Ly1and Ly2each independently comprise an alkylene;Ty1and Ty2are each independently a bond or a self-immolative moiety; andBy1and By2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl; or(C) wherein V2is CH and V2, T2, and B2together represent a branched moiety having a structure represented by formula (III-e-7) or a pharmaceutically acceptable salt thereof:wherein:Ay3represents a linkage to L3; andLy1and Ly2each independently comprise an alkylene;Gy1, Gy2, and Gy3are each independently an alkylene,each Ry1is independently H, alkyl, or aralkyl;Ty1and Ty2are each independently a bond or a self-immolative moiety; andBy1and By2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl; or wherein V2is C and V2, T2and B2together represent a branched moiety having a structure represented by formula (III-e-8) or a pharmaceutically acceptable salt thereof:wherein:Ay3represents a linkage to L3;Ly1, Ly2, and Ly3each independently comprise an alkylene;Ty1, Ty2, and Ty3are each independently a bond or a self-immolative moiety; andBy1, By2, and By3are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

102. The conjugate of any one of claims 77-100, (A) wherein V3is N and V3, T3and D3together represent a branched moiety having a structure represented by formula (III-e-9) or a pharmaceutically acceptable salt thereof:wherein:Az3represents a linkage to L5;Lz1and Lz2each independently comprise an alkylene;Tz1and Tz2are each independently a bond or a cleavage group; andBz1and Bz2are each independently an active agent (e.g., a drug or a toxin); or(B) wherein V3is CH and V3, T3, and D3together represent a branched moiety having a structure represented by formula (III-e-10) or a pharmaceutically acceptable salt thereof:(iii-e-10) wherein:Az3represents a linkage to L5;Lz1and Lz2each independently comprise an alkylene;Tz1and Tz2are each independently a bond or a self-immolative moiety; andBz1and Bz2are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

103. The conjugate of any one of claims 77-100, wherein V3is CH and V3, T3, and D3together represent a branched moiety having a structure represented by formula (III-e-11) or a pharmaceutically acceptable salt thereof:wherein:Az3represents a linkage to L5;Lz1and Lz2each independently comprise an alkylene;Gz1, Gz2, and Gz3are each independently an alkylene,each Rz1is independently H, alkyl, or aralkyl;Lz1and Lz2each independently comprise an alkylene;Tz1and Tz2are each independently a bond or a self-immolative moiety; andBz1and Bz2are each independently an active agent (e.g., a drug or a toxin).

104. The conjugate of any one of claims 77-100, wherein V3is CH and V3, T3, and D3together represent a branched moiety having a structure represented by formula (III-e-12) or a pharmaceutically acceptable salt thereof:wherein:Az3represents a linkage to L5;Lz1, Lz2, and Lz3each independently comprise an alkylene;Tz1, Tz2, and Tz3are each independently a bond or a self-immolative moiety; andBz1, Bz2, and Bz3are each independently an active agent (e.g., a drug or a toxin), amido, carboxyl, ester, urea, or heteroaryl.

105. The conjugate of any one of claims 95-104, wherein:Az3is a bond or C1-20 alkylene;Lz1and Lz2each independently comprises C1-20 alkylene and / or an oligoethylene glycol;Tz1and Tz2are each independently a bond or a cleavage group represented by structural formula (III-d); andBz1and Bz2are each independently an active agent (e.g., a drug or a toxin).; wherein formula (III-d) is represented by:Y is selected from - NHC(O)-, -#C(O)NH-, -#(CH2)tNHC(O)-, and -#COO-, R1is -CH2OR1A, or -CO2R1B;R1Ais H or a hydroxyl protecting group;R1Bis H or a carboxyl protecting group; each R2is independently H or a hydroxyl protecting group; t is 1, 2, or 3, preferably 1; indicates the point of attachment to Bz1or Bz2of formula (III-e-9, III-e-10, III- e-11, and III-e-12), respectively;* indicates the point of attachment to the Lz1or Lz2of formula III-e-9, III-e-10, III- e-11, and III-e-12) respectively; and# indicates the point of attachment to the phenyl ring of formula (III-d).

106. The conjugate of any one of claims 97-104, wherein Lzl and Lz2are each independently C1-6 alkylene and / or an oligoethylene glycol (e.g., oligoethylene glycol comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ethylene glycol moieties).

107. The conjugate of any one of claims 97-104, wherein Lz1and Lz2each independently further comprises an amido moiety.

108. The conjugate of claim 107, wherein Lz1and Lz2each independently comprises 1, 2, 3, 4, 5, or 6 amido moieties.

109. The conjugate of any one of claims 97-104, wherein Lz1and Lz2each independently further comprises a heteroaryl (e.g., pyrazolyl, triazolyl).

110. The conjugate of any one of claims 77-109, wherein L1Acomprises *-(CH2CH2)- (OCH2CH2)I -20-**, wherein * indicates the point of attachment to the X3; and ** indicates the point of attachment to formula (II-OXMI) or (II-0XM2).

111. The conjugate of any one of claims 77-110, wherein L1Acomprises a moiety represented by the formula:wherein * indicates the point of attachment to the X3of formula (III-TAB) and ** indicates the point of attachment to the remainder of LAB.

112. The conjugate of any one of claim 77-111, wherein LABcomprises a moiety represented by structural formula (II):wherein:Y is selected from - NHC(O)-, -#C(O)NH-, -#(CH2)tNHC(O)-, and -#COO-;G is represented by one of the following structural formulas:wherein:R3is H, alkyl, CH2OR3A, or CO2R3B; each R4is independently H or a hydroxyl protecting group;R3Ais H or a hydroxyl protecting group; andR3Bis H or a carboxyl protecting group; each Z is independently C1-5 alkyl, halogen, cyano, or nitro; nzis 0, 1, 2 or 3;* indicates the point of attachment to the remainder of LAB; indicates the point of attachment to L2or V; and# indicates the point of attachment to the phenyl ring.

113. The conjugate of any one of claims 73-112, wherein LABcomprises a moiety represented by structural formula (Ila):wherein:Y is selected from - NHC(O)-, -#C(O)NH-, -#(CH2)tNHC(O)-, and -#COO-, R1is -CH2OR1A, or -CO2R1B;R1Ais H or a hydroxyl protecting group;R1Bis H or a carboxyl protecting group; each R2is independently H or a hydroxyl protecting group; t is 1, 2, or 3, preferably 1; indicates the point of attachment to L2or V;* indicates the point of attachment to the remainder of LAB; and# indicates the point of attachment to the phenyl ring.

114. The conjugate of claim 113, wherein R1is -CH2OR1A.

115. The conjugate of claim 114, wherein R1Ais H.

116. The conjugate of claim 113, wherein R1is -COOR1B.

117. The conjugate of claim 116, wherein R1Bis H.

118. The conjugate of any one of claims 73-117, wherein LABcomprises a peptide.

119. The conjugate of claim 118, wherein the peptide comprises at least one hydrophilic amino acid.

120. The conjugate of claim 118 or 119, wherein the peptide comprises an amino acid having a side chain having a moiety that bears a charge at neutral pH in aqueous solution (e.g., an amine, guanidine, or carboxyl moiety).

121. The conjugate of any one of claims 118-119, wherein the peptide comprises an amino acid selected from alanine, aspartate, asparagine, glutamate, glutamine, glycine, lysine, ornithine, proline, serine, histidine, arginine and threonine.

122. The conjugate of any one of claims 73-121, wherein LABcomprises from 1 to 20 -OCH2CH2- moieties.

123. The conjugate of claim 122, wherein LABcomprises from 2 to 6 -OCH2CH2- moieties.

124. The conjugate of any one of claims 73-123, wherein LABcomprises a moiety represented by structural formula (lie):wherein:L6is a linker,Y is selected from - NHC(O)-, -#C(O)NH-, -#(CH2)tNHC(O)-, and -#COO-, R3is -CH2OR1A, or -CO2R1B;R1Ais H or a hydroxyl protecting group;R1Bis H or a carboxyl protecting group; each R4is independently H or a hydroxyl protecting group; t is 1, 2, or 3, preferably 1; ## indicates the point of attachment to L2, and* indicates the point of attachment to the remainder of LAB.

125. The conjugate of claim 124, wherein Y is -^NHC^)-, wherein # indicates the point of attachment to the phenyl ring.

126. The conjugate of claim 125, wherein Y is -#C(O)NH-, wherein # indicates the point of attachment to the phenyl ring.

127. The conjugate of any one of claims 73-126, wherein LABcomprises a moiety represented by structural formula (IV):wherein:Y is selected from - NHC(O)-, -#c(O)NH-, -#(CH2)tNHC(O)-, and -#COO-, wherein # indicates the point of connection to the phenyl;D is an active agent, e.g., selected from a STING agonist; wherein the STING agonist is independently a structure represented by formula (la)) MMAE, ProMMAE, MMAF, taltobulin, Genz-644282, dasatinib and exatecan;* indicates the point of attachment to the remainder of LABand# indicates the point of attachment to L2or V.

128. The conjugate of any one of claims 124-127, wherein L6comprises: a C1-50 alkylene or C1-50 heteroalkylene wherein the C1-50 alkylene or C1-50 heteroalkylene comprises one or more of:(i) one or more unsaturated bonds;(ii) a heteroarylene (e.g., a heteroarylene in the alkylene or heteroalkylene chain);(iii) at least one C1-20 alkyl substituent; and(iv) at least one isoprenyl group having a structure represented by Formula (V):

129. The conjugate of claim 128, wherein L6comprises a C1-50 alkylene.

130. The conjugate of claim 128 or claim 129, wherein L6comprises a C1-50 heteroalkylene.

131. The conjugate of any one of claims 128-130, wherein L6comprises an unsaturated bond (e.g., 1, 2, 3, 4 or 5 unsaturated bonds).

132. The conjugate of any one of claims 128-131, wherein L6is substituted with a C1-20 alkyl.

133. The conjugate of any one of claims 128-132, wherein L6comprises an isoprenyl group having a structure represented by formula below:wherein nv is an integer of 1-20.

134. The conjugate of any one of claims 124-133, wherein L6comprises a peptide comprising at least one hydrophilic amino acid and the nitrogen of Y forms a peptide bond with a carbonyl of a hydrophilic amino acid.

135. The conjugate of claim 134, wherein the hydrophilic amino acid comprises a side chain having a moiety which has electric charge in aqueous solution at a neutral pH in aqueous solution (e.g., an amine, guanidine, or carboxyl moiety).

136. The conjugate of claim 134 or claim 135, wherein the hydrophilic amino acid is selected from arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine and threonine.

137. The conjugate of any one of claims 124-136, wherein L6comprises a unit represented by structural formula (VI) or (VII)-(CH2)r(L7(CH2)o)s- (VI), -(CH2CH2L8)W- (VII); wherein:L7is a single bond, -O-, -S-, -NR21-, -C(O)NR22-, -NR23C(O)-, -NR24SO2-, or - SO2NR25-, preferably -O-;L8is -O-, C1-8 alkylene, or -NR21-, preferably -O-;R21to R25are each independently H, C1-6 alkyl, C1-6 alkyl(Ce-2o aryl), or C1-6 alkyl(C3-2o heteroaryl); r is an integer of 0 to 10; o is an integer of 0 to 12; s is an integer of 1 to 20; and w is an integer of 1 to 20.

138. The conjugate of claim 137, wherein L7is -O-.

139. The conjugate of claim 137 or claim 138, wherein L8is -O-.

140. The conjugate of any one of claims 137-139, wherein R21is H.

141. The conjugate of any one of claims 137-140, wherein R22is H.

142. The conjugate of any one of claims 137-141, wherein R23is H.

143. The conjugate of any one of claims 137-142, wherein R24is H.

144. The conjugate of any one of claims 137-143, wherein R25is H.

145. The conjugate of any one of claims 137-144, wherein r is 1 or 2.

146. The conjugate of any one of claims 137-145, wherein o is 1 or 2.

147. The conjugate of any one of claims 137-146, wherein s is 1 to 12.

148. The conjugate of any one of claims 137-147, wherein w is 1 to 12.

149. The conjugate of any one of claims 137-148, wherein L6comprises at least one polyethylene glycol monomer represented by150. The conjugate of any one of claims 137-149, wherein L6comprises a unit represented by structural formula (Va), (Vb), (Vc), (Vd), or (Ve):(Va) (Vb) (Vc) (Vd) (Ve) whereinL9is a single bond or C1-30 alkylene; andR11is H or Ci-10 alkyl.

151. The conjugate of claim 150, wherein L9is a single bond.

152. The conjugate of claim 150, wherein L9is C1-30 alkylene.

153. The conjugate of any one of claims 150-152, wherein R11is H.

154. The conjugate of any one of claims 150-153, wherein R11is C1-10 alkyl (c.g, methyl).

155. The conjugate of any one of claims 1-154, wherein L6comprises: i) a branching unit covalently coupled to AB by a primary linker; ii) a first branch which couples a first D to the branching unit; and iiia) a second branch which couples a second D to the branching unit; or iiib) a second branch comprising an alkyl or heteroalkyl (e.g., a polyethylene glycol monomer or a polyethylene glycol oligomer) is covalently coupled the branching unit.

156. The conjugate of claim 155, wherein L6comprises a second branch which couples a second D, via a second cleavage group, to the branching unit.

157. The conjugate of claim 155, wherein L6comprises a second branch comprising an alkyl or heteroalkyl (e.g., a polyethylene glycol monomer or a polyethylene glycol oligomer) coupled the branching unit.

158. The conjugate of any one of claims 155-157, wherein the branching unit has a structure represented by formula (Via), (VIb), (Vic), or (Vid):R30is H or alkyl;R40is H, alkyl or L5’-CO2R50;R50is H or alkyl; andL2, L3, L4, and L5are each independently a bond or alkylene.

159. The conjugate of any one of claims 155-158, wherein the branching unit has a structure represented by formula (wherein R30is H or alkyl.

160. The conjugate of any one of claims 155-159, wherein the branching unit has a structure represented by formula VIf:wherein R30is H or alkyl.

161. The conjugate of any one of claims 1-160, wherein the conjugate comprises 1, 2, 3, or 4 branched linkers.

162. The conjugate of claim 161, wherein each branched linker comprises at least two active agents.

163. The conjugate of claim 162, wherein each branched linker comprises two active agents.

164. The conjugate of any one of claims 155-163, wherein the branching unit comprises a lysine residue and the primary linker is bound to a C-terminus of lysine.

165. The conjugate of any one of claims 1-164, wherein the conjugate is cleavable in a target cell (e.g., the conjugate cleaves to release one or more active agents).

166. The conjugate of any one of claims 124-165, wherein L6comprises a moiety represented by structural formula (Vf), (Vg), (Vh), (Vi) or (Vj):whereinD is an active agent independently selected from a STING agonist; wherein the STING agonist is independently a structure represented by formula (la), MMAE, ProMMAE, MMAF, exatecan, taltobulin, Genz-644282, and dasatinib,** indicates the point of connection to Y, and* indicates the point of connection to the remainder of LAB.

167. The conjugate of claim 1 or 2, wherein D is a moiety represented by one of the following structural formulas:wherein indicates the point of attachment to the remainder of LAB.

168. The conjugate of claim 1 or 2, wherein D is a moiety represented by one of the following structural formulas:, indicates the point of attachment to the remainder of LAB169. The conjugate of any one of claims 1, and 3-6, wherein D is a moiety represented by one of the following structural formulas:

170. The conjugate of claim 1 or 2, wherein the conjugate comprises a structure selected from:wherein indicates the point of attachment to the remainder of LAB.

171. The conjugate of claim 1 or 2, wherein the conjugate comprises a structure selected from:wherein indicates the point of attachment to the remainder of LAB.

172. The conjugate of claim 1 or 3-6, wherein the conjugate comprises a structure selected from:

173. The conjugate of claim 1 or 2, wherein the conjugate comprises a structure selected from:wherein ' indicates the point of attachment to the remainder of LAB.

174. The conjugate of claim 1 or 2, wherein the conjugate comprises a structure selected from:wherein indicates the point of attachment to the remainder of LAB.

175. The conjugate of any one of claims 1-3, wherein the conjugate comprises a structure selected from:wherein ' indicates the point of attachment to the remainder of LAB.

176. The conjugate of claim 1 or 2, wherein the conjugate comprises a structure selected from:wherein indicates the point of attachment to the remainder of LAB.

177. The conjugate of any one of claims 1-3, wherein the conjugate comprises a structure selected from:wherein indicates the point of attachment to the remainder of LAB.

178. The conjugate of any one of claims 1-3, wherein the conjugate comprises a structure selected from:wherein indicates the point of attachment to the remainder of LAB.

179. The conjugate of any one of claims 1-178, wherein AB comprises a cysteine residue and LABis covalently connected to AB by a sulfur atom in the cysteine residue (e.g., by a sulfur atom in the side chain of the cysteine residue) via a thioether bond.

180. The conjugate of any one of claims 1-179 wherein a C-terminus of AB comprises an amino acid motif that is recognized by an isoprenoid transferase.

181. The conjugate of any one of claims 1-180, wherein the amino acid motif comprises a sequence of CY’Y’X’; whereinC is cysteine; each Y’ is independently an aliphatic amino acid; andX’ is selected from glutamine, glutamate, serine, cysteine, methionine, alanine and leucin.

182. The conjugate of claim 181, wherein each Y’ is independently selected from alanine, isoleucine, leucine, methionine and valine.

183. The conjugate of any one of claims 179-180, wherein the amino acid motif comprises a sequence of CAAX’.

184. The conjugate of any one of claims 1-183, wherein AB specifically binds to a target selected from:(a) cell surface proteins or transmembrane proteins (e.g., receptors (e.g., growth factor receptors, cytokine receptors), cluster of differentiation (CD) markers, ion channels, and transporters);(b) cytokines and chemokines (e.g., tumor necrosis factors, interferons, and growth factors);(c) enzymes (e.g., proteases, kinases, phosphatases, and polymerases);(d) hormones and hormone receptors (e.g., peptide hormones and steroid hormone receptors);(e) pathogen-associated antigens (e.g., viral proteins, bacterial proteins, fungal antigens, and parasitic antigens);(f) tumor-associated antigens (e.g., cancer / testis antigens, oncofetal antigens, and overexpressed or mutated proteins in cancer);(g) extracellular matrix proteins (e.g., collagens, fibronectin, and laminins);(h) intracellular proteins (e.g., transcription factors, signaling molecules, and structural proteins);(i) toxins and venoms, (e.g., bacterial toxins and animal venoms);(j) blood group antigens (e.g., ABO antigens and Rh antigens);(k) autoantigens (e.g., nuclear antigens and cytoplasmic antigens);(l) allergens (e.g., environmental allergens and food allergens);(m) metabolites and small molecules (e.g., drugs and haptens);(n) viral vectors and gene therapy components (e.g., capsid proteins and transgene products); and(o) synthetic or engineered proteins (e.g., fusion proteins and chimeric proteins).

185. The conjugate of any one of claims 1-184, wherein AB specifically binds to a cell surface protein or transmembrane protein, wherein the surface protein or transmembrane protein is selected from CD3, CD4, CD8, CD19, CD20, CD28, CD30, CD45, CD56, CD133, CD44, CD47, CD79b, CD80, CD86, DLK1, PD-1, PD-L1, CTLA-4, EGFR, HER2, Nectin-4, TR0P2, LI CAM, CCR5, CCR8, TIM-3 Siglec-15, B7-H7 (HHLA2) and CXCR4.

186. The conjugate of any one of claims 1-184, wherein AB specifically binds to a cytokine or chemokine, wherein the cytokine or chemokine is selected from IL-ip, IL-2, IL-4, IL-6, IL-8 (CXCL8), IL-10, IL-12, IL-17A, TNF-a, IFN-y, IFN-a, TGF-P, GM-CSF, MCP-1 (CCL2), MIP-la (CCL3), MIP-ip (CCL4), RANTES (CCL5), SDF-1 (CXCL12), CXCL10 (IP-10), and Eotaxin (CCL11).

187. The conjugate of any one of claims 1-184, wherein AB specifically binds to a tumor-associated antigen, wherein the tumor-associated antigen is selected from B7-H4, B7-H7 (HHLA2), HER2, EGFR, MUC1, CEA (Carcinoembryonic Antigen), PSA (Prostate-Specific Antigen), CA19-9, CA125, NY-ESO-1, WT1 (Wilms Tumor 1), MAGE-A1, MAGE-A3, Survivin (BIRC5), p53, MART-1 (Melan-A), gplOO (PMEL), Tyrosinase, GD2, CD20, CD 19, PSMA (Prostate-Specific Membrane Antigen), CLDN18.2, Mesothelin, SSEA-4 (Stage-Specific Embryonic Antigen-4), BCMA (B-cell Maturation Antigen), CD22, CD33, CD138 (Syndecan-1), R0R1 (Receptor tyrosine kinase-like Orphan Receptor 1), GPC3 (Glypican-3), TF (Tissue Factor), Lewis-Y and AFP (Alpha-fetoprotein).

188. The conjugate of any one of claims 1-184, wherein AB is an anti-Lewis-Y antibody (e.g., hu3S193 or BR96).

189. The conjugate of claim 188, wherein AB comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1),a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,(i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 211;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 212;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 213;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 214;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 215; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 216.

190. The conjugate of claim 188 or 189, wherein AB comprises a combination of a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 217, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 218.

191. The conjugate of any one of claims 1-184, wherein AB is an anti-EGFR antibody (e.g., cetuximab, panitumumab, necitumumab, nimotuzumab, zalutumumab, or matuzumab).

192. The conjugate of claim 191, wherein AB comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,(i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 221;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 222;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 223;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 224;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 225; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 226.

193. The conjugate of claim 191 or 192, wherein AB comprises a combination of a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 227, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 228.

194. The conjugate of any one of claims 1-184, wherein AB is an anti-PD-1 antibody (e.g., pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, MGA012, AMP -224, or AMP- 514).

195. The conjugate of claim 194, wherein AB comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,(a) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 1;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 2;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 3;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 4;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 5; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 6; or(b) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 11;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 12;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 13;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 14;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 15; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 16; or(c) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 19;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 20;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 21;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 22;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 23; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 24; or(d) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 27;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 28;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 29;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 30;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 31; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 32; or(e) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 37;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 38;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 39;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 40;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 41; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 42; or(f) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 45;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 46;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 47;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 48;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 49; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 50; or(g) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 53;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 54;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 55;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 56;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 57; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 58; or(h) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 61;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 62;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 63;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 64;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 65; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 66; or(i) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 69;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 70;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 71;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 72;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 73; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 74 ; or(j) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 239;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 240;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 241;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 242;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 243; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 244.

196. The conjugate of claim 194, wherein AB comprises: (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 11; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 12; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 13;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 14; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 15; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 16.

197. The conjugate of claim 194, wherein AB comprises a combination of:(a) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 7; and a variable light chain comprising the amino acid sequence of SEQ ID NO: 8; or(b) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 10, or(c) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 25, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 26, or(d) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 33, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 34, or(e) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 35, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 36, or(f) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 43, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 44, or(g) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 51, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 52, or(h) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 60, or(i) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 67, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 68, or(j) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 75, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 76.

198. The conjugate of claim 194, wherein AB comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 10.

199. The conjugate of any one of claims 1-185, wherein AB is an anti-PD-Ll antibody (e.g., atezolizumab, avelumab, durvalumab, or cosibelimab).

200. The conjugate of claim 199, wherein AB comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,(a) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 77;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 78;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 79;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 80;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 81; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 82; or(b) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 87;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 88;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 89;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 90;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 91; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 92; or(c) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 95;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 96;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 97;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 98;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 99; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 100 ; or(d) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 259;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 260;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 261;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 262;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 263; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 264;(e) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 267;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 268;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 269;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 270;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 271; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 272.

201. The conjugate of claim 199, wherein AB comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 77; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 78; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 79;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 80; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 81; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 82.

202. The conjugate of claim 199, wherein AB comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 87; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 88; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 89;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 90; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 91; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 92.

203. The conjugate of claim 199, wherein AB comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 267; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 268; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 269;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 270; (v) CDRL2comprises the amino acid sequence of SEQ ID NO: 271; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 272.

204. The conjugate of claim 199, wherein AB comprises a combination of:(a) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 83, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 84, or(b) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 93, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 94, or(c) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 101, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 102, or(d) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 103, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 104; or(e) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 273, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 274.

205. The conjugate of claim 199, wherein AB comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 83, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 84.

206. The conjugate of claim 199, wherein AB comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 93, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 94.

207. The conjugate of claim 199, wherein AB comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 273, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 274.

208. The conjugate of any one of claims 1-185, wherein AB is an anti-TIM-3 antibody (e.g., LY3321367, MBG453, TSR-022, Sym023, BGBA425, R07121661, ICAGN02390, BMS-986258, or sabatolimab).

209. The conjugate of claim 208, wherein AB comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,(i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 105;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 106;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 107;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 108;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 109; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 110.

210. The conjugate of claim 208, wherein AB comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 111, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 112.

211. The conjugate of any one of claims 1-185, wherein AB is an anti-Siglec-15 antibody (e.g., NC318 or PYX-106).

212. The conjugate of any one of claims 1-185, wherein AB is an anti-B7-H7 antibody (e.g., NPX267 or HBM1020).

213. The conjugate of any one of claims 1-185, wherein AB is an anti-HER2 antibody (e.g., trastuzumab, pertuzumab, sacituzumab, patritumab, or margetuximab).

214. The conjugate of claim 213, wherein AB comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementarity determining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein,(a) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 113;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 114;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 115;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 116,(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 117; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 118, or(b) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 123;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 124;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 125;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 126,(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 127; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 128, or(c) (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 132;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 133;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 134;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 135,(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 136; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 137.

215. The conjugate of claim 213, wherein AB comprises (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 113; (ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 114; (iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 115;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 116; (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 117; and (vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 118.

216. The conjugate of claim 213, wherein AB comprises a combination of:(a) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 119, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 120, or(b) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 129, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 130, or(c) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 138, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 139.

217. The conjugate of claim 213, wherein AB comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 119, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 120.

218. The conjugate of any one of claims 1-185, wherein AB is an anti-RORl antibody (e.g., cirmtuzumab or zilovertamab).

219. The conjugate of any one of claims 1-185, wherein AB is an anti-CD19 antibody (e.g., tafasitamab, coltuximab, loncastuximab, MOR208, MEDI-551, denintuzumab, taplitumomab, XmAb 5871, MDX-1342, AFM11, or blinatumomab).

220. The conjugate of any one of claims 1-185, wherein AB is an anti-LlCAM antibody (e.g., Ab417 or chCE7).

221. The conjugate of any one of claims 1-185, wherein AB is an anti-CLDN18.2 antibody (e.g., claudiximab, zolbetuximab, ASKB589, or osemitamab).

222. The conjugate of any one of claims 1-185, wherein AB is an anti-B7-H4 antibody (e.g., FPA150).

223. The conjugate of any one of claims 1-185, wherein AB is an anti-DLKl antibody (e.g., CBA-1205).

224. The conjugate of any one of claims 1-185, wherein AB is an anti-CCR8 antibody (e.g., BMS-986340, S-531011, BAY3375968, or GS-1811).

225. The conjugate of any one of claims 1-185, wherein AB is an anti-TROP2 antibody (e.g., datopotamab).

226. The conjugate of claim 225, wherein AB comprises a variable heavy chain complementarity determining region 1 (CDRH1), a variable heavy chain complementaritydetermining region 2 (CDRH2), a variable heavy chain complementarity determining region 3 (CDRH3), a variable light chain complementarity determining region 1 (CDRL1), a variable light chain complementarity determining region 2 (CDRL2), and a variable light chain complementarity determining region 3 (CDRL3); wherein(i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 303;(ii) CDRH2 comprises the amino acid sequence of SEQ ID NO: 304;(iii) CDRH3 comprises the amino acid sequence of SEQ ID NO: 305;(iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 306;(v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 307; and(vi) CDRL3 comprises the amino acid sequence of SEQ ID NO: 308.

227. The conjugate of claim 225, wherein AB comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 309, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 310.

228. The conjugate of any one of claims 1-227, wherein AB is a monoclonal antibody, a single chain antibody (scAb), a Fab fragment, a F(ab’)2 fragment, a single chain variable fragment (scFv), a scFv-Fc fragment, a multimeric antibody, or a bispecific antibody.

229. The conjugate of any one of claims 1-228, wherein AB is a chimeric, humanized or fully human monoclonal antibody.

230. The conjugate of any one of claims 1-229, wherein AB is an IgG isotype (e.g., IgGl, IgG2, IgG3, or IgG4 isotype).

231. The conjugate of claim 230, wherein AB is an IgGl isotype.

232. The conjugate of claim 231, wherein AB comprises a N297A substitution according to EU numbering convention.

233. The conjugate of claim 231 or 232, wherein AB comprises L234A and L235A substitutions according to EU numbering convention.

234. The conjugate of claim 233, wherein AB comprises a P329G substitution or a P329A substitution according to EU numbering convention.

235. The conjugate of claim 230, wherein AB is an IgG4 isotype.

236. The conjugate of claim 235, wherein AB comprises a S228P substitution according to EU numbering convention.

237. A pharmaceutical composition comprising a conjugate of any one of claims 1-236 and a pharmaceutically acceptable excipient.

238. A method of treating a disease in a subject in need thereof, comprising administering a conjugate of any one of claims 1-236 or a pharmaceutical composition of claim 237, wherein the disease is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease, and allergic disease.

239. The method of claim 238, wherein the disease is an infectious disease.

240. The method of claim 238, wherein the disease is cancer.

241. The method of claim 240, wherein the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi’s sarcoma, and melanoma.

242. A method of inducing an immune response in a subject in need thereof, comprising administering to the subject a conjugate of any one of claims 1-236 or a pharmaceutical composition of claim 237.

243. The method of claim 242, wherein the inducing of the immune response is effective to prevent or treat a disease in the subject.

244. The method of claim 243, wherein the disease is cancer.

245. The method of claim 244, wherein the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi’s sarcoma, and melanoma.

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