WO2021202830A2 - Hsp90-binding conjugates and formulations thereof - Google Patents

Abstract

Conjugates comprising an active agent, a HSP90 binding moiety, a chelator, a linker, and a spacer, have been designed. Such conjugates can provide improved temporospatial delivery of the active agent, improved biodistribution and penetration in tumor, and/or decreased toxicity. Methods of making the conjugates and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer.

Description

HSP90-BINDING CONJUGATES AND FORMULATIONS THEREOF REFERENCED TO RELATED APPLICATIONS [0001] The present application claims priority to U.S. Provisional Patent Application No.63/003,528, filed April 1, 2020, entitled HSP90-TARGETING CONJUGATES AND FORMULATIONS THEREOF, the contents of which are herein incorporated by reference in their entirety. FIELD OF THE DISCLOSURE [0002] The invention relates to the use of molecules targeting heat shock proteins including heat shock protein 90 (HSP90), e.g., for treating cancer. BACKGROUND [0003] Heat shock protein 90 (HSP90) is a molecular chaperone that is important for maintaining stability and function of numerous client proteins. It is considered a major therapeutic target for anticancer drug development. SUMMARY OF THE DISCLOSURE [0004] The present disclosure provides a conjugate comprising at least one active agent, at least one targeting moiety (TM), and at least one chelator, wherein the chelator is covalently attached to the TM via a spacer, wherein the active agent is covalently attached to the chelator or the TM via a linker, and wherein the TM binds to HSP90. Compositions comprising the conjugates and methods of using the conjugates are also provided. DETAILED DESCRIPTION [0005] Applicants have designed HSP90 targeting conjugates comprising an active agent. Such targeting can, for example, improve the amount of active agent at a site and decrease active agent toxicity to the subject. HSP90 targeting conjugates of the present invention have deep and rapid tumor penetration. High accumulation and long retention time of HSP90 targeting conjugates enable the use of cytotoxic and non- cytotoxic payloads, such as radionuclides, chemotherapeutic agents, kinase inhibitors, or immuno-oncology modulators. 1 [0006] As used herein, “toxicity” refers to the capacity of a substance or composition to be harmful or poisonous to a cell, tissue organism or cellular environment. Low toxicity refers to a reduced capacity of a substance or composition to be harmful or poisonous to a cell, tissue organism or cellular environment. Such reduced or low toxicity may be relative to a standard measure, relative to a treatment or relative to the absence of a treatment. [0007] Toxicity may further be measured relative to a subject’s weight loss where weight loss over 15%, over 20% or over 30% of the body weight is indicative of toxicity. Other metrics of toxicity may also be measured such as patient presentation metrics including lethargy and general malaiase. Neutropenia or thrombopenia may also be metrics of toxicity. [0008] Pharmacologic indicators of toxicity include elevated AST/ALT levels, neurotoxicity, kidney damage, GI damage and the like. [0009] In addition, the toxicity of a conjugate containing an HSP90 targeting moiety linked to an active agent for cells that do not overexpress HSP90 is predicted to be decreased compared to the toxicity of the active agent alone. Without committing to any particular theory, applicants believe that this feature is because the ability of the conjugated active agent to be retained in a normal cell is decreased relative to a tumor cell. [0010] In some embodiments, the active agent and the targeting moiety, when connected by a linker into a conjugate, have synergistic effects. The efficacy of the conjugate is better than the active agent and/or the targeting moiety alone. [0011] In some embodiments, the potency of the active agent is reduced when it is connected to a targeting moiety by a cleavable linker. Upon cleavage of the linker at a target site, such as a tumor site, the active agent is released and full potency is recovered. [0012] It is an object of the invention to provide improved compounds, compositions, and formulations for temporospatial drug delivery. [0013] It is further an object of the invention to provide methods of making improved compounds, compositions, and formulations for temporospatial drug delivery. [0014] It is also an object of the invention to provide methods of administering the improved compounds, compositions, and formulations to individuals in need thereof. I. Conjugates [0015] Conjugates include an active agent or prodrug thereof attached to a targeting moiety, e.g., a molecule that can bind to HSP90, by a linker. The conjugates can be a conjugate between a single active agent and a single targeting moiety, e.g., a conjugate having the structure X-Y-Z where X is the targeting moiety, Y is the linker, and Z is the active agent. [0016] In some embodiments the conjugate contains more than one targeting moiety, more than one linker, more than one active agent, or any combination thereof. The conjugate can have any number of targeting moieties, linkers, and active agents. The conjugate can have the structure X-Y-Z-Y-X, (X-Y)_n-Z, X-(Y-Z)_n, X_n-Y-Z, X-Y- Z_n, (X-Y-Z)_n, (X-Y-Z-Y)_n-Z, where X is a targeting moiety, Y is a linker, Z is an active agent, and n is an integer between 1 and 50, between 2 and 20, for example, between 1 and 5. Each occurrence of X, Y, and Z can be the same or different, e.g., the conjugate can contain more than one type of targeting moiety, more than one type of linker, and/or more than one type of active agent. [0017] The conjugate can contain more than one targeting moiety attached to a single active agent. For example, the conjugate can include an active agent with multiple targeting moieties each attached via a different linker. The conjugate can have the structure X-Y-Z-Y-X where each X is a targeting moiety that may be the same or different, each Y is a linker that may be the same or different, and Z is the active agent. [0018] The conjugate can contain more than one active agent attached to a single targeting moiety. For example, the conjugate can include a targeting moiety with multiple active agents each attached via a different linker. The conjugate can have the structure Z-Y-X-Y-Z where X is the targeting moiety, each Y is a linker that may be the same or different, and each Z is an active agent that may be the same or different. [0019] The conjugate may also contain other moieties, such as chelator moieties, spacers, and pharmacokinetic modulating units. In some embodiment, the conjugate comprises at least one active agent, at least one targeting moiety (TM), at least one chelator, wherein the chelator is covalently attached to the TM via a spacer, the active agent is covalently attached to the chelator or the TM via a linker, and the TM binds to HSP90. [0020] The molecular weight of the conjugate of the present disclosure may be less than 5000 Da, less than 4000 Da, less than 3000 Da, less than 2000 Da, or less than 1000 Da. In some embodiments, the molecular weight of the conjugate is between about 1000 Da and about 3000 Da, or between about 1500 Da and 2500 Da. A. Active Agents [0021] A conjugate as described herein contains at least one active agent (a first active agent). The conjugate can contain more than one active agent, that can be the same or different from the first active agent. The active agent can be a therapeutic, prophylactic, diagnostic, or nutritional agent. A variety of active agents are known in the art and they or analogs and derivatives thereof may be used in the conjugates described herein. The active agent can be a protein or peptide, small molecule, nucleic acid or nucleic acid molecule, lipid, sugar, carbohydrate, glycolipid, glycoprotein, lipoprotein, or combination thereof. In some embodiments, the active agent is an antigen, an adjuvant, radioactive, an imaging agent (e.g., a fluorescent moiety) or a polynucleotide. In some embodiments the active agent is an organometallic compound or a radioactive element. [0022] The active agents have been modified appropriately to allow linking to the targeting moieties via the linkers. In some cases, the active agent has chemical functionality for covalent attachment to a linker or is modified to an analog or derivative for the purpose of covalent attachment to a linker. [0023] In certain embodiments, the active agent of the conjugate comprises a predetermined molar weight percentage from about 1% to about 10%, or about 10% to about 20%, or about 20% to about 30%, or about 30% to about 40%, or about 40% to about 50%, or about 50% to about 60%, or about 60% to about 70%, or about 70% to about 80%, or about 80% to about 90%, or about 90% to about 99% such that the sum of the molar weight percentages of the components of the conjugate is 100%. The amount of active agent(s) of the conjugate may also be expressed in terms of proportion to the targeting ligand(s). For example, the present teachings provide a ratio of active agent to ligand of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4; 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. [0024] In some embodiments, the active agent can be a cancer therapeutic. Cancer therapeutics include, for example, death receptor agonists such as the TNF-related apoptosis-inducing ligand (TRAIL) or Fas ligand or any ligand or antibody that binds or activates a death receptor or otherwise induces apoptosis. Suitable death receptors include, but are not limited to, TNFR1, Fas, DR3, DR4, DR5, DR6, LTβR and combinations thereof. [0025] Cancer therapeutics such as chemotherapeutic agents, cytokines, chemokines, and radiation therapy agents can be used as active agents. Chemotherapeutic agents include, for example, alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and other antitumor agents. Such agents typically affect cell division or DNA synthesis and function. Additional examples of therapeutics that can be used as active agents include monoclonal antibodies and the tyrosine kinase inhibitors e.g. imatinib mesylate, which directly targets a molecular abnormality in certain types of cancer (e.g., chronic myelogenous leukemia, gastrointestinal stromal tumors). [0026] Chemotherapeutic agents include, but are not limited to cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, vincristine, vinblastine, vinorelbine, vindesine, taxol and derivatives thereof, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, epipodophyllotoxins, trastuzumab, cetuximab, and rituximab, bevacizumab, and combinations thereof. Any of these may be used as an active agent in a conjugate. [0027] The small molecule active agents used in this invention (e.g. antiproliferative (cytotoxic and cytostatic) agents) include cytotoxic compounds (e.g., broad spectrum), angiogenesis inhibitors, cell cycle progression inhibitors, PBK/m- TOR/AKT pathway inhibitors, MAPK signaling pathway inhibitors, kinase inhibitors, protein chaperones inhibitors, HDAC inhibitors, PARP inhibitors, Wnt/Hedgehog signaling pathway inhibitors, RNA polymerase inhibitors and proteasome inhibitors. The small molecule active agents in some embodiments the active agent is an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof. [0028] Broad spectrum cytotoxins include, but are not limited to, DNA-binding or alkylating drugs, microtubule stabilizing and destabilizing agents, platinum compounds, and topoisomerase I or II inhibitors. [0029] Exemplary DNA-binding or alkylating drugs include, CC-1065 and its analogs, anthracyclines (doxorubicin, epirubicin, idarubicin, daunorubicin) and its analogs, alkylating agents, such as calicheamicins, dactinomycines, mitromycines, pyrrolobenzodiazepines, and the like. [0030] Exemplary doxorubicin analogs include nemorubicin metabolite or analog drug moiety disclosed in US 20140227299 to Cohen et al., the contents of which are incorporated herein by reference in their entirety. [0031] Exemplary CC-1065 analogs include duocarmycin SA, duocarmycin CI, duocarmycin C2, duocarmycin B2, DU-86, KW-2189, bizelesin, seco-adozelesin, and those described in U.S. Patent Nos.5,475,092; 5,595,499; 5,846,545; 6,534,660; 6,586,618; 6,756,397 and 7,049,316. Doxorubicin and its analogs include PNU- 159682 and those described in U.S. Patent No.6,630,579 and nemorubicin metabolite or analog drugs disclosed in US 20140227299 to Cohen et al., the contents of which are incorporated herein by reference in their entirety. [0032] Calicheamicins include those described in U.S. Patent Nos.5,714,586 and 5,739,116. Duocarmycins include those described in U.S. Patent Nos.5,070,092; 5,101,038; 5,187,186; 6,548,530; 6,660,742; and 7,553,816 B2; and Li et al., Tet Letts., 50:2932 - 2935 (2009). Pyrrolobenzodiazepines include SG2057 and those described in Denny, Exp. Opin. Ther. Patents., 10(4):459-474 (2000), Anti-Cancer Agents in Medicinal Chemistry, 2009, 9, 1-31; WO 2011/130613 A1; EP 2789622 A1; Blood 2013, 122, 1455; J. Antimicrob. Chemother.2012, 67, 1683–1696; Cancer Res.2004, 64, 6693–6699; WO 2013041606; US 8481042; WO 2013177481; WO 2011130613; WO2011130598 [0033] Exemplary microtubule stabilizing and destabilizing agents include taxane compounds, such as paclitaxel, docetaxel, cabazitaxel; maytansinoids, auristatins and analogs thereof, tubulysin A and B derivatives, vinca alkaloid derivatives, epothilones, PM060184 and cryptophycins. [0034] Exemplary maytansinoids or maytansinoid analogs include maytansinol and maytansinol analogs, maytansine or DM-1 and DM-4 are those described in U.S. Patent Nos.5,208,020; 5,416,064; 6,333.410; 6,441,163; 6,716,821; RE39,151 and 7,276,497. In certain embodiments, the cytotoxic agent is a maytansinoid, another group of anti-tubulin agents (ImmunoGen, Inc.; see also Chari et al., 1992, Cancer Res.52: 127-131), maytansinoids or maytansinoid analogs. Examples of suitable maytansinoids include maytansinol and maytansinol analogs. Suitable maytansinoids are disclosed in U.S. Patent Nos.4,424,219; 4,256,746; 4,294,757; 4,307,016; 4,313,946; 4,315,929; 4,331,598; 4,361,650; 4,362,663; 4,364,866; 4,450,254; 4,322,348; 4,371,533; 6,333,410; 5,475,092; 5,585,499; and 5,846,545. [0035] Exemplary auristatins include auristatin E (also known as a derivative of dolastatin-10), auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F and dolastatin. Suitable auristatins are also described in U.S. Publication Nos.2003/0083263, 2011/0020343, and 2011/0070248; PCT Application Publication Nos. WO 09/117531, WO 2005/081711, WO 04/010957; WO02/088172 and WO01/24763, and U.S. Patent Nos.7,498,298; 6,884,869; 6,323,315; 6,239,104; 6,124,431; 6,034,065; 5,780,588; 5,767,237; 5,665,860; 5,663,149; 5,635,483; 5,599,902;5,554,725; 5,530,097; 5,521,284; 5,504,191; 5,410,024; 5,138,036; 5,076,973; 4,986,988; 4,978,744; 4,879,278; 4,816,444; and 4,486,414, the disclosures of which are incorporated herein by reference in their entirety. [0036] Exemplary tubulysin compounds include compounds described in U.S. Patent Nos.7,816,377; 7,776,814; 7,754,885; U.S. Publication Nos.2011/0021568; 2010/004784; 2010/0048490; 2010/00240701; 2008/0176958; and PCT Application Nos. WO 98/13375; WO 2004/005269; WO 2008/138561; WO 2009/002993; WO 2009/055562; WO 2009/012958; WO 2009/026177; WO 2009/134279; WO 2010/033733; WO 2010/034724; WO 2011/017249; WO 2011/057805; the disclosures of which are incorporated by reference herein in their entirety. [0037] Exemplary vinca alkaloids include vincristine, vinblastine, vindesine, and navelbine (vinorelbine). Suitable Vinca alkaloids that can be used in the present invention are also disclosed in U.S. Publication Nos.2002/0103136 and 2010/0305149, and in U.S. Patent No.7,303,749 Bl, the disclosures of which are incorporated herein by reference in their entirety. [0038] Exemplary epothilone compounds include epothilone A, B, C, D, E and F, and derivatives thereof. Suitable epothilone compounds and derivatives thereof are described, for example, in U.S. Patent Nos.6,956,036; 6,989,450; 6,121,029; 6,117,659; 6,096,757; 6,043,372; 5,969,145; and 5,886,026; and WO 97/19086; WO 98/08849; WO 98/22461; WO 98/25929; WO 98/38192; WO 99/01124; WO 99/02514; WO 99/03848; WO 99/07692; WO 99/27890; and WO 99/28324; the disclosures of which are incorporated herein by reference in their entirety. [0039] Exemplary cryptophycin compounds are described in U.S. Patent Nos. 6,680,311 and 6,747,021, the disclosures of which are incorporated herein by reference in their entirety. [0040] Exemplary platinum compounds include cisplatin (PLATINOL®), carboplatin (PARAPLATIN®), oxaliplatin (ELOX ATINE®), iproplatin, ormaplatin, and tetraplatin. [0041] Exemplary topoisomerase I inhibitors include camptothecin, camptothecin, derivatives, camptothecin analogs and non-natural camptothecins, such as, for example, CPT-11 (irinotecan), SN-38, topotecan, 9-aminocamptothecin, rubitecan, gimatecan, karenitecin, silatecan, lurtotecan, exatecan, diflomotecan, belotecan, lurtotecan and S39625. Other camptothecin compounds that can be used in the present invention include those described in, for example, J. Med. Chem., 29:2358-2363 (1986); J. Med. Chem., 23:554 (1980); J. Med. Chem., 30: 1774 (1987). [0042] Exemplary topoisomerase II inhibitors include azonafide and etoposide. [0043] Additional agents acting on DNA include Lurbinectedin (PM01183), Trabectedin (also known as ecteinascidin 743 or ET-743) and analogs as described in WO 200107711, WO 2003014127. [0044] Angiogenesis inhibitors include, but are not limited to, MetAP2 inhibitors. [0045] Exemplary MetAP2 inhibitors include fumagillol analogs, meaning any compound that includes the fumagillin core structure, including fumagillamine, that inhibits the ability of MetAP-2 to remove NH2-terminal methionines from proteins as described in Rodeschini et al., /. Org. Chem., 69, 357-373, 2004 and Liu, et al., Science 282, 1324-1327, 1998. Non limiting examples of "fumagillol analogs" are disclosed in /. Org. Chem., 69, 357, 2004; J.Org. Chem., 70, 6870, 2005; European Patent Application 0354787; /. Med. Chem., 49, 5645, 2006; Bioorg. Med. Chem., 11, 5051, 2003; Bioorg. Med. Chem., 14, 91, 2004; Tet. Lett.40, 4797, 1999; W099/61432; U.S. Patent Nos.6,603,812; 5,789,405; 5,767,293; 6,566,541; and 6,207,704. [0046] Exemplary cell cycle progression inhibitors include CDK inhibitors such as BMS-387032 and PD0332991; Rho-kinase inhibitors such as GSK429286; checkpoint kinase inhibitors such as AZD7762; aurora kinase inhibitors such as AZD1152, MLN8054 and MLN8237; PLK inhibitors such as BI 2536, BI6727 (Volasertib), GSK461364, ON-01910 (Estybon); and KSP inhibitors such as SB 743921, SB 715992 (ispinesib), MK-0731, AZD8477, AZ3146 and ARRY-520. [0047] Exemplary PI3K/m-TOR/AKT signaling pathway inhibitors include phosphoinositide 3-kinase (PI3K) inhibitors, GSK-3 inhibitors, ATM inhibitors, DNA-PK inhibitors and PDK-1 inhibitors. [0048] Exemplary PI3 kinase inhibitors are disclosed in U.S. Patent No.6,608,053, and include BEZ235, BGT226, BKM120, CAL101, CAL263, demethoxyviridin, GDC-0941, GSK615, IC87114, LY294002, Palomid 529, perifosine, PF-04691502, PX-866, SAR245408, SAR245409, SF1126, Wortmannin, XL147, XL765, GSK2126458 (Omipalisib), GDC-0326, GDC-0032 (Taselisib, RG7604), PF- 05212384 (Gedatolisib, PKI-587), BAY 80-6946 (copanlisib), PF-04691502, PF- 04989216, PI-103, PKI-402 VS-5584 (SB2343), GDC-0941, NVP-BEZ235 (Dactoslisib), BGT226, NVP-BKM120 (Buparlisib), NVP-BYL719 (alpelisib), GSK2636771, AMG-319, GSK2269557, PQR309, PWT143, TGR-1202 (RP5264), PX-866, GDC-0980 (apitolisib), AZD8835, MLN1117, DS-7423, ZSTK474, CUDC- 907, IPI-145 (INK-1197, Duvelisib), AZD8186, XL147 (SAR245408), XL765 (SAR245409), CAL-101 (Idelalisib, GS-1101), GS-9820 (Acalisib) and KA2237. [0049] Exemplary AKT inhibitors include, but are not limited to, AT7867, MK- 2206, Perifosine, GSK690693, Ipatasertib, AZD5363, TIC10, Afuresertib, SC79, AT13148, PHT-427, A-674563, and CCT128930. [0050] Exemplary MAPK signaling pathway inhibitors include MEK, Ras, JNK, B-Raf and p38 MAPK inhibitors. [0051] Exemplary MEK inhibitors are disclosed in U.S. Patent No.7,517,994 and include GDC-0973, GSK1120212, MSC1936369B, AS703026, R05126766 and R04987655, PD0325901, AZD6244, AZD 8330 and GDC-0973. [0052] Exemplary B-raf inhibitors include CDC-0879, PLX-4032, and SB590885. [0053] Exemplary B p38 MAPK inhibitors include BIRB 796, LY2228820 and SB202190 [0054] Receptor tyrosine kinases (RTK) are cell surface receptors which are often associated with signaling pathways stimulating uncontrolled proliferation of cancer cells and neoangiogenesis. Many RTKs, which over express or have mutations leading to constitutive activation of the receptor, have been identified, including, but not limited to, VEGFR, EGFR, FGFR, PDGFR, EphR and RET receptor family receptors. Exemplary RTK specific targets include ErbB2, FLT-3, c-Kit, c-Met, and HIF. [0055] Exemplary inhibitors of ErbB2 receptor (EGFR family) include but not limited to AEE788 (NVP-AEE 788), BIBW2992 (Afatinib), Lapatinib, Erlotinib (Tarceva), and Gefitinib (Iressa). [0056] Exemplary RTK inhibitors targeting more then one signaling pathway (multitargeted kinase inhibitors) include AP24534 (Ponatinib) that targets FGFR, FLT-3, VEGFR-PDGFR and Bcr-Abl receptors; ABT-869 (Linifanib) that targets FLT-3 and VEGFR- PDGFR receptors; AZD2171 that targets VEGFR-PDGFR, Flt-1 and VEGF receptors; CHR-258 (Dovitinib) that targets VEGFR-PDGFR, FGFR, Flt- 3, and c-Kit receptors. [0057] Exemplary kinase inhibtiors include inhibitors of the kinases ATM, ATR, CHK1, CHK2, WEE1, and RSK. [0058] Exemplary protein chaperon inhibitors include HSP90 inhibitors. Exemplary HSP90 inhibitors include 17AAG derivatives, BIIB021, BIIB028, SNX- 5422, NVP-AUY-922, and KW-2478. [0059] Exemplary HDAC inhibitors include Belinostat (PXD101), CUDC-101, Doxinostat, ITF2357 (Givinostat, Gavinostat), JNJ-26481585, LAQ824 (NVP- LAQ824, Dacinostat), LBH-589 (Panobinostat), MC1568, MGCD0103 (Mocetinostat), MS-275 (Entinostat), PCI-24781, Pyroxamide (NSC 696085), SB939, Trichostatin A, and Vorinostat (SAHA). [0060] Exemplary PARP inhibitors include iniparib (BSI 201), olaparib (AZD- 2281), ABT-888 (Veliparib), AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281), LT-673, 3- aminobenzamide, A-966492, and AZD2461 [0061] Exemplary Wnt/Hedgehog signaling pathway inhibitors include vismodegib (RG3616/GDC-0449), cyclopamine (11-deoxojervine) (Hedgehog pathway inhibitors), and XAV-939 (Wnt pathway inhibitor). [0062] Exemplary RNA polymerase inhibitors include amatoxins. Exemplary amatoxins include a- amanitins, β- amanitins, γ- amanitins, ε-amanitins, amanullin, amanullic acid, amaninamide, amanin, and proamanullin. [0063] Exemplary proteasome inhibitors include bortezomib, carfilzomib, ONX 0912, CEP-18770, and MLN9708. [0064] In one embodiment, the drug of the invention is a non-natural camptothecin compound, vinca alkaloid, kinase inhibitor (e.g., PI3 kinase inhibitor (GDC-0941 and PI- 103)), MEK inhibitor, KSP inhibitor, RNA polymerse inhibitor, PARP inhibitor, docetaxel, paclitaxel, doxorubicin, duocarmycin, tubulysin, auristatin or a platinum compound. In specific embodiments, the drug is a derivative of SN-38, vindesine, vinblastine, PI- 103, AZD 8330, auristatin E, auristatin F, a duocarmycin compound, tubulysin compound, or ARRY-520. [0065] In another embodiment, the drug used in the invention is a combination of two or more drugs, such as, for example, PI3 kinases and MEK inhibitors; broad spectrum cytotoxic compounds and platinum compounds; PARP inhibitors and platinum compounds; broad spectrum cytotoxic compounds and PARP inhibitors. [0066] The active agent can be a cancer therapeutic. The cancer therapeutics may include death receptor agonists such as the TNF-related apoptosis-inducing ligand (TRAIL) or Fas ligand or any ligand or antibody that binds or activates a death receptor or otherwise induces apoptosis. Suitable death receptors include, but are not limited to, TNFR1, Fas, DR3, DR4, DR5, DR6, LTβR and combinations thereof. [0067] The active agent can be a DNA minor groove binders such as lurbectidin and trabectidin. [0068] The active agent can be E3 ubiquitin ligase inhibitors, adeubiquitinase inhibitors or an NFkB pathway inhibitor. [0069] The active agent can be a phopsphatase inhibitors including inhibitors of PTP1B, SHP2, LYP, FAP-1, CD45, STEP, MKP-1, PRL, LMWPTP or CDC25. [0070] The active agent can be an inhibitor of tumor metabolism, such as an inhibitor of GAPDH, GLUT1, HK II, PFK, GAPDH, PK, LDH orMCTs. [0071] The active agent can target epigenetic targets including EZH2, MLL, DOT1-like protein (DOT1L), bromodomain-containing protein 4 (BRD4), BRD2, BRD3, NUT, ATAD2, or SMYD2. [0072] The active agent can target the body's immune system to help fight cancer, including moecules targeting IDO1, IDO2, TDO, CD39, CD73, A2A antagonists, STING activators, TLR agonists (TLR 1–13), ALK5, CBP/EP300 bromodomain, ARG1, ARG2, iNOS, PDE5, P2X7, P2Y11, COX2, EP2 Receptor, or EP4 receptor, [0073] The active agent can target Bcl-2, IAP, or fatty acid synthase. [0074] In some embodiments, the active agent can be 20-epi-l,25 dihydroxyvitamin D3, 4-ipomeanol, 5-ethynyluracil, 9-dihydrotaxol, abiraterone, acivicin, aclarubicin, acodazole hydrochloride, acronine, acylfulvene, adecypenol, adozelesin, aldesleukin, all-tk antagonists, altretamine, ambamustine, ambomycin, ametantrone acetate, amidox, amifostine, aminoglutethimide, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, anthramycin, anti-dorsalizing morphogenetic protein-1, antiestrogen, antineoplaston, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene modulators, apoptosis regulators, apurinic acid, ARA-CDP-DL-PTBA, arginine deaminase, asparaginase, asperlin, asulacrine, atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azacitidine, azasetron, azatoxin, azatyrosine, azetepa, azotomycin, baccatin III derivatives, balanol, batimastat, benzochlorins, benzodepa, benzoylstaurosporine, beta lactam derivatives, beta-alethine, betaclamycin B, betulinic acid, BFGF inhibitor, bicalutamide, bisantrene, bisantrene hydrochloride, bisaziridinylspermine, bisnafide, bisnafide dimesylate, bistratene A, bizelesin, bleomycin, bleomycin sulfate, BRC/ ABL antagonists, breflate, brequinar sodium, bropirimine, budotitane, busulfan, buthionine sulfoximine, cabazitaxel, cactinomycin, calcipotriol, calphostin C, calusterone, camptothecin, camptothecin derivatives, canarypox IL-2, capecitabine, caracemide, carbetimer, carboplatin, carboxamide-amino-triazole, carboxyamidotriazole, carest M3, carmustine, earn 700, cartilage derived inhibitor, carubicin hydrochloride, carzelesin, casein kinase inhibitors, castano spermine, cecropin B, cedefingol, cetrorelix, chlorambucil, chlorins, chloroquinoxaline sulfonamide, cicaprost, cirolemycin, cisplatin, cis-porphyrin, cladribine, clomifene analogs, clotrimazole, collismycin A, collismycin B, combretastatin A4, combretastatin analog, conagenin, crambescidin 816, crisnatol, crisnatol mesylate, cryptophycin 8, cryptophycin A derivatives, curacin A, cyclopentanthraquinones, cyclophosphamide, cycloplatam, cypemycin, cytarabine, cytarabine ocfosfate, cytolytic factor, cytostatin, dacarbazine, dacliximab, dactinomycin, daunorubicin hydrochloride, decitabine, dehydrodidemnin B, deslorelin, dexifosfamide, dexormaplatin, dexrazoxane, dexverapamil, dezaguanine, dezaguanine mesylate, diaziquone, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine, dioxamycin, diphenyl spiromustine, docetaxel, docosanol, dolasetron, doxifluridine, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, dronabinol, duazomycin, duocarmycin SA, ebselen, ecomustine, edatrexate, edelfosine, edrecolomab, eflornithine, eflornithine hydrochloride, elemene, elsamitrucin, emitefur, enloplatin, enpromate, epipropidine, epirubicin, epirubicin hydrochloride, epristeride, erbulozole, erythrocyte gene therapy vector system, esorubicin hydrochloride, estramustine, estramustine analog, estramustine phosphate sodium, estrogen agonists, estrogen antagonists, etanidazole, etoposide, etoposide phosphate, etoprine, exemestane, fadrozole, fadrozole hydrochloride, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, flezelastine, floxuridine, fluasterone, fludarabine, fludarabine phosphate, fluorodaunorunicin hydrochloride, fluorouracil, flurocitabine, forfenimex, formestane, fosquidone, fostriecin, fostriecin sodium, fotemustine, gadolinium texaphyrin, gallium nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcitabine, gemcitabine hydrochloride, glutathione inhibitors, hepsulfam, heregulin, hexamethylene bisacetamide, hydroxyurea, hypericin, ibandronic acid, idarubicin, idarubicin hydrochloride, idoxifene, idramantone, ifosfamide, ilmofosine, ilomastat, imidazoacridones, imiquimod, immunostimulant peptides, insulin-like growth factor- 1 receptor inhibitor, interferon agonists, interferon alpha-2A, interferon alpha-2B, interferon alpha-Nl, interferon alpha-N3, interferon beta-IA, interferon gamma-IB, interferons, interleukins, iobenguane, iododoxorubicin, iproplatin, irinotecan, irinotecan hydrochloride, iroplact, irsogladine, isobengazole, isohomohalicondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, larotaxel, lanreotide acetate, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibiting factor, leukocyte alpha interferon, leuprolide acetate, leuprolide/estrogen/progesterone, leuprorelin, levamisole, liarozole, liarozole hydrochloride, linear polyamine analog, lipophilic disaccharide peptide, lipophilic platinum compounds, lissoclinamide 7, lobaplatin, lombricine, lometrexol, lometrexol sodium, lomustine, lonidamine, losoxantrone, losoxantrone hydrochloride, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, lytic peptides, maitansine, mannostatin A, marimastat, masoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, maytansine, maytansinoid, mertansine (DM1), mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, merbarone, mercaptopurine, meterelin, methioninase, methotrexate, methotrexate sodium, metoclopramide, metoprine, meturedepa, microalgal protein kinase C inhibitors, MIF inhibitor, mifepristone, miltefosine, mirimostim, mismatched double stranded RNA, mitindomide, mitocarcin, mitocromin, mitogillin, mitoguazone, mitolactol, mitomalcin, mitomycin, mitomycin analogs, mitonafide, mitosper, mitotane, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mitoxantrone hydrochloride, mofarotene, molgramostim, monoclonal antibody, human chorionic gonadotrophin, monophosphoryl lipid a/myobacterium cell wall SK, mopidamol, multiple drug resistance gene inhibitor, multiple tumor suppressor 1 - based therapy, mustard anticancer agent, mycaperoxide B, mycobacterial cell wall extract, mycophenolic acid, myriaporone, n-acetyldinaline, nafarelin, nagrestip, naloxone/pentazocine, napavin, naphterpin, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidant, nitrullyn, nocodazole, nogalamycin, n-substituted benzamides, 06-benzylguanine, octreotide, okicenone, oligonucleotides, onapristone, ondansetron, oracin, oral cytokine inducer, ormaplatin, osaterone, oxaliplatin, oxaunomycin, oxisuran, paclitaxel, paclitaxel analogs, paclitaxel derivatives, palauamine, palmitoylrhizoxin, pamidronic acid, panaxytriol, panomifene, parabactin, pazelliptine, pegaspargase, peldesine, peliomycin, pentamustine, pentosan polysulfate sodium, pentostatin, pentrozole, peplomycin sulfate, perflubron, perfosfamide, perillyl alcohol, phenazinomycin, phenylacetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pipobroman, piposulfan, pirarubicin, piritrexim, piroxantrone hydrochloride, placetin A, placetin B, plasminogen activator inhibitor, platinum(IV) complexes, platinum compounds, platinum-triamine complex, plicamycin, plomestane, porfϊmer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, propyl bis-acridone, prostaglandin J2, prostatic carcinoma antiandrogen, proteasome inhibitors, protein A-based immune modulator, protein kinase C inhibitor, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, puromycin, puromycin hydrochloride, purpurins, pyrazofurin, pyrazoloacridine, pyridoxylated hemoglobin polyoxy ethylene conjugate, RAF antagonists, raltitrexed, ramosetron, RAS farnesyl protein transferase inhibitors, RAS inhibitors, RAS-GAP inhibitor, retelliptine demethylated, rhenium RE 186 etidronate, rhizoxin, riboprine, ribozymes, RII retinamide, RNAi, rogletimide, rohitukine, romurtide, roquinimex, rubiginone Bl, ruboxyl, safingol, safingol hydrochloride, saintopin, sarcnu, sarcophytol A, sargramostim, SDI 1 mimetics, semustine, senescence derived inhibitor 1 , sense oligonucleotides, siRNA, signal transduction inhibitors, signal transduction modulators, simtrazene, single chain antigen binding protein, sizofiran, sobuzoxane, sodium borocaptate, sodium phenylacetate, solverol, somatomedin binding protein, sonermin, sparfosate sodium, sparfosic acid, sparsomycin, spicamycin D, spirogermanium hydrochloride, spiromustine, spiroplatin, splenopentin, spongistatin 1, squalamine, stem cell inhibitor, stem-cell division inhibitors, stipiamide, streptonigrin, streptozocin, stromelysin inhibitors, sulfinosine, sulofenur, superactive vasoactive intestinal peptide antagonist, suradista, suramin, swainsonine, synthetic glycosaminoglycans, talisomycin, tallimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan sodium, tegafur, tellurapyrylium, telomerase inhibitors, teloxantrone hydrochloride, temoporfin, temozolomide, teniposide, teroxirone, testolactone, tetrachlorodecaoxide, tetrazomine, thaliblastine, thalidomide, thiamiprine, thiocoraline, thioguanine, thiotepa, thrombopoietin, thrombopoietin mimetic, thymalfasin, thymopoietin receptor agonist, thymotrinan, thyroid stimulating hormone, tiazofurin, tin ethyl etiopurpurin, tirapazamine, titanocene dichloride, topotecan hydrochloride, topsentin, toremifene, toremifene citrate, totipotent stem cell factor, translation inhibitors, trestolone acetate, tretinoin, triacetyluridine, triciribine, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tropisetron, tubulozole hydrochloride, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, uracil mustard, uredepa, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, velaresol, veramine, verdins, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinleurosine sulfate, vinorelbine, vinorelbine tartrate, vinrosidine sulfate, vinxaltine, vinzolidine sulfate, vitaxin, vorozole, zanoterone, zeniplatin, zilascorb, zinostatin, zinostatin stimalamer, or zorubicin hydrochloride. [0075] The active agent can be an inorganic or organometallic compound containing one or more metal centers. In some examples, the compound contains one metal center. The active agent can be, for example, a platinum compound, a ruthenium compound (e.g., trans-[RuCl₂ (DMSO)₄], or trans-[RuCl₄(imidazole) ₂, etc.), cobalt compound, copper compound, or iron compounds. [0076] In some embodiments, the active agent is a small molecule. In some embodiments, the active agent is a small molecule cytotoxin. In one embodiment, the active agent is cabazitaxel, or an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof. In another embodiment, the active agent is mertansine (DM1) or DM4, or an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof. DM1 or DM4 inhibits the assembly of microtubules by binding to tubulin. Structure of DM1 is shown below:

[0077] In some embodiments, the active agent Z is Monomethyl auristatin E (MMAE), or an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof. Structure of MMAE is shown below:

(MMAE). [0078] In some embodiments, the active agent Z is a sequence-selective DNA minor-groove binding crosslinking agent. For example, Z may be pyrrolobenzodiazepine (PBD), a PBD dimer, or an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof. Structures of PBD and PBD dimer are shown below:

[0079] In some embodiments, the active agent Z is a topoisomerase I inhibitor, such as camptothecin, irinotecan, SN-38, or an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof.

SN-38 (7-Ethyl-10-hydroxy-camptothecin) [0080] Any PI3K inhibitor may be used as an active agent. In some embodiments, the PI3K inhibitor may be a small molecule. Non-limiting examples include Omipalisib (GSK2126458, GSK458), BAY 80-6946 (Copanlisib), PF-04691502, PI- 103, BGT226 (NVP-BGT226), Apitolisib (GDC-0980, RG7422), Duvelisib (IPI-145, INK1197), AZD8186, Pilaralisib (XL147), PIK-93, Idelalisib (GS-1101), MLN1117, VS-5584, SB2343, GDC-0941, BM120, NVP-BKM120, Buparlisib, AZD8835, XL765 (SAR245409), GS-9820 Acalisib, GSK2636771, AMG-319, IPI-549, Perifosine, Alpelisib, TGR 1202 (RP5264), PX-866, AMG-319, GDC-0980, GDC- 0941, Sanofi XL147, XL499, XL756, XL147, PF-46915032, BKM 120, CAL 263, SF1126, PX-886, KA2237, a dual PI3K inhibitor (e.g., Novartis BEZ235), an isoquinolinone, or derivatives/analogs thereof. [0081] In some embodiments, the PI3K inhibitor may be an inhibitor of delta and gamma isoforms of PI3K. In some embodiments, the PI3K inhibitor is an inhibitor of alpha isoforms of PI3K. In other embodiments, the PI3K inhibitor is an inhibitor of one or more alpha, beta, delta and gamma isoforms of PI3K. Non-limiting examples of PI3K inhibitors include compounds disclosed in US 9,546,180 (Infinity Pharmaceuticals), WO 2009088990 (Intellikine Inc.), WO 2011008302 (Intellikine Inc.), WO 2010036380 (Intellikine Inc.), WO 2010/006086 (Intellikine Inc.), WO 2005113556 (Icos Corp.), US 2011/0046165 (Intellikine Inc.), or US 20130315865 (Pfizer), the contents of each of which are incorporated herein by reference in their entirety. [0082] In some embodiments, the PI3K inhibitor is selected from the group of Omipalisib (GSK458) or its derivatives/analogs, BAY 80-6946 (Copanlisib) or its derivatives/analogs, PF-04691502 or its derivatives/analogs, PI-103 or its derivatives/analogs, BGT226 (NVP-BGT226) or its derivatives/analogs, Apitolisib (GDC-0980, RG7422) or its derivatives/analogs, Duvelisib (IPI-145, INK1197) or its derivatives/analogs, AZD8186 or its derivatives/analogs, Pilaralisib (XL147) or its derivatives/analogs, and PIK-93 or its derivatives/analogs.

Pilaralisib (XL147) PIK-93 Idelalisib (GS-1101) [0083] Any PARP inhibitor may be used as an active agent. In some embodiments, the PARP inhibitor may be a small molecule. Non-limiting examples include olaparib, veliparib (ABT-888), rucaparib (AG014699 or PF-01367338), ganetespib, talazoparib (BMN673), niraparib, iniparib (BSI 201), CEP 9722, E7016, BGB-290, or derivatives/analogs thereof. [0084] In some embodiments, the PARP inhibitor is selected from the group of olaparib or its derivatives/analogs and talazoparib or its derivatives/analogs. The conjugates of the present application may comprise an HSP90 targeting moiety connected to olaparib or its derivatives/analogs or talazoparib or its derivatives/analogs.

[0085] Any cytotoxic moiety disclosed in WO2013158644, WO2015038649, WO2015066053, WO2015116774, WO2015134464, WO2015143004, WO2015184246, the contents of each of which are incorporated herein by reference in their entirety, such as bendamustine, VDA, doxorubicin, pemetrexed, vorinostat, lenalidomide, docetaxel, 17-AAG, 5-FU, abiraterone, crizotinib, KW-2189, BUMB2, DC1, CC-1065, adozelesin, or derivatives/analogs thereof, may be used as an active agent in conjugates of the present invention. [0086] In some embodiments, the active agents are compounds for treating infections such as hepatitis (such as HBV infection or HCV infection), RSV, influenza, adenovirus, rhinovirus, or other viral infections, wherein the compounds are disclosed in US20190046552, US20190290673, US20190070212, US20180110796, WO2019071105, and US10376533, the contents of each of which are incorporated herein by reference in their entirety. Immuno-oncology Active Agents [0087] In some embodiments, a payload may be an active agent that can boost or provoke an anti-cancer immune response in a subject. Immunotherapy is an advantageous strategy to treat cancer. Any compound that can provoke and/or enhance an immune response to destroy tumor cells in a subject may be included in the present conjugate. [0088] In some embodiments, the active agent is able to induce the expression of a pattern recognition receptor (e.g., RIG-I, NOD2, MDA5, LPG2, or STING) in a subject. The subject may have a microbial infection, e.g., a viral infection, a bacterial infection, a fungal infection, or a parasitic infection. Retinoic acid-inducible gene-I (RIG-I) protein and STING (stimulator of interferon genes) are important mediators of innate and adaptive immunity, and RIG-I and STING agonists have been recognized as immuno-oncology agents in cancer therapy. Upon ligand binding, STING activates the innate immune response through interaction with RIG-I and IPS- 1, resulting in interferon production (e.g., IFN-a and IFN-β) and other downstream signaling events. As non-limiting examples, the active agents may be any compound disclosed in WO2017/011622, the contents of which are incorporated herein by reference in their entirety, such as compounds of Formula (la):

(lie), or any prodrug or salt thereof. 1. Tumor associated antigens (TAAs) and antigenic peptides [0089] In some embodiments, the active agents may be tumor associated antigens (TAAs), antigen epitopes including antigen peptides presented by either MHC (major histocompatibility complex) class I or MHC class II molecules; cytokines, chemokines, other immunomodulators, T cell receptors (TCRs), CD (cell differentiation molecules) antigens, antibodies, cytotoxic agents, cell adhesion molecules and any components that are involved in an immune response; or variants thereof. A payload may be a protein including a peptide, a nucleic acid, a sugar, a lipid, a lipoprotein, a glycoprotein, a glycolipid, or a small molecule. [0090] In embodiments that a plural of payloads are included in one conjugate, the plural payloads may belong to the same category such as multiple epitope peptides derived from a single TAA, or multiple different tumor associated antigens isolated from a tumor tissue. In other aspects, a plural of payloads having different functionality such as a mix of tumor associated antigens and co-stimulatory factors may be included in the same conjugate to synergistically enhance the antigen presentation to T cells. [0091] The initiation of an immune response against diseased tumor cells involves presenting a tumor specific antigen to the immune system. It has been known that tumor cells express specific antigens that are not normally expressed by normal cells. Many tumor associated antigens (TAAs) have been identified and antigenic peptides (epitopes) (either MHC class I specific or MHC class II specific) are isolated that can specifically activate an immune response (e.g., cytotoxic T lymphocyte response/CTL response) to attack abnormal tumor cells and promote their lysis in vivo. TAAs and epitope peptides derived from TAAs can be selected as antigens to selectively stimulate cytotoxic T lymphocyte (CTL) response. The ability of a TAA or a TAA peptide to induce CTL response depends on its ability to bind to specific MHC molecules and its ability to break immune tolerance. [0092] There are two types of MHC/HLA molecules used for presenting antigens. (e.g.,TAAs) MHC/HLA class I molecules are expressed on the surface of all cells and MHC/HLA class II are expressed on the surface of professional antigen presenting cells (APCs). MHC/HLA class II molecules bind primarily to peptides derived from proteins made outside of an APC, but can present self (endogenous) antigens. In contrast, HLA class I molecules bind to peptides derived from proteins made inside a cell, including proteins expressed by an infectious agent (e.g., such as a virus) in the cell and by a tumor cell. When the HLA class I proteins reach the surface of the cell these molecules will thus display any one of many peptides derived from the cytosolic proteins of that cell, along with normal “self” peptides being synthesized by the cell. Peptides presented in this way are recognized by T-cell receptors which engage T- lymphocytes in an immune response against the antigens to induce antigen-specific cellular immunity. [0093] In accordance with the present disclosure, a payload may be a TAA or an antigenic peptide (epitope) derived from a TAA. An antigenic peptide may be a CD8 + T cell epitope that binds to specific MHC (HLA in human) class I molecules with a high affinity. An antigenic peptide may be a CD4+ T cell epitope that binds to specific MHC (HLA in human) class II molecules with a high affinity. The antigenic peptide may be about 5 to 50 amino acids in length. The antigenic peptide may be greater than 5 amino acids in length, or greater than 10 amino acids in length, or greater than 15 amino acids in length, or greater than 20 amino acids in length, or greater than 25 amino acids in length, or greater than 30 amino acids in length, or greater than 35 amino acids in length, or greater than 40 amino acids in length, or greater than 45 amino acids in length. For example, the antigenic peptide may contain 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 amino acids. It is generally preferable that the antigenic peptide be as small as possible while still maintaining substantially all of the immunologic activity of the native protein. In some aspects, the HLA class I binding antigenic peptides (epitopes) may have a length of about 6 to about 15 amino acid residues, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In other aspects, the HLA class II binding peptides (epitopes) may have about 6 to about 30 amino acid residues, e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 amino acids, preferably to between about 13 and about 20 amino acids, e.g., 13, 14, 15, 16, 17, 18, 19 or 20 amino acids. [0094] In some embodiments, the antigenic epitope from a TAA may be an epitope that induces a B cell response in a subject to generate TAA specific antibody mediated immune responses. [0095] TAAs or TAA derived antigenic peptides may be delivered directly to activate T cells through the targeting moieties of the conjugate. Conjugates of the present disclosure comprising one or more TAAs and/or antigenic peptides derived from TAAs may provide vaccine platforms that can enhance immunogenicity and reduce toxicity such as autoimmune toxicity. [0096] A TAA payload may be an oncofetal antigen that is typically only expressed at different stages during the development of the fetus and in cancerous somatic cells. Many proteins are normally expressed during fetal development but are transcriptionally repressed after birth or at early stage of infancy, therefore are not present, or are expressed in significantly lower levels in the corresponding normal adult tissue. Some of these developmental proteins are re-expressed in certain tumor cells and become oncofetal antigens. The oncofetal antigens have the potential to be used as tumor markers for diagnosis, treatment monitoring, follow-up after therapy and/or ultimately as targets for specific therapy of malignancy. Examples of oncofetal antigens may include, but are not limited to CEA (carcinoembryonic antigen) in colorectal carcinorma, iLRP/OFA (immature laminin receptor protein/oncofetal antigen) in renal cell carcinoma (RCC), TAG-72 (tumor associated glycoprotein-72) in prostate carcinoma, AFP (alpha-fetoprotein) in hepatocellular carcinoma (HCC), ROR1 (a receptor tyrosine kinase) in many malignant cells such as brain tumors, sperm protein 17, HMGA2 (high mobility group A2) in ovarian carcinoma, oncofetal H19, CR-1 (Cripto-1, a member of epidermal growth factor (EGF)-CFC family), trophoblast glycoprotein precursor and GPC-3 (Glypican-3, a member of heparan sulphate proteoglycans) in HCC. Some examples of T cell epitope peptides derived from oncofetal antigens may be used as payloads, such as those peptides disclosed in U.S. Pat. NOs.: 7,718,762; 7,968,097; 7,994,276; 8,080,634; 8,669,230; 8,709,405; and U.S. patent publication NO: 2007/0049960; each of which is incorporated herein by reference in their entirety. [0097] A TAA payload may be an oncoviral antigen that is encoded by tumorigenic transforming viruses (also called oncogenic viruses). Oncogenic viruses, when they infect host cells, can insert their own DNA (or RNA) into that of the host cells. When the viral DNA or RNA affects the host cell’s genes, it can push the cell toward becoming cancer. Oncogenic viruses include, but are not limited to, RNA viruses, such as Flaviviridae and Retroviridae, and DNA viruses, such as Hepadnaviridae, Papovaviridae, specifically Papillomaviruses, Adenoviridae, Herpesviridae, and Poxviridae. Some examples of commonly known oncoviruses include human papilloma viruses (HPVs) which are main causes of cervical cancer, Epstein-Barr virus (EBV) which may cause nasopharyngeal cancer, certain types of fast-growing lymphomas (e.g., Burkitt lymphoma) and stomach cancer, hepatitis B, C and D viruses (HBV, HCV and HDV) in hepatocellular carcinoma (HCC), human immunodeficiency virus (HIV) which increases the risk of getting many typese of cancer (e.g., liver cancer, anal cancer and Hodgkin cancer), Kaposi sarcoma herpes virus (KSHV; also known as human herpes virus 8 (HHV8)) which is linked to lymphoma, human T-lymphotrophic virus (HTLV-1) and merkel cell polymavirus (MCV). [0098] A viral antigen can be any defined antigen of a virus that is associated with a cancer in a human. A viral antigen is one that results in a CD8+ T-cell response that can be readily/easily measured. Desirably, the viral antigen is one to which an immune response can be induced or stimulated in a human and is universally recognized. Examples of suitable EBV antigens include, but are not limited to, Epstein-Barr nuclear antigen-1 (EBNA1), latent membrane protein 1 (LMP1), or latent membrane protein 2 (LMP2). Examples of suitable HPV antigens for conjugates include, but are not limited, L1 and L2 protein, and E5, E6, and E7. Examples of suitable KSHV antigens for conjugates may include but are not limited to, latency nuclear antigen (LANA) and v-cyclin. Examples of suitable HIV antigens include, but are not limited to gp160, gp120 and gag protein. It is within the scope of the present disclosure that any antigenic peptides derived from oncoviral antigens may be used as active payloads of the present conjugates. [0099] A TAA payload may be an overexpressed or accumulated antigen that is expressed by both normal and neoplastic tissue, with the level of expression highly elevated in cancer tissues. Numerous proteins (e.g. oncogenes) are up-regulated in tumor tissues, including but not limited to adipophilin, AIM-2, ALDH1A1, BCLX(L), BING-4, CALCA, CD45, CD274, CPSF, cyclin D1, DKK1, ENAH, epCAM, ephA3, EZH2, FGF5, G250, HER-2/neu, HLA-DOB, Hepsin, IDO1, IGFB3, IL13Ralpha2, Intestinal carboxyl esterase, kallikrein 4, KIF20A, lengsin, M-CSF, MCSP, mdm-2, Meloe, Midkine, MMP-2, MMP-7, MUC-1, MUC5AC, p53, Pax5, PBF, PRAME, PSMA, RAGE-1, RGS5, RhoC, RNF43, RU2A5, SECERNIN 1, SOX10, STEAP1, survivin, Telomerase, TPBG, VEGF, and WT1. [0100] Antigenic peptides derived from TAAs that are overexpressed in tumor tissues can be found in many references. Some examples may be U.S. Pat. NO.: 7,371,840; 7, 906, 620; U.S. patent publication No.2010/0074925; the content of each of which is incorporated herein in their entirety. [0101] A TAA payload may be a cancer-testis antigen that is expressed only by cancer cells and adult reproductive tissues such as testis and placenta. A TAA in this category may include, but are not limited to antigens from BAGE family, CAGE family, HAGE family, GAGE family, MAGE family (e.g., MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A6 and MAGE-A13), SAGE family, XAGE family, MCAK, NA88-A (cancer/testis antigen 88), PSAD1, SSX-2, and SLLP-1. As a non-limiting example, NY-ESO-1 is one of the most immunogenic TAAs which expression is limited to testis in healthy subjects, but often overexpressed in various cancers such as HCC, melanoma, ovarian, and breast cancer. [0102] A TAA payload may be a lineage restricted antigen that is expressed largely by a single cancer histotype. A lineage restricted antigen may include, but are not limited to, Melan-A/MART-1, Gp100/pmel17, Tyrosinase, TRP-1/-2, P.polypeptide, MC1R in melanoma; and prostate specific antigen (PSA) in prostate cancer. Any antigenic peptides derived from these TAAs may be used as active payloads of the present conjugates. [0103] A TAA payload may be a mutated antigen that is only expressed by tumor cells as a result of genetic mutations or alterations in transcription. The antigen may be resulted from genetic substitution, insertion, deletion or any other genetic changes of a native cognate protein (i.e. a molecule that is expressed in normal cells). A subset of these mutations can alter protein coding sequences, therefore creating novel, foreign antigens: tumor neoantigen. As used herein, the term “tumor neoantigens” refers to tumor antigens that are present in tumor cells but not normal cells and do not induce deletion of their cognate antigen specific T cells in thymus (i.e., central tolerance). These tumor neoantigens may provide a “foreign” signal, similar to pathogens, to induce an effective immune response needed for cancer immunotherapy. A neoantigen may be restricted to a specific tumor. A neoantigen be a peptide/protein with a missense mutation (missense neoantigen), or a new peptide with long, completely novel stretches of amino acids from novel open reading frames (neoORFs). The neoORFs can be generated in some tumors by out-of-frame insertions or deletions (due to defects in DNA mismatch repair causing microsatellite instability), gene-fusion, read-through mutations in stop codons, or translation of improperly spliced RNA (e.g., Saeterdal et al., Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer, Proc Natl Acad Sci USA, 2001, 98: 13255-13260). Studies have showed that neoORFs generated by frameshift mutations, which are not subject to central tolerance, induce highly specific antitumor immunity, and are thus highly valuable as antigens for cancer immunotherapy. [0104] A series of murine and human studies have revealed that various gene products with missense mutations can encode peptides recognized by cognate cytotoxic T lymphocytes (CTLs) (Sensi and Anichini, Unique tumor antigens: evidence for immune control of genome integrity and immunogenic targets for T cell- mediated patent-specific immunotherapy. Clin Cancer Res., 2006, 12: 5023-5032). As non-limiting examples, these neoantigens may include mutated new peptides derived from alpha-actinin-4, ARTC1, BCR-ABL fusion protein (b3a2), B-RAF, CASP-5, CASP-8, beta-catenin, Cdc27, CDK4, CDKN2A, CLPP, CML-66, COA-1, connexin 37, dek-can fusion protein, EFTUD2, Elongation factor 2, ETV6-AML1 fusion protein, fibronectin, FLT3-ITD, FN1, GPNM8, LDLR-fucosyltransferase AS fusion protein, HLA-A2, HLA-A11, Hsp-70-1B, MART-2, ME1, MUM-1, MUM-2, MUM- 3, Myosin class I, NFYC, neo-PAP, OGT, OS-9, p53, pml-RARalpha fusion protein, PRDX5, PTPRK, K-Ras, N-Ras, RBAF600, sirtuin-2, SNRPD1, SYT-SSX1/SSX2 fusion protein, TGF-beta receptor II, etc. [0105] Additional neoantigen peptides may include SF3B1 peptides, MYD peptides, TP53 peptides, Abl peptides, FBXW7 peptides, MAPK peptides, and GNB1 peptides disclosed in US patent publication NO.: 20110293637; the content of which in incorporated herein in its entirety. [0106] Tumor associated mutations are discovered rapidly through DNA and RNA sequencing of tumor and normal tissues. Massively parallel sequencing techniques can sequence the entire genome or exome of tumor and matched normal cells to identify all of the mutations that have occurred in tumor cells. The comprehensive maps of mutated antigens in tumor genomes bring new targets for therapeutic or prophylactic vaccines (Wood LD, et al., The genomic landscapes of human breast and colorectal cancers. Science, 2007, 318:1108-1113; PCT patent publication NO.: WO2014168874; the content of each of which is incorporated by reference in their entirety). In addition to de novo sequencing of tumor genomes to identify tumor specific mutations, many algorithms (e.g., NetMHC, IEDB) are applied to identify potential antigenic peptides (epitopes) generated by these mutations by predicting peptides binding to the cleft of patient-specific HLA (human leukocyte antigen) class I and class II molecules. (Castle et al., Exploiting the mutanome for tumor vaccination. Cancer Res, 2012, 72: 1081-1091). [0107] Accordingly, these new neoantigens identified through large-scale sequencing and algorithm calculation may be linked to conjugates of the present disclosure as payloads. Novel tumor antigenic peptides are identified by some studies may be used as payloads of the conjugates. See, e.g., Nishimura et al., Cancer immunotherapy using novel tumor associated antigenic peptides identified by genome-wide cDNA microarray analyses, Cancer Sci.2015, 106(5): 505-511; and Linnemann et al., high-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma, Nat. Med., 2015, 21(1): 81-85; the content of each of which is incorporated by reference in their entirety. Conjugates comprising tumor neoantigens may be used as ideal therapeutic and prophylactic vaccines. [0108] A TAA payload may be an idiotypic antigen that is generated from highly polymorphic genes where a tumor cell expresses a specific “clonotype”, i.e., as in B cell, T cell lymphoma/leukemia resulting from clonal aberrancies, such as Immunoglobulin and T cell receptors (TCRs). Idiotypic antigens are a class of nonpathogen-associated neoantigens. For example, the malignant B cells express rearranged and multiply mutated surface immunoglobulins (Ig). Tumor specific idiotypes (e.g., immunoglobulin idiotypes) are regarded as particularly attractive tumor-specific antigens that can be successfully targeted by immunotherapy (e.g., Alejandro et al., Idiotypes as immunogens: facing the challenge of inducing strong therapeutic immune responses against the variable region of immunoglobulins, Front Oncol., 2012, 2: 159 [0109] A TAA payload may be a post-translationally altered antigen due to tumor - associated alterations in glycosylation, and other posttranslational modifications. Some examples may include MUC1 in colorectal carcinoma. [0110] Some examples of antigenic peptides and their corresponding genes/proteins, HLA subtypes to which an antigenic peptide binds and tumors associated with them are listed in Table 1 (e.g., Vanern et al., Database of T cell defined human tumor antigens: the 2013 update, Cancer Imus.2013, 13: 15). Table 1: Examples of peptide antigen epitopes

*The mutation creates a start codon (ATG) that opens an alternative ORF encoding the antigenic peptide. This peptide is recognized by regulatory T cells (Tregs). [0111] Additionally, payloads of the present conjugates may be tumor specific antigens and /or their antigenic peptides disclosed in U.S. Pat. NOs: 8,961,985; 8,951,975; 8,933,014; 8,889,616; 8,895,514; 8,889,616; 8,871,719; 8,697,631; 8,669,230; 8,647,629; 8,653, 035; 8,569, 244; 8, 455, 615; 8,492,342; 8, 318, 677; 8, 258, 260 ; 8,212,000; 8,211,999; 8,147,838; 8,119,139; 8,080,634; 8,067,529; 8,034,334; 8,007,810; 7,994,276; 7,939,627; 7,833,970; 7,833,969; 7,846,446; 7,807,642; 7,247,615; 6,063,900; U.S. Patent publication Nos.: 2015/0147347; 2015/0125477; 2015/0125478; 2015/0110797; 2015/0010587; 2014/0348902; 2014/0322253; 2014/0256648; 2014/0255437; 2014/0178409; 2014/0154281; 2013/0108664; 2012/0308590; 2011/0229504; 2011/0212116; 2011/ 0052614; PCT patent publication NOs.: WO2015/082499; WO2015/071763; WO2015/018805; WO2014/188721; WO2014/136453; WO2014/141683; WO2014/141652; WO2014/106886; WO2014/087626; WO2014/010232; WO2014/010231; WO2014/010229; WO2013/135553; WO2000023584; the content of each of which is herein incorporated by reference in their entirety. [0112] Antigenic peptides may also include those identified by methods disclosed in, e.g., US pat. NOs.: 9,090, 322; 8, 945, 573; 8, 883,164; and US patent publication NOs.: 2014/0370040; the content of each of which is herein incorporated by reference in their entirety. [0113] Other potential TAAs and antigenic peptides may include those discussed by, e.g., Akiyama et al., Cancer Immunol. Immunother.2012, 61: 2311-2319; Alisa et al., J Immunol 2008, 180: 5109-5117; Alves et al., Cancer Res 2003; 63: 8476-8480; Anderson et al., Cancer Res 2004, 64: 5456-5460; Bae et al., Br J Haematol 2012, 157: 687-701; Belle et al., Eur J Haematol 2008, 81: 26-35; Bund et al., Exp Hematol 2007, 35: 920-930; Chen et al., Neoplasia 2008, 10: 977-986; Coleman et al., Int J Cancer 2011, 128: 2114-2124; Dong et al., Cancer Lett 2004, 211: 219-25; Erfurt et al., Int J Cancer 2009, 124: 2341-2346; Flad et al., Proteomics 2006, 6: 364-374; Fleischhauer et al., Cancer Res 1998, 58: 2969-2972; Friedman et al., J Immunol 2004, 172: 3319-3327; Gardyan et al., Int J Cancer, 2015, 136911): 2588-2597; Gomi et al., J Immunol 1999, 163: 4994-5004; Greiner et al., Blood 2005, 106: 938-945; Greiner et al., Blood 2012, 120: 1282-1289; Hardwick et al., Cancer Immun.2013, 13: 16; Harz et al., J Immunol.2014, 193(6): 3146-3154; Hernandez et al., Proc Natl Acad Sci USA 2002, 99: 12275-80; Hundemer et al., Exp Hematol 2006, 34: 486-496; Ito et al., Int J Cancer 2000, 88: 633-639; Kao et al., J Exp Med 2001, 194: 1313- 1323; Kawahara et al., Oncol Rep 2011, 25: 469-476; Keogh et al., Cancer Res 2000, 60: 3550-3558; Kierstead et al., Br J Cancer 2001, 85: 1738-1745; Kikuchi et al., Int J Cancer 1999, 81: 459-466;Koga et al., Tissue Antigens 2003, 61: 136-145; Li et al., Clin Exp Immunol 2005, 140: 310-319; Li et al., Med oncol., 2014, 31(12): 293; Maccalli et al., Clin Cancer Res 2008, 14: 7292-7303; Machlenkin et al., Cancer Res 2005, 65: 6435-6442; Mahlendorf et al., Cancer Biol. Ther.2013, 14: 254- 261;Maletzki et al., Eur. J. Cancer 2013, 49: 2587-2595; Meier et al., Cancer Immunol Immunother 2005, 54: 219-228; Nonaka et al., Tissue Antigens 2002, 60: 319-327; Sedegah et al., PLos One, 2014, 9(9): e106241; Quintarelli et al.,. Blood 2011, 117: 3353-3362; Tang et al., Mol Med Rep.2015, 12(2): 1741-1752; and Tu et al., J Immunother 2012, 35: 235-244; the content of each of which is herein incorporated by reference in their entirety. [0114] In some embodiments, payloads of the conjugates may be TAA or antigenic peptide analogs. An antigenic peptide analog such as a neoantigen analog may be a molecule that is not identical, but retains the biological activity (e.g., immunogenicity) and/or has analogous structural features to a corresponding naturally occurring tumor specific antigen such as neoantigen.TAA and antigenic peptide analogs may be substituted and/or homologous peptides related to a naturally occurring antigenic peptide, such as altered peptide ligands (Kersh and Allen, Essential flexibility in the T-cell recognition of antigen. Nature.1996, 380: 495-498). Those substitutes and homologs retain similarities to the original peptides and are recognized in a highly similar fashion (e.g., Macdonald et al., T cell allorecognition via molecular mimicry. Immunity.2009, 31:897–908). The peptide analogs are intended to increase characteristics of naturally occurring antigenic peptides such as resistance against peptide degradation and enhancing the activity of the native epitope to induce cytotoxic T lymphocytes. [0115] In some embodiments, TAA or antigenitc peptide analogs may be biochemically modified as necessary to provide some desired attributes such as improved pharmacological characteristics, while increasing or at least retaining substantially all of the biological activity of the unmodified antigenic peptides to bind the desired MHC molecules and activate the appropriate T cells. Such modifications may also increase the protease resistance, membrane permeability, or half-life without altering, for example, ligand binding. [0116] Accordingly, a TAA or an antigen peptide may be subject to various modifications, such as substitutions, either conservative or non-conservative, where such changes might provide for certain advantages in their use, such as improved MHC molecule binding. By conservative substitutions is meant replacing an amino acid residue with another which is biologically and/or chemically similar, e.g., one hydrophobic residue for another, or one polar residue for another. The substitutions include combinations such as Gly, Ala; Val, Ile, Leu, Met; Asp, Glu; Asn, Gln; Ser, Thr; Lys, Arg; and Phe, Tyr. The effect of single amino acid substitutions may also be probed using D-amino acids. Such modifications may be made using well known peptide synthesis procedures, as described in e.g., Stewart & Young, Solid Phase Peptide Synthesis, (Rockford, Ill., Pierce), 2d Ed. (1984). [0117] The TAA and antigenic peptide may also be modified by extending or decreasing the amino acids of the peptide, such as by the addition or deletion of amino acids. [0118] In one embodiment, an antigenic peptide may include amino acid minics and unnatural amino acids, such as 4-chlorophenylalanine, D- or L-naphylalanine; D- or L-phenylglycine; D- or L-2-thieneylalanine; D- or L-l, -2, 3-, or 4-pyreneylalanine; D- or L-3 thieneylalanine; D- or L-(2- pyridinyl)-alanine; D- or L-(3-pyridinyl)- alanine; D- or L-(2-pyrazinyl)-alanine; D- or L-(4-isoρropyl)-phenylglycine; D- (trifluoromethyl)-phenylglycine; D-(trifluoro- methyl)-phenylalanine; D-p- fluorophenylalanine; D- or L-p-biphenyl-phenylalanine; D- or L-p- methoxybiphenylphenylalanine; D- or L-2-indole(alkyl)alanines; and, D- or L- alkylalanines, where the alkyl group can be a substituted or unsubstituted methyl, ethyl, propyl, hexyl, butyl, pentyl, isopropyl, iso-butyl, sec-isotyl, iso-pentyl, or a non-acidic amino acid residues. Aromatic rings of a non-natural amino acid include, e.g., thiazolyl, thiophenyl, pyrazolyl, benzimidazolyl, naphthyl, furanyl, pyrrolyl, and pyridyl aromatic rings. Modified peptides with amino acid mimetics or unnatural amino acid residues may manifest increased stability in vivo. [0119] In addition, an antigenic peptide may be modified by N-terminal acylation, e.g., by alkanoyl (Cι-C₂o) or thioglycolyl acetylation, and/or C-terminal amidation, e.g., ammonia, methylamine, etc. In some instances these modifications may provide sites for connecting to a linker within the conjugate. [0120] In some embodiments, a mixture of antigenic peptides derived from a single TAA may be used as payloads of the present conjugates. In some instances, the peptide mixture may be a mixture of HLA class I specific epitopes and HLA class II specific epitopes. [0121] In some embodiments, more than one antigenic peptide may be included into a conjugate. The peptides may be selected from a spectrum of different antigens that are associated with a particular cancer. Multiple TAA payloads may enhance the coverage of tumor antigens from a target cancer and therefore enhance the capability of antigen presentation and infiltrate sufficient effector T cells to kill tumor cells. There are several advantages using multiple antigens including i): increasing likelihood of generating a robust immune response against at least some of the antigens; and ii): decreasing the likelihood of a tumor escaping the immune response by immunoediting, because it must downregulate multiple targets. As a non-limiting example, two, three, four, five, six or seven antigens from a list of known HCC specific antigens: alpha-fetoprotein (AFP), glypican-3 (GPC3), NY-ESO-1, SSX-2, melanoma antigen gene-A (MAGE-A), telomerase reverse transcriptase (TERT), and hepatocellular carcinoma-associated antigen-519/targeting protein for Xklp-2 (HCA519/TPX2), may be selected as payloads of a conjugate. Such conjugates may enhance an immune response against HCC tumor cells. [0122] In some aspects, Conjugates comprising antigen payloads may comprise at least two or more neoantigenic peptides. In some embodiments the composition contains at least two distinct peptides. Preferably, the at least two distinct peptides are derived from the same polypeptide (e.g., the same TAA). By distinct polypeptides is meant that the peptide vary by length, amino acid sequence or both. [0123] In some embodiments, payloads of the conjugates of the present disclosure may comprise between 1 to 20 antigen peptides, for example, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 different antigen peptides. In other aspects, more than 20 antigen peptides may be included in the conjugates as payloads. [0124] In some embodiments, antigen payloads may be “personalized” tumor antigens from a subject who has a tumor. As used herein, the term “personalized tumor antigens” refers to individual patient specific neoantigens that are encoded by a collective of the individual patient’s tumor-specific alternations and mutations. In other aspects, tumor antigen payloads may be “shared” tumor antigens. As used herein, the term “shared tumor antigens” refers to a collective of neoantigens that are commonly presented in a specific type of tumor for example breast tumor. [0125] In accordance with the present disclosure, for the activation of fully functional cytotoxic T lymphocytes, TAA-derived CD4+ T helper cell epitopes may be induced in a conjugate along with CD8+ T-cell epitopes. [0126] In some embodiments, TAAs may be lipid molecules, polysaccharides, saccharides, nucleic acids, haptens, carbohydrate, or the combinations thereof. 2. APC activation, maturation and migration [0127] Antigen presenting cells (APCs), in particular dendritic cells (DCs) are required for presenting a TAA to T cells and activating cancer specific immune responses. Many strategies have been developed to enhance activity of DCs to elicit a specific immune response. Accordingly, payloads of the present conjugates may be any active agents that can increase APCs (i.e. DCs) activity. The active agents may function at any step during the process of dendritic cell maturation, migration, activation and antigen presentation, and/or cytokine production. [0128] In some embodiments, a payload may be an active agent that can promote DCs recruitment, maturation and migration along the lymphatic vessels and into the Lymph Node (LN) (e.g., tumor draining lymph node), therefore, promoting scanning a vast T cell repertoire within the LN. [0129] In some embodiments, a payload may be an agent that can enhance antigen presentation of DCs, i.e. converting antigens into peptide-MHC complexes. The active agent may increase antigen uptake from e.g., death cells of tumors, and efficiently extract peptides from them. [0130] In some embodiments, an active agent may be a chemokine that binds to a chemokine receptor on DCs to regulate DCs. Migration of antigen loaded dendritic cells into lymphatic vessels to lymph node to encounter T cells requires chemokine stimulation and induction of the chemokine receptors (e.g., CCR7). DCs express a panel of inflammatory chemokine receptors including CCR1, CCR2, CCR4, CCR5, CCR6, CCR 8, CCR9, CXCR3, CX3CR, CXCR4 and CCR7, each of which binds to one or more ligands to regulate different aspects of DC maturation, migration, and interaction with naïve T cells in lymph nodes. Some ligands that bind to and activate these receptors include, but are not limited to, CCL3 (MIP1α), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CCL9 (MRP-2), CCL14 (HCC1), CCL16 (HCC4) which are CCR1 ligands; CCL2 (MCP-1), CCL7 (MCP-3), CCL12 (MCP-5), CCL8 (MCP-2), CCL16 (HCC4) which are CCR2 ligands; CCL17 (TARC), CCL19 (MIP- 3β, ELC) which are CCR4 ligands; CCL3 (MIP1α), CCL4 (MIP1β), CCL5 (RANTES), CCL8 (MCP-2), CCL11 (eotaxin), CCL14 (HCC1), CCL16 (HCC4) which are CCR5 ligands; CCL20 (MIP-3α), a ligand of CCR6; CCL1 (TCA3), a ligand of CCR8; CCL25 (TECK), a ligand of CCR9; CXCL9 (Mig), CXCL10 (IP10), CXCL11 (ITAC) which are ligands of CXCR3; CX3Cl1 (fractalkine), a ligand of CX3CR; CCL12 (SDF-1), a ligand of CXCR4; CCL19 (MIP-3β, ELC), CCL21 (6- Ckine, SLC) which are ligands of CCR7. [0131] For instance, the chemokine receptor CCR7 on DCs, when binding to its ligand CCL19 and CCL21 can regulate the migratory speed of DCs, directing DCs to secondary lymphoid nodes and to elicit an adaptive immune response. (Riol-Blanco et al., The chemokine receptor CCR7 activates in dendritic cells two signaling modules that independently regulate chemotaxis and migratory speed. J Immnuno., 2007, 174(7):4070-80; and Verdijk et al., Maximizing dendritic cell migration in cancer immunotherapy.2008, Expert Opin Biol Ther., 8(7): 865-874). [0132] In some embodiments, a payload may be a cytokine that can stimulate/regulate the expression both MHC/HLA class I and class II molecules on APCs (i.e., DCs). Interferon-γ (IFN-γ), for example, increases the expression of MHC/HLA class I and MHC/HLA class II molecules, and can induce the expression of MHC/HLA class II molecules on certain cell types that do not normally express them. Interferons also enhance the antigen presenting function of MHC/HLA class I molecules by inducing the expression of key components of the intracellular machinery that enables peptides to be loaded onto the MHC molecules. [0133] Payloads may also be other agents that can stimulate and induce antigen presenting function of other cells for example, γδ T cells. As non-limiting examples, some small molecular weight non-peptide compounds that can stimulate and induce antigen presenting function of γδ T cells may include isopentenyl pyrophosphate (IPP) and others disclosed by Brandes et al (US Pat. No.: 8, 153, 426, which is incorporated herein by reference in its entirety). [0134] It is indicated in many studies that in some tumor cells, antigen presentation is reduced or impaired due to impairment of one or more components of MHC class I/II antigen presenting pathway. For example, mutations which cause a reduced expression of a component, e.g., reduced expression of MHC class I gene due to changes in methylation or chromatin structure, or cause a mutated component that has reduced or no function. Impairments in these components typically affect processing (e.g., proteolysis) of proteins to form peptide epitopes, or transporting peptide to the endoplasmic reticulum, or formation or transport of peptide/MHC molecule (pMHC) complex to the cell surface. As non-limiting examples, components may be MHC class I alpha chain polypeptide, beta2m macroglobulin and TAP. [0135] In certain embodiment, the payload of the conjugate may be a MHC/HLA molecule or a variant thereof that contains sequences to match any known TAA or peptide epitope. Conjugates comprising such molecules may mimic DC derived function to directly activate CD8+ and CD4+ T cells inducing a strong immunogenic response against tumor. The antigen presenting molecules may be MHC/HLA class I or class II molecules. [0136] MHC/HLA class I molecules are cell surface glycoproteins and are heterodimeric and composed of a polymorphic, MHC-encoded, approximately 45 kD ^ chain, which is non-covalently associated with an approximately 12 kD β-2 microglobulin (β-2m). The extracellular portion of the MHC Class I ^ chain is divided into three domains, α-1, α-2, and α-3, each approximately 90 amino acids long and encoded on separate exons. The α-3 domain and β-2m are relatively conserved and show amino-acid sequence homology to immunoglobulin constant domains. The polymorphic α-1 and α-2 domains show no significant sequence homology to immunoglobulin constant or variable region. The polymorphic α-1 (approximately 90 amino acids) and α-2 (approximately 92 amino acids) domains are responsible to antigen recognition. The α-2 domain is attached to the less- polymorphic, membrane-proximal α-3 (approximately 92 amino acids) domain which is followed by a conserved transmembrane (25 amino acids) and an intra-cytoplasmic (approximately 30 amino acids) segment. [0137] The classical class I gene family includes the highly polymorphic human class I molecules HLA-A, HLA-B, and HLA-C. HLA-A, -B, and -C genes encode molecules that bind antigenic peptides, and present the peptides to CD8⁺ T cells, thereby initiating a cytotoxic T cell (CTL) response during infection. Extensive allelic polymorphisms are observed in the HLA-A, B and C genes, concentrated primarily among nucleotides that encode residues within the peptide binding grooves of the HLA class I molecules, which determine specificity for the associated peptide ligands. [0138] In some embodiments, payloads may be a polypeptide encoded by any of the known HLA genetic loci, as well as polypeptides encoded by genetic loci not yet discovered so long as these can present antigen to a T cell in a manner effective to activate the T cell receptor. Examples of known HLA class I genetic alleles include: for HLA-A: A*01, A*02, A*03, A*11, A*23, A*24, A*25, A*26, A*28, A*29, A*30, A*31, A*32, A*33, A*34, A*36, A*43, A*66, A*68, A*74 and A*80; for HLA-B: B*07, B*08, B*13, B*14, B*15, B*18, B*27, B*35, B*37, B*38, B*39, B*40, B*41, B*42, B*44, B*45, B*46, B*47, B*48, B*49, B*50, B*51, B*52, B*53, B*54, B*55, B*56, B*57, B*58, B*59, B*67, B*73, B*78, B*81, B*82 and B*83; and for HLA-C: C*01, C*02, C*03, C*04, C*05, C*06, C*07, C*08, C*12, C*14, C*15, C*16, C*17 and C*18. [0139] The polypeptides of HLA class II ^ and β chain proteins may include polypeptides from genetic loci for HLA-DRA, HLA-DRB1, HLA-DRB3, HLA- DRB4, HLA-DRB5, HLA-DQA, HLA-DQB, HLA-DOA, HLA-DOB, HLA-DMA, HLA-DMB, HLA-DPA and HLA-DPB. [0140] The MHC/HLA polypeptides selected for inclusion in the present conjugates may also include polypeptide variants such as a modified polypeptide. [0141] In some embodiments, conjugates comprising HLA-A, HLA-B, HLA-C, TAP and beta2m polypeptides may be delivered to tumor cells to restore antigen presentation in tumor cells, therefore activate and expand tumor specific cytotoxic T lymphocytes (CTL) to kill tumor cells. [0142] In some aspects, HLA-A, HLA-B and HLA-C, TAP and beta2m payloads of the conjugates may be connected to a targeting moiety through the linker. Such conjugates, in some aspects, may be fused or co-conjugated with one or more TAAs or peptide epitopes. The peptide- MHC molecule (pMHC) complexes may be delivered to a subject directly targeted to tumor cells. [0143] In addition to dendritic cells, accumulating evidence demonstrates that B cells can serve for the antigen-presenting function, beside antibody mediated mechanisms. CD40 Activated antigen-presenting B cells have been shown to efficiently induce both CD4⁺ and CD8⁺ T cells responses in vitro and in vivo. B cell- based vaccines as an alternative to DC-based vaccines for cancer immunotherapy (von Bergwelt-Baildon et al., Human primary and memory cytotoxic T lymphocyte responses are efficiently induced by means of CD40-activated B cells as antigen-presenting cells: potential for clinical application, Blood, 2012, 99:3319-3325). In some embodiments, the conjugate of the present disclosure may comprise an active agent that can activate B cell antigen presentation. 3. T cell activation or NK cell activation [0144] During a cancer specific immune response, effector T cells (e.g. CD4+ T cells and CD8+ T cells) which are activated by tumor antigen specific APCs can recognize antigen specific tumor cells to kill them. In accordance to the present disclosure, a payload may an agent that can active effector T cells, or assist T cells in killing tumor cells, or increase the specificity of effector T cells to specific tumor cells. [0145] In some embodiment, the active agent may be an agent that can enhance TAA processing and presentations such as other signals that are provided to T cells by natural antigen presenting cells (APCs). T cell immune responses are mediated by the signals received from APCs. In addition to the interaction between a T cell receptor (TCR) and specific tumor antigen in the form of a peptide/major histocompatibility complex (pMHC) on APCs, co-stimulation between T cells and APCs can amplify antigen-specific T cell responses (Michel, et al., Immunity, 2001, 15(6):935-945). Co- stimulation can be mediated by the interaction between receptors on APCs and their corresponding receptors on T cells. Additionally, cytokines secreted by activated APCs after T cell encounters can stimulate T cell response (Schluns and Lefrancois, Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol., 2003, 3(4):269-79). Accordingly, active agents of the present conjugates may be one or more co-stimulatory agents. In addition to tumor antigens/MHC complexes, such co-stimulatory agents may impact expansion, survival, effector function, and memory of stimulated T cells, the co-stimulatory agents may include but are not limited to antigens, polyclonal T cell receptor activators, co-stimulatory and targeting molecules, and cytokines, which allow for control over the signals provided to T cells by natural APCs. These fully activated signals can be transmitted to the nucleus and result in clonal expansion of T cells, upregulation of activation markers on the cell surface, differentiation into effector cells and induction of cytotoxicity or cytokine secretion. [0146] In some embodiments, the active agent may be a polyclonal T cell receptor activator. As used herein, a polyclonal TCR activator can activate T cells in the absence of specific antigens. Suitable polyclonal T cell activators include the mitogenic lectins concanavalin-A (ConA), phytohemagglutinin (PHA) and pokeweed mitogen (PWM), and antibodies that crosslink the T cell receptor/CD3 complex. Exemplary antibodies that crosslink the T cell receptor include the HIT3a, UCHT1 and OKT3 monoclonal antibodies. [0147] In some embodiments, the active agent may be a co-stimulatory molecule, or any compound that has similar function. Activation and proliferation of T cells are also regulated by both positive and negative signals from costimulatory molecules. One extensively characterized T cell costimulatory pathway is B7-CD28, in which CD80 (B7-1) and CD86 (B7-2) on APCs can interact with stimulatory CD28 receptor and the inhibitory CTLA-4 (CD152) receptor on T cells, respectively. In conjunction with signaling through the T cell receptor, CD28 ligation increases antigen-specific proliferation of T cells, enhances production of cytokines, stimulates differentiation and effector function, and promotes survival of T cells. [0148] In some aspects, a conjugate of the present disclosure may comprise at least one costimulatory molecule or agent that can stimulate those co-stimulatory effects, as an active agent to be connected to the targeting moiety through the linker. As used herein, the term “co-stimulatory molecule”, in accordance with its meaning in immune T cell activation, refers to a group of immune cell surface receptor/ligands which engage between T cells and APCs and generate a stimulatory signal in T cells which combines with the stimulatory signal in T cells that results from T cell receptor (TCR) recognition of antigen/MHC complex (pMHC) on APCs. Exemplary co- stimulatory molecules, also referred to as “co-stimulators”, include, but are not limited to, CD7, B7-1 (CD80), B7-2 (CD86), 4-1BBL receptor (CD137), 4-1BB ligand (CD137-L), OX40L, inducible co-stimulatory ligand (ICOS-L), intercellular adhesion molecule (ICAM), CD2, CD5, CD9, CD30L, CD40, CD70, CD83, HLA-G, MICA, MICB, HVEM, lymphotoxin beta receptor, 3/TR6, ILT3, ILT4, HVEM, glucocorticoid-induced tumor necrosis factor receptor ligand (GITR-L), an agonist or antibody that binds Toll ligand receptor and a ligand that specifically binds with B7- H3. Other exemplary co-stimulatory molecules that can be used include antibodies that specifically bind with a co-stimulatory molecule present on a T cell, such as, but not limited to, CD27, CD28, 4-IBB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83. Other suitable costimulatory molecules include, but are not limited to, costimulatory variants and fragments of the natural ligands described above. [0149] As a non-limiting example, a variant may be a soluble form of a co- stimulatory molecule. The soluble form of a co-stimulatory molecule is a fragment of a full length co-stimulatory molecule only containing one or more extracellular domains of the co-stimulatory molecule (e.g., U. S. Pat No.: 8, 268,788). The soluble form of a co-stimulatory molecule derived from an APC retains the ability of the native co-stimulatory molecule to bind to its cognate receptor/ligand on T cells and stimulate T cell activation. A non-limiting example is a soluble form of CD137-L. [0150] In other aspects, the active agent of the conjugate may be a T cell adhesion molecule that can increase the binding association between the antigen- loaded/activated APCs and T cells. Suitable adhesion molecules include, but are not limited to, CD11a (LFA-1), CD11c, CD49d/29(VLA-4), CD50 (ICAM-2), CD54 (ICAM-1), CD58 (LFA-3) CD102 (ICAM-3) and CD106 (VCAM), and antibodies to their ligands. Other suitable adhesion molecules include antibodies to selectins L, E, and P. [0151] In some embodiments, the active agent of the conjugate may be a cytokine or other immunoregulatory agent. Cytokines may be secreted by activated APCs after T cell encounters and impact expansion, survival, effector function, and memory of stimulated T cells. In some embodiments, at least one cytokine may be connected to the targeting moiety through the linker. Suitable cytokines include, but are not limited to, hematopoietic growth factors, interleukins, interferons, immunoglobulin superfamily molecules, tumor necrosis factor family molecules and chemokines. Preferred cytokines include, but are not limited to, granulocyte macrophage colony stimulating factor (GM-CSF), tumor necrosis factor alpha (TNFα), tumor necrosis factor beta (TNFβ), macrophage colony stimulating factor (M-CSF), interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-21 (IL-21), interferon alpha (IFNα), interferon beta (IFNβ), interferon gamma (IFNγ), and interferon-gamma inducing factor (IGIF), and variants and fragments thereof. [0152] In some embodiments, TAAs and/or antigenic peptides derived from TAAs, costimulatory factors, T cell adhesion molecules and cytokines secreted by activated APCs may be connected to the targeting moiety through the linker in one conjugate. Alternatively, conjugates comprising each individual agent may be packaged into one particle or a formulation of the present disclosure. [0153] In certain embodiment, a payload may be a T cell receptor (TCR) or a TCR analog (e.g., engineered CAR) having antigenic specificity for a TAA, e.g., any antigen peptide as discussed above. Mature T cells express a unique αβ TCR that can bind to peptides presented by MHC molecules. Unlike antibodies, TCRs generally have low affinity for ligands, facilitating a rapid scanning of antigen peptide-MHC complexes. Particularly, CDR3 loops of a TCR primarily engage the binding with antigen peptide presented in the MHC groove, while CDR1 and CDR2 loops can contact with the tops of the MHC helices (Garcia and Adams, How the T cell receptor sees antigen-a structural view. Cell.2005, 122: 333–336; Rudolph et al., How TCRs bind MHCs, peptides, and coreceptors. Annual Review of Immunology.2006, 24: 419–466). [0154] Tumor specific TCRs may be obtained from spontaneously occurring tumor-specific T cells in patients, such as the melanocyte differentiation antigens MART-1 and gp100, as well as the MAGE antigens and NY-ESO-1, with expression in a broader range of cancers. TCRs may also be isolated from viral infected cells in some viral-associated malignancies. Additionally, TCRs specific to a TAA may also be identified by, for example, allogeneic TCR and transgenic mice expressing human a HLA molecule. Alternatively, recombinant technology can be used to generate TCRs on phage display libraries, which can be used to identify novel high affinity tumor-specific TCRs (Zhao et al., High-affinity TCRs generated by phage display provide CD4+ T cells with the ability to recognize and kill tumor cell lines. J Immunol.2007, 179:5845–5854). Isolated TCRs may be used as active agents of the conjugates of the present disclosure. [0155] In one example, a TCR active agent of the conjugate of the present disclosure may be a CDR3 region peptide of TCR against a specific TAAs such as WT-1 as disclosed in US patent publication NO.2014/0315735; the content of which is herein incorporated by reference in its entirety. [0156] In other embodiments, the TCR may be γδ T-cell receptors consisting of a γ chain and a δ chain polypeptide. γδ T-cell receptors may be specialized to bind certain kinds of ligands, including heat-shock proteins and nonpeptide ligands such as mycobacterial lipid antigens. It seems likely that γδ T-cell receptors are not restricted by the ‘classical’ MHC class I and class II molecules. They may bind the free antigen, much as immunoglobulins do, and/or they may bind to peptides or other antigens presented by non-classical MHC-like molecules. These are proteins that resemble MHC class I molecules but are relatively nonpolymorphic. [0157] In accordance with the present disclosure, a TCR analog may be a chimeric antigen receptor (CAR) that can recognize a specific cell surface tumor antigen independent of MHC/HLA molecules and employs one or more signaling molecules to activate genetically modified T cells for killing, proliferation, and cytokine production. An engineered chimeric antigen receptor (CAR) may be composed of an antibody-derived targeting domain (i.e., an extracellular domain derived from tumor- specific antibody) fused with T-cell signaling domains that, when expressed by a T- cell, endows the T-cell with antigen specificity determined by the targeting domain of the CAR. [0158] The targeting domain of a CAR may be derived from any antibody that specifically recognizes a tumor specific antigen. In some aspects, a single-chain variable fragment (ScFv) of antibodies are used in the extracellular domain of CARs, which are joined through hinge and transmembrane regions to intracellular signaling domains. Tumor-specific antibodies may be generated through immunization of mice. Recombinant techniques can be used to humanize antibodies, or mice expressing human immunoglobulin genes can be used to generate fully human antibodies. [0159] As discussed previously, complete T cell activation is a complex process involving several signals including a primary initiating signal and secondary costimulatory signals. Inclusion of such signals in CARs can enable responses against cancer cells. For example, inclusion of a primary signaling molecule CD3-ζ in CARs can induce T cell activation. Inclusion of the cytoplasmic domain of CD28, CD134 or 4-1BB (CD137) in CARs can lead to increased cytokine production in response to a TAA (e.g., Carpenito et al., Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and 4-1BB (CD137) domains. Proc Natl Acad Sci USA.2009, 106:3360–3365). [0160] CARs specific for a wide range of TAAs have been developed, for example, CD19 specific CAR for leukemia (Kochenderfer et al., adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood, 2010, 116: 3875–3886), Chmielewski et al., T cells that target carcinoembryonic antigen eradicate orthotopic pancreatic carcinomas without inducing autoimmune colitis in mice. Gastroenterology.2012, 143:1095–1107; Westwood et al. Adoptive transfer of T cells modified with a humanized chimeric receptor gene inhibits growth of Lewis-Y- expressing tumors in mice. Proc Natl Acad Sci USA.2005, 102:19051–19056). [0161] In some embodiment, the active agent of the conjugate may be co-receptors of TCRs such as CD4 and CD8. The payload may be a full length of co-receptors CD4 and CD8, or a domain thereof that can bind to a MHC/HLA molecule. In one example, the payload may be a CD4 immunoglobulin-like domain that can bind to an invariant site of the MHC class II molecule, such as the β2 domain. In another example, the payload may be a CD8 domain that can bind to an invariant site of the MHC class I molecule, such as the ^3 domain. CD4 and CD8 co-receptors that bind to MHC class II and I molecules respectively, can markedly increase the sensitivity of a T cell to antigen presented by MHC molecules on APCs. [0162] Conjugates comprising TCRs, CARs or co-receptors, or variants thereof may be used to engineered T cells for adoptive immunotherapy. A detailed discussion of adoptive T cell immunotherapy is described in the following sections. [0163] In some embodiments, the active agent of the conjugate is a CD3-binding agent, such as a peptide or derivative that binds to CD3, a CD3 antibody or a CD3- binding fragment thereof. Activation of cytotoxic T cell may occur via binding of the CD3 antigen as effector antigen on the surface of the cytotoxic T cell by the conjugates of the present disclosure. CD3 (cluster of differentiation 3) complex, or CD3 antigen, is a T cell co-receptor that helps to activate T cells. CD3 complex may comprise several chains: CD3D (CD3 delta chain), CD3G (CD3 gamma chain), CD3E (CD3 epsilon chain) and/or CD247 (CD3 zeta chain). The CD3-binding agent, CD3 antibody or the CD3-binding fragment may bind to any epitope on any of the chains. [0164] CD3 antigens are cell-surface proteins and are bound to the membranes of all mature T cells. Conjugates of the present disclosure comprising CD3 binding agents may bind to and activate T cells in the absence of independent TCR/MHC binding. The activated T cell can then exert a cytotoxic effect on tumor cells. In one embodiment, CD3 antigents do not internalize upon binding of the conjugates. [0165] The CD3 binding agent may be a Fab fragment of a CD3 antibody, a single CDR CD3 antibody, a single chain variable fragment (scFv) of a CD3 antibody, a single-chain antibody mimic that is much smaller than an antibody such as nanofitin® (Affilogic). Non-limiting examples of CD3 antibodies or fragments thereof include, a humanized CD3-specific scFv disclosed by Liddy et al. (Nature Medicine, vol.18(6):980 (2012)), a single-chain anti-CD3 antibody derived from UCHT1 disclosed by Kuo et al. (Protein Engineering, Design & Selection, vol.25(10):561 (2012)), an anti-CD3 scFv comprising an amino acid sequence of SEQ ID No.2 in CA2561826 to Wang et al., an anti-CD3 portion of an anti-CD3&anti-EpCAM bispecific antibody (SEQ ID No.1) disclosed in WO2005061547 to Baeuerle et al., a reshaped Fab antibody against human CD3, a reshaped single-domain antibody against human CD3 or a reshaped scFv against human CD3 disclosed in US20050175606 to Huang et al., anti-CD3 V_H disclosed in US20050079170 to Gall et al., any CD3-binding scFv including scFv(UCHT-1)-PE38 disclosed in US20020142000 to Digan et al., the contents of each of which are incorporated herein by reference in their entirety. [0166] Alternatively, the active agent of the conjugate activates other effector cells, such as natural killer cells. In some embodiments, the active agent of the conjugate is a CD16 antibody or a CD16-binding fragment thereof. CD16 is an Fc receptor found on the surface of natural killer cells. Conjugates of the present disclosure binds to CD16 on natural killer cells and activate natural killer cells. Non- limiting examples of CD16 antibodies or CD16-binding fragment thereof include monoclonal antibody of the IgGl class against human CD16 antigen disclosed in US5643759 to Pfreundschuh, FV antibody constructs comprising binding sites for a CD16 receptor as disclosed in WO2001011059 to Arndt et al., antibodies exhibiting high affinity for the CD16 receptor disclosed in US20060127392 to de Romeuf et al., the contents of each of which are incorporated herein by reference in their entirety. [0167] In some embodiments, the active agent of the conjugate binds to a universal CAR T cell and activates the CAR T cell. The binding between the active agent and the CAR T cell may occur only in the tumor microenvironment, or is activated by light, heat, radiation, or chemical agents such as but not limited to tetracycline. [0168] In some embodiments, the binding site on the CAR T cell, or the active agent may comprise a masking moiety described herein. The binding of the active agent to the CAR T cell may be inhibited or hindered by the masking moiety. For example, the binding may be sterically hindered by the presence of the masking moiety or may be inhibited by the charge of the masking moiety. [0169] Cleavage of the masking moiety, a conformation change, or a chemical transformation may unmask/activate the binding site on the CAR T cells or the active agent. The masking/unmasking process may be reversible or irreversible. [0170] As a non-limiting example, CAR T cells may be constructed by fusing an anti-fluorescein isothiocyanate (FITC) scFv to a CD3 zeta chain containing the intracellular domain of CD137. The active agent may comprise fluorescein. Therefore, the active agent binds to the CAR T cells and activates T cell cytotoxcity. 4. Cytokines, chemokines and immunoregulatory molecules [0171] In addition to cytokines, chemokines and growth factors that involve in APC maturation and migration, and T cell activation, as described previously, an immunoregulatory profile is required to trigger an efficient immune response and balance the immunity in a subject. In certain embodiment, a payload of a conjugate of the present disclosure may be an immunoregulatory molecule. Conjugates may comprise more than one immunoregulatory molecules as payloads, e.g., two, three, four, five, six, seven or more immunoregulatory molecules. [0172] Examples of suitable immunoregulatory cytokines include, but are not limited to, interferons (e.g., IFNα, IFNβ and IFNγ), interleukins (e.g., IL-1, IL-2, IL- 3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 and IL-20), tumor necrosis factors (e.g., TNFα and TNFβ), erythropoietin (EPO), FLT-3 ligand, gIp10, TCA-3, MCP-1, MIF, MIP-1α, MIP-1β, Rantes, macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), and granulocyte-macrophage colony stimulating factor (GM-CSF), as well as functional fragments thereof. The most preferred immunomodulatory cytokine is GM-CSF, such as human GM-CSF, including a functional fragment thereof. An alternatively preferred immunomodulatory cytokine is IL-2 or a functional fragment thereof. Any immunomodulatory chemokine that binds to a chemokine receptor, i.e., a CXC, CC, C, or CX3C chemokine receptor, can be used in the context of the present disclosure. Examples of chemokines include, but are not limited to, MIP-3α (Lax), MIP-3β, Hcc- 1, MPIF-1, MPIF-2, MCP-2, MCP-3, MCP-4, MCP-5, Eotaxin, Tarc, Elc, I309, IL-8, GCP-2 Groα., Gro-β., Gro-β, Nap-2, Ena-78, Ip-10, MIG, I-Tac, SDF-1, and BCA-1 (Blc), as well as functional fragments thereof. [0173] In some embodiments, an immunoregulatory payload may be a T cell growth factor, derivative thereof, or any agent that can stimulate T cell proliferation and/or enhance T cell survival during an immune response, resulting in a more effective immune response and increased memory T cell function. T cell growth factors may include, but are not limited to, interleukin (IL)-2, IL-7, IL-IL-9, IL-12, IL-14, IL-15, IL-16, IL-21 and IL-23. In particular, the active agent may be IL-12 alone, or 2 interleukins in different combinations such as IL-2 and IL-7, IL-2 and IL- 15, IL-7 and IL-15, IL-2, IL-7 and IL-15, IL-12 and IL-7, IL-12 and IL-15, or IL-12 and IL2. [0174] In some embodiments, an immunoregulatory payload may be a cytokines that can provide a stimulating environment for T cells differentiation. In the context of CD4+ T cells, Naive CD4⁺ T cells have the capacity to differentiate into either polarized Th1, Th2 or Th0 cells with the capacity to produce type 1 (IFN-γ), type 2 (IL-4) or type 0 (IFN-γ+IL-4) cytokines, respectively. [0175] In some embodiments, a payload of a conjugate of the present disclosure may be any other immunomodulator that can modulate the activity of the immune system. The “immunomodulator” can be a cytokine, a chemokine or an adjuvant, for example, obtained from any suitable source, such as a mammal, e.g., a human. [0176] The cytokine payload may be a full length of a cytokine or functional variants thereof. As used herein, the term “functional variant” as used herein is synonymous with “biologically equivalent variant, “biologically equivalent derivative,” or “biologically equivalent analog”. A function variant may be a functional portion, fusion, or variant of a cytokine, e.g., is capable of engaging respective receptors and initiating signal transduction. Examples of function variants include cytokines lacking their signal peptides, conservative amino acid substitutions, or amino acid substitution at non-essential regions. [0177] As non-limiting examples, cytokine payloads may be a recombinant interferon (rSIFN-co) with changed spatial configuration disclosed by Wei (PCT patent publication No. WO2014/106459, the content of which is incorporated herein by reference it its entirety). 5. Antibodies [0178] In certain embodiments, a payload may be an antibody, a fragment of an antibody or a derivative thereof. Antibodies may be immuno-specific for a tumor cell antigen or against immuno-modulatory factors. An antibody that can recognize a TAA and/or a TAA antigenic peptide may be a monoclonal antibody or a polyclonal antibody. The antibody may be generated by standard hybridoma techniques, phase display and recombinant techniques. In some examples, antibodies may recognize tumor antigens that are overexpressed in tumor cells, or tumor antigens associated with Leukaemias and lymphomas such as cell differentiation (CD) antigens, e.g. CD19, CD20, CD21, CD25 and CD37 in non-hodgkin lymphoma, CD33 in acute myeloid leukemia; CD5 in T cell leukemia, or glycoproteins on the cell surface. In other examples, antibodies may recognize non protein antigens such as glycolipids, e.g., ganglioside, and carbohydrates that are associated with tumors. In other examples, antibodies may recognize any one of TAAs as discussed hereinabove. [0179] Some examples of antibodies that can recognize a specific antigen epitope may include, without limitation, anti-HER2, anti-EGFR as disclosed in US Pat. No.: 9,023,362 and 8,722, 362; anti-FcγRIIB as disclosed in US Pat. No.: 8, 784,808; and antibodies against PSCA (prostate stem cell antigen) as disclosed in US Pat. No.: 8, 404, 817; [0180] In some embodiments, a payload may be an agonist antibody that can manipulate a process of a cancer specific immune response. As non-limiting examples, an agonist antibody may be an antibody specific to 4-1BB (CD137) (e.g., PCT patent publication NO.2006/088464 to Chen et al.; the content of which is incorporated by reference in its entirety). Stimulation of CD137 by agonistic antibody induces vigorous T-cell proliferation and prevents activation-induced cell death, and induces dendritic and NK cell activation as well. [0181] In other aspects, the active agent of the conjugate may be an agonist antibody that specifically binds to an costimulatory molecule selected from CD28, B7-1 (CD80), B7-2 (CD86), 4-1BB (CD137), 4-1BB ligand (CD137-L), OX40, OX40L, inducible co-stimulatory ligand (ICOS-L), ICOS, intercellular adhesion molecule (ICAM), CD30, CD30L, CD40, CD27, CD70, CD83, HLA-G, MICA, MICB, HVEM, lymphotoxin beta receptor, 3/TR6, ILT3, ILT4, HVEM, GITR, GITR-L, TLR agonist, B7-H3, B7-H3 ligand, CD226, ICOS, LFA-1, CD2, CD7, LIGHT, NKG2D, and DNAM-1. [0182] In other aspects, the active agent of the conjugate may be an antagonist antibody that specifically binds to a coinhibitory molecule selected from CTLA-4, PD-1, PD-L1, PD-L2, TIM-3, LAG-3, BTLA, CD160, C200R, TIGIT, KLRG-1, KIR, 2B4/CD244, VISTA and Ara2R. [0183] In some embodiments, an antibody payload may be a bispecific antibody (bsAb) or multiple specific antibody (msAb) (Weidle et al., Tumor-Antigen–Binding Bispecific Antibodies for Cancer Treatment, Seminars in Oncology, 2014, 41(5): 653- 660). As used herein, the term “bispecific antibody” refers to an antibody construct that is capable of redirecting immune effector cells to the tumor microenvironment. Clinical studies of various bsAb constructs have shown impressive results in terms of immune effector cell retargeting, target dependent activation and the induction of anti- tumor responses. Some examples of bispecific antibodies include bispecific antibody against TIM-3 and PD-1 in WO201159877 to Kuchroo et al., the content of which is incorporated by reference in its entirety. 6. Cell surface antigens [0184] In some embodiments, payloads may be cell surface antigens or fragments thereof. The cell surface antigens may be tumor antigens, which are present by MHC I or MHC II molecules on the surface of tumor cells. Tumor antigens may be tumor specific antigens (TSA), which are present only on tumor cells and not on any other cells, or tumor associated antigens (TAA), which are present on some tumor cells and also some normal cells. Tumor antigens may be cancer testis antigens (CTAs), melanocyte differentiation antigens, mutated proteins, overexpressed proteins, and viral antigens. The cell surface antigens may be shared tumor antigens, or neoantigens. Neoantigens, as used herein, refers to tumor-specific antigens derived from mutated proteins that are present only in the tumor. Neoantigens may be identified with any suitable method known in the art, such as reverse immunology comprising the steps of mutanome screening of a subject using massive parallel sequencing (MPS), computational eptitope prediction, and experimental validation of cancer neoantigens disclosed by Yoshimura et al. in J. of Clinical & Cellular Immunology, vol.6:2 (2015), the contents of which are incorporated herein by reference in their entirety. [0185] The cell surface antigens may be recognized by the immune system of a subject. Conjugates of the present disclosure comprising such cell surface antigens and targeting moieties attach to a group of target cells in the subject, turning the cells into antigen-presenting cells (APCs) and allowing the cells to be recognized by the immune system of the subject. The attachment of the conjugates of the present disclosure to the target cells may be in vivo or ex vivo. The receptors on the target cells that bind to the targeting moieties of the conjugates do not internalize after the attachment. 7. Other immunoactive agents [0186] In some embodiments, cytotoxic agents may be used as payloads (referring to US6572856) (induce innate immune response to destroy cancer cells). One immunotherapeutic approach involves conjugating cytotoxic agents to monoclonal antibodies (mAbs) specific for a particular cancer cell epitope, therefore treating cancers using tissue specific delivery of anti-cancer agents. The cytotoxic agents may include, but are not limited to maytansinoids, auristatins, calicheamicins, CC-1065, duocarmycins, anthracyclines, and doxorubicin derivatives. In some embodiments, cytotoxic agents may be cytotoxic protein including diphtheria toxin, Pseudomonas exotoxin, or cytotoxic portions or variants thereof. [0187] In some embodiments, the active agent of the conjugate of the present disclosure may be a complement component (e.g., 21 plasma protein C3b) [0188] In some embodiments, the active agent of the conjugate of the present disclosure may further include an immunomodulatory adjuvant. The immunomodulatory adjuvants are molecules that can increase the immunogenicity of a TAA or conquer the immune tolerance in the tumor microenvironment. (Sun and Liu, Listeriolysin O as a strong immunogenic molecule for the development of new anti-tumor vaccines. Hum Vaccin Immunother, 2013, 9(5): 1058-1068). [0189] In some embodiments, a payload of a conjugate may be a TLR (toll like receptor) agonist. As used herein, the term “TLR agonist” refers to a compound that acts as an agonist of a TLR. TLR agonists can trigger broad inflammatory responses that elicit rapid innate immune response and promote the activation of the adaptive immune response. Examples of TLR agonists include, but are not limited to, polyinosinic acid (poly I:C), an agonist for TLR3; Cytosine-phosphorothioate-guanine (CpG), an agonist for TLR9; imiquimod, a TLR7 agonist; resiquimod, a TLR7/8 agonist; loxoribine, a TLR7/8 agonist; sialyl-Tn (STn), a carbohydrate associated with the MUCI mucin on a number of human cancer cells and a TLR4 agonist; monophosphoryl lipid A (MPL), a TLR-4 agonist; FSL-1, a TLR-2 agonist; CFA, a TLR2 agonist and Pam3Cys, a TLR1/2 agonist. In some aspects, a TLR agonist may be a TLR1 agonist, a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR6 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a TLR10 agonist. In one example, a TLR agonist may be an agonist disclosed in U.S. Pat. No.: 7,993,659, which is incorporated herein by reference in its entirety.) [0190] In some embodiments, the payload of a conjugate may an agonist of stimulator of interferon gene (STING) or retinoic acid-inducible gene-I (RIG-I)-like Receptors (RLRs). [0191] In some embodiments the payload of a conjugate may be an activator of NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3). [0192] In some embodiments, a payload of the conjugate of the present disclosure may be mifamurtide. Mifamurtide, muramyl tripeptide phophatidylethanolamine (MTP-PE), is a synthetic analog of a muramyl dipeptide (MDP). Mifamurtide has a longer half-life than MDP, but has similar pharmacological behaviors. The intracellular pattern recognition molecule NOD2 detects mifamurtide and enhances NF- κB signaling. Therefore, conjugates of the present invention comprising mifamurtide can be recoganized by NOD2 and can stimulate the production of IL-1β, IL-6 and TNF-α via the activation of NF-κB signaling in moncytes and macrophages. 8. Checkpoint inhibitors [0193] During adaptive immune response, activation of cytotoxic T cells is mediated by a primary signal between antigenic peptide/MHC molecule complexes on antigen presenting cells and the T cell receptor (TCR) on T cells. A secondary co- stimulatory signal is also important to active T cells. Antigen presentation in the absence of the secondary signal is not sufficient to activate T cells, for example CD4+ T helper cells. The well-known co-stimulatory signal involves co-stimulatory receptor CD28 on T cells and its ligands B7-1/CD80 and B7-2/CD86 on antigen presenting cells (APCs). The B7-1/2 and CD28 interaction can augment antigen specific T cell proliferation and cytokine production. To tightly regulate an immune response, T cells also express CTLA-4 (anti-cytotoxic T-lymphocyte antigen 4), a co-inhibitory competitor of CD80 and CD86 mediated co-stimulation through the receptor CD28 on T cells, which can effectively inhibit T cell activation and function. CTLA-4 expression is often induced when CD28 interacts with B7-1/2 on the surface of an APC. CTLA-4 has higher binding affinity to the co-stimulatory ligand B7-1/2 (CD80/CD86) than the co-stimulatory receptor CD28, and therefore tips the balance from the T cell activating interaction between CD28 and B7-1/2 to inhibitory signaling between CTLA-4 and B7-1/2, leading to suppression of T cell activation. CTLA-4 upregulation is predominantly during the initial activation of T cells in the lymph node. [0194] Antibodies that specifically bind to CTLA-4 have been used to inhibit this inhibitory checkpoint. The anti CTLA-4 IgG1 humanized antibody: ipilimumab binds to CTLA-4 and prevents the inhibition of CD28/B7 stimulatory signaling. They can lower the threshold for activation of T cells in lymphoid organs, also can deplete T regulatory cells within the tumor microenvironment (Simpson et al., Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti- CTLA-4 therapy against melanoma. J Exp. Med., 2013, 210: 1695-1710). Ipilimumab was recently approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic melanoma. [0195] In some embodiments, the payload of the conjugate of the present disclosure may be an antagonist agent against CTLA-4 such as an antibody, a functional fragment of the antibody, a polypeptide, or a functional fragment of the polypeptide, or a peptide, which can bind to CTLA-4 with high affinity and prevent the interaction of B7-1/2 (CD80/86) with CTLA-4. In one example. The CTLA-4 antagonist is an antagonistic antibody, or a functional fragment thereof. Suitable anti- CTLA-4 antagonistic antibody include, without limitation, anti-CTLA-4 antibodies, human anti-CTLA-4 antibodies, mammalian anti-CTLA-4 antibodies, humanized anti-CTLA-4 antibodies, monoclonal anti-CTLA-4 antibodies, polyclonal anti-CTLA- 4 antibodies, chimeric anti-CTLA-4 antibodies, MDX-010 (ipilimumab), tremelimumab (fully humanized), anti-CD28 antibodies, anti-CTLA-4 adnectins, anti- CTLA-4 domain antibodies, single chain anti-CTLA-4 antibody fragments, heavy chain anti-CTLA-4 fragments, light chain anti-CTLA-4 fragments, and the antibodies disclosed in U.S. Pat. Nos.: 8,748, 815; 8, 529, 902; 8, 318, 916; 8,017, 114; 7,744, 875; 7, 605, 238; 7, 465, 446; 7,109,003; 7,132,281; 6, 984,720; 6,682,736; 6, 207,156; 5,977,318; and European Patent No. EP1212422B1; and U.S. Publication Nos. US 2002/0039581 and US 2002/086014; and Hurwitz et al., Proc. Natl. Acad. Sci. USA, 1998, 95(17):10067-10071; the contents of each of which are incorporated by reference herein in their entirety. [0196] Additional anti-CTLA-4 antagonist agents include, but are not limited to, any inhibitors that are capable of disrupting the ability of CTLA-4 to bind to the ligands CD80/86. [0197] The inhibitory receptor PD-1 (programmed death-1) is expressed on activated T cells and can induce inhibition and apoptosis of T cells following ligation by programmed death ligands 1 and 2 (PD-L1, also known as B7-H1, CD274), and PD-L2 (also known as B7-DC, CD273), which are normally expressed on epithelial cells and endothelial cells and immune cells (e.g., DCs, macrophages and B cells). PD-1 modulates T cell function mainly during the effector phase in peripheral tissues including tumor tissues. PD-1 is expressed on B cells and myeloid cells, in addition to activated T cells. Many human tumor cells can express PD-L1 and hijack this regulatory function to evade immune recognition and destruction by cytotoxic T lymphocytes. Tumor-associated PD-L1 has been shown to induce apoptosis of effector T cells and is thought to contribute to immune evasion by cancers. [0198] The PD-1/PD-L1 immune checkpoint appears to be involved in multiple tumor types, for example, melanoma. PD-L1 not only provides immune escape for tumor cells but also turns on the apoptosis switch on activated T cells. Therapies that block this interaction have demonstrated promising clinical activity in several tumor types. [0199] Agents used for blocking the PD-1 pathway include antagonistic peptides/antibodies and soluble PD-L1 ligands (See Table 2). Table 2: Agents that block the inhibitory PD-1 and PD-L1 pathway

[0200] In accordance with the present disclosure, the payload of the conjugate, in some embodiments, may be an antagonist agent against PD-1 and PD-L1/2 inhibitory pathway. In one embodiment, the antagonist agent may be an antagonistic antibody that specifically binds to PD-l or PD-L1/L2 with high affinity, or a functional fragment thereof. The PD-1 antibodies may be antibodies taught in US Pat. Nos: 8,779,105; 8, 168, 757; 8, 008, 449; 7, 488, 802; 6, 808, 710; and PCT publication No.: WO 2012/145493; the contents of which are incorporated by references herein in their entirety. Antibodies that can specifically bind to PD-L1 with high affinity may be those disclosed in US Pat. Nos.: 8, 552, 154; 8, 217, 149; 7, 943, 743; 7, 635, 757; U.S. Publication No.2009/0317368, and PCT Publication Nos. WO 2011/066389 and WO 2012/145493; the contents of which are incorporated herein by references in their entirety. In some examples, the payload of the conjugate may be an antibody selected from 17D8, 2D3, 4H1, 5C4 (also known as nivolumab or BMS-936558), 4A11, 7D3 and 5F4 disclosed in US Pat. NO.: 8,008, 449; AMP-224, Pidilizumab (CT-011), and Pembrolizumab. In other examples, the anti-PD-1 antibody may be a variant of a human monoclonal anti-PD-1 antibody, for example a “mixed and matched” antibody variant in which a VH sequence from a particular VH/VL pairing is replaced with a structurally similar VH sequence, or a VL sequence from a particular VH/VL pairing is replaced with a structurally similar V_L sequence, as disclosed in US publication NO.: 2015/125463; the contents of which are incorporated by reference herein in its entirety. [0201] In some embodiments, the payload of the conjugate may be an antagonistic antibody that binds to PD-L1 with high affinity and disrupts the interaction between PD-1/PD-L1/2. Such antibodies may include, without limitation, 3G10, 12A4 (also referred to as BMS-936559), 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 disclosed in US Pat. NO.: 7,943, 743 (the contents of which are incorporated by reference in its entirety), MPDL3280A, MEDI4736, and MSB0010718. In another example, the anti-PD-L1 antibody may be a variant of a human monoclonal anti-PD- L1 antibody, for example a “mixed and matched” antibody variant in which a VH sequence from a particular V_H/V_L pairing is replaced with a structurally similar V_H sequence, or a V_L sequence from a particular V_H/V_L pairing is replaced with a structurally similar VL sequence, as disclosed in US publication NO.: 2015/125463; the contents of which are incorporated by reference in its entirety. [0202] In some embodiments, the payload of the conjugate may be an antagonistic antibody that binds to PD-L2 with high affinity and disrupts the interaction between PD-1/PD-L1/2. Exemplary anti-PD-L2 antibodies may include, without limitation, antibodies taught by Rozali et al (Rozali et al., Programmed Death Ligand 2 in Cancer-Induced Immune Suppression, Clinical and Developmental Immunology, 2012, Volume 2012 (2012), Article ID 656340), and human anti-PD-L2 antibodies disclosed in US Pat. No.: 8, 552, 154 (the contents of which are incorporated herein by reference in their entirety). [0203] In some embodiments, the payload of the conjugate may compounds that inhibit immunosuppressive signal induced due to PD-1, PD-L1 and/or PD-L2 such as cyclic peptidomimetic compounds disclosed in US9233940 to Sasikumar et al. (Aurigene Discovery Tech.), WO2015033303 to Sasikumar et al.; immunomodulating peptidomimetic compounds disclosed in WO2015036927 to Sasikumar et al.; 1,2,4- oxadiazole derivatives disclosed in US2015007302 to Govindan et al.; 1,3,4- oxadiazole and 1,3,4-thiadiazole compounds disclosed in WO2015033301 to Sasikumar et al.; or therapeutic immunomodulating compounds and derivatives or pharmaceutical salts of a peptide derivative of formula (I) or a stereoisomer of a peptide derivative of formula (I) disclosed in WO2015044900 to Sasikumar et al., the contents of each of which are incorporated herein by reference in their entirety. [0204] In other embodiments, the payload of the conjugate may be an antibody having binding affinity to both PD-L1 and PD-L2 ligands, for example the single agent of anti-PD-L1 and PD-L2 antibodies disclosed in PCT publication NO.: WO2014/022758; the contents of which are incorporated by reference in its entirety. [0205] In some embodiments, the conjugate of the present disclosure may comprise two or more antibodies selected from anti-PD-1 antibodies, PD-L1 antibodies and PD-L2 antibodies. In one example, an anti-PD-L1 antibody and an anti-PD-L2 antibody may be included in a single conjugate through the linkers to the targeting moiety. [0206] In some embodiments, the payload of the conjugate may be a modulatory agent that can simultaneously block the PD-1 and PD-L1/2 mediated negative signal transduction. This modulatory agent may be a non-antibody agent. In some aspects, the non-antibody agents may be PD-L1 proteins, soluble PD-L1 fragments, variants and fusion proteins thereof. The non-antibody agents may be PD-L2 proteins, soluble PD-L2 fragments, variants and fusion proteins thereof. PD-L1 and PD-L2 polypeptides, fusion proteins, and soluble fragments can inhibit or reduce the inhibitory signal transduction that occurs through PD-1 in T cells by preventing endogenous ligands (i.e. endogenous PD-L1 and PD-L2) of PD-1 from interacting with PD-1. Additionally, the non-antibody agent may be soluble PD-1 fragments, PD- 1 fusion proteins which bind to ligands of PD-1 and prevent binding to the endogenous PD-1 receptor on T cells. In one example, the PD-L2 fusion protein is B7-DC-Ig and the PD-1 fusion protein is PD-1-Ig. In another example, the PD-L1, PD-L2 soluble fragments are the extracellular domains of PD-L1 and PD-L2, respectively. In one embodiment, the payload of the conjugate may be a non-antibody agent disclosed in US publication No.: 2013/017199; the contents of which are incorporated by reference herein in its entirety. [0207] In addition to CTLA-4 and PD-1, other known immune inhibitory checkpoints include TIM-3 (T cell immunoglobulin and mucin domain-containing molecule 3), LAG-3 (lymphocyte activation gene-3, also known as CD223), BTLA (B and T lymphocyte attenuator), CD200R, KRLG-1, 2B4 (CD244), CD160, KIR (killer immunoglobulin receptor), TIGIT (T-cell immune-receptor with immunoglobulin and ITIM domains), VISTA (V-domain immunoglobulin suppressor of T-cell activation) and A2aR (A2a adenosine receptor) (Ngiow et al., Prospects for TIM3 targeted antitumor immunotherapy, Cancer Res., 2011, 71(21): 6567-6571; Liu et al., Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses, PNAS, 2015, 112(21): 6682-6687; and Baitsch et al., Extended Co- Expression of Inhibitory Receptors by Human CD8 T-Cells Depending on Differentiation, Antigen-Specificity and Anatomical Localization.2012, Plos One, 7(2): e30852). These molecules that similarly regulate T-cell activation are being assessed as targets of cancer immunotherapy. [0208] TIM-3 is a transmembrane protein constitutively expressed on IFN-γ– secreting T-helper 1 (Th1/Tc1) cells (Monney et al., Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature.2002, 415:536-541), DCs, monocytes, CD8⁺ T cells, and other lymphocyte subsets as well. TIM-3 is an inhibitory molecule that down-regulates effector Th1/Tc1 cell responses and induces cell death in Th1 cells by binding to its ligand Galectin-9, and also induces peripheral tolerance (Fourcade et al. Upregulation of Tim-3 and PD- 1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J experimental medicine.2010; 207:2175-2186). Blocking TIM-3 can enhance cancer vaccine efficacy (Lee et al., The inhibition of the T cell immunoglobulin and mucin domain 3(Tim-3) pathway enhances the efficacy of tumor vaccine. Biochem. Biophys. Res Commun, 2010, 402: 88-93). [0209] It has been shown that extracellular adenosine generated from hypoxia in the tumor microenvironment binds to A2a receptor which is expressed on a variety of immune cells and endothelial cells. The activation of A2aR on immune cells induces increased production of immunosuppressive cytokines (e.g., TGF-β, IL-10), upregulation of alternate immune checkpoint pathway receptors (e.g., PD-1, LAG-3), increased FOXP3 expression in CD4+ T cells driving a regulatory T cell phenotype, and induction of effector T cell anergy. Beavis et al demonstrated that A2aR blockade can improve effector T cell function and suppress metastasis (Beavis et al., Blockade of A2A receptors potently suppresses the metastasis of CD73 + tumors. Proc Natl Acad Sci USA, 2013, 110: 14711–14716). Some A2aR inhibitors are used to block A2aR inhibitory signal, including, without limitation, SCH58261, SYN115, ZM241365 and FSPTP (Leone et al., A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy, Comput Struct Biotechnol. J 2015, 13: 265-272). [0210] LAG-3 is a type I transmembrane protein expressed on activated CD4⁺ and CD8⁺ T cells, a subset of γδ T cells, NK cells and regulatory T cells (Tregs), and can negatively regulate immune response (Jha et al., Lymphocyte Activation Gene-3 (LAG-3) Negatively Regulates Environmentally-Induced Autoimmunity, PLos One, 2014, 9(8): e104484). LAG-3 negatively regulates T-cell expansion by inhibiting T cell receptor–induced calcium fluxes, thus controlling the size of the memory T-cell pool. LAG-3 signaling is important for CD4⁺ regulatory T-cell suppression of autoimmune responses, and LAG-3 maintains tolerance to self and tumor antigens via direct effects on CD8⁺ T cells. A recent study showed that blockade of both PD-1 and LAG-3 could provoke immune cell activation in a mouse model of autoimmunity, supporting that LAG-3 may be another important potential target for checkpoint blockade. [0211] BTLA, a member of the Ig superfamily, binds to HVEM (herpesvirus entry mediator; also known as TNFRSF14 or CD270), a member of the tumor necrosis factor receptor superfamily (TNFRSF) (Watanabe et al., BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1 Nat Immunol, 2003, 4670– 679. HVEM is expressed on T cells (e.g. CD8+ T cells). The HVEM-BTLA pathway plays an inhibitory role in regulating T cell proliferation (Wang et al., The role of herpesvirus entry mediator as a negative regulator of T cell-mediated responses, J Clin Invest., 2005, 115: 74-77). CD160 is another ligand of HVEM. The co-inhibitory signal of CD160/HVEM can inhibit the activation of CD4+ helper T cell (Cai et al., CD160 inhibits activation of human CD4⁺ T cells through interaction with herpesvirus entry mediator. Nat Immunol.2008; 9:176–185). [0212] CD200R is a receptor of CD200 that is expressed on myeloid cells. CD200 (OX2) is a highly expressed membrane glycoprotein on many cells. Studies indicated that CD200 and CD200R interaction can expand the myeloid-derived suppressor cell (MDSC) population (Holmannova et al., CD200/CD200R paired potent inhibitory molecules regulating immune and inflammatory responses; Part I: CD200/CD200R structure, activation, and function. Acta Medica (Hradec Kralove) 2012, 55(1):12–17; and Gorczynski, CD200 and its receptors as targets of immunoregulation, Curr Opin Investig Drug, 2005, 6(5): 483-488). [0213] TIGIT is a co-inhibitory receptor that is highly expressed tumor-infiltrating T cells. In the tumor microenvironment, TIGIT can interact with CD226, a costimulatory molecule on T cells in cis, therefore disrupt CD226 dimerization. This inhibitory effect can critically limit antitumor and other CD8+ T cell-dependent responses (Johnston et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function, Cancer cell, 2014, 26(6):923-937). [0214] KIRs are a family of cell surface proteins expressed on natural killer cells (NKs). They regulate the killing function of these cells by interacting with MHC class I molecules expressed on any cell types, allowing the detection of virally infected cells or tumor cells. Most KIRs are inhibitory, meaning that their recognition of MHC molecules suppresses the cytotoxic activity of their NK cell (Ivarsson et al., Activating killer cell Ig-like receptor in health and disease, Frontier in Immu., 2014, 5: 1-9). [0215] Additional coinhibitory signals that affect T cell activation include, but are not limited to KLRG-1, 2B4 (also called CD244), and VISTA (Lines et al., VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy, Cancer Immunol Res., 2014, 2(6): 510-517). [0216] In accordance with the present disclosure, the payload of the conjugate may be an antagonist or inhibitor of a co-inhibitory molecule selected from CTLA-4, PD- 1, PD-L1, PD-L2, TIM-3, LAG-3(CD223), BTLA, CD160, CD200R, TIGIT, KRLG- 1, KIR, 2B4 (CD244), VISTA, A2aR and other immune checkpoints. In some aspects, the antagonist agent may be an antagonistic antibody, or a functional fragment thereof, against a coinhibitory checkpoint molecule selected from CTLA-4, PD-1, PD-L1, PD-L2, TIM-3, LAG-3(CD223), BTLA, CD160, CD200R, TIGIT, KRLG-1, KIR, 2B4 (CD244), VISTA and A2aR. [0217] In some embodiments, the payload that is an antagonist or inhibitor of a co- inhibitory molecule selected from CTLA-4, PD-1, PD-L1, PD-L2, TIM-3, LAG- 3(CD223), BTLA, CD160, CD200R, TIGIT, KRLG-1, KIR, 2B4 (CD244), VISTA, A2aR and other immune checkpoints may be conjugated to a cell penetrating peptide via a first cleavable linker, wherein the cell penetrating peptide is further conjugated to a chemotherapy agent or cytotoxic agent via a second cleavable linker. The payloads may act as a targeting moiety and target the conjugate to the immune checkpoints in tumor microenvironment. The cell penetrating peptide is capable of penetrating cell membrane. The cytotoxic agent is thereafter released to the tumor microenvironment and kills the tumor cells. [0218] In some embodiments, the payload of the conjugate may be an antagonistic antibody, and/or a functional fragment thereof, specific to LAG-3(CD223). Such antagonistic antibodies can specifically bind to LAG-3(CD223) and inhibit regulatory T cells in tumors. In one example, it may be an antagonistic anti-LAG-3(CD223) antibody disclosed in US Pat NOs.9, 005, 629 and 8,551,481. The payload may also be any inhibitor that binds to the amino acid motif KIEELE in the LAG-3(CD223) cytoplasmic domain which is essential for CD223 function, as identified using the methods disclosed in US Pat. NOs.9,005,629 and 8, 551, 481; the contents each of which are incorporated herein by reference in their entirety. Other antagonistic antibodies specific to LAG-3(CD223) may include antibodies disclosed in US publication NO.20130052642; the contents of which is incorporated herein by reference in its entirety. [0219] In some embodiments, the payload of the conjugate may be an antagonistic antibody, and/ or a functional fragment thereof, specific to TIM-3. Such antagonistic antibodies specifically bind to TIM-3 and can be internalized into TIM-3 expressed cells such as tumor cells to kill tumor cells. In other aspects, TIM-3 specific antibodies that specifically bind to the extracellular domain of TIM-3 can inhibit proliferation of TIM-3 expressing cells upon binding, e.g., compared to proliferation in the absence of the antibody and promote T-cell activation, effector function, or trafficking to a tumor site. In one example, the antagonistic anti-TIM-3 antibody may be selected from any antibody disclosed in US Pat. NOs.8,841,418; 8,709, 412; 8,697,069; 8,647,623; 8,586,038; and 8,552,156; the contents of each of which are incorporated herein by reference in their entirety. [0220] In addition, the antagonistic TIM-3 specific antibody may be monoclonal antibodies 8B.2C12, 25F.1D6 as disclosed in US Pat. NO.8, 697,069; 8, 101,176; and 7, 470, 428; the contents of each of which are incorporated herein by reference in their entirety. [0221] In other embodiments, the payload of the conjugate may be an agent that can specifically bind to galectin-9 and neutralize its binding to TIM-3, including neutralizing antibodies disclosed in PCT publication NO.2015/013389; the contents of which are incorporated by reference in its entirety. [0222] In some embodiments, the payload of the conjugate may be an antagonistic antibody, and/or a functional fragment thereof, specific to BTLA, including but not limited to antibodies and antigen binding portion of antibodies disclosed in US Pat. NOs.8, 247, 537; 8, 580, 259; fully human monoclonal antibodies in US Pat. NO.: 8,563,694; and BTLA blocking antibodies in US Pat. NO.: 8,188, 232; the contents of each of which are incorporated herein by reference in their entirety. [0223] Other additional antagonist agents that can inhibit BTLA and its receptor HVEM may include agents disclosed in PCT publication NOs.: 2014/184360; 2014/183885; 2010/006071 and 2007/010692; the contents of each of which are incorporated herein by reference in their entirety. [0224] In certain embodiments, the payload of the conjugate may be an antagonistic antibody, and/or or a functional fragment thereof, specific to KIR, for example IPH2101 taught by Benson et al., (A phase I trial of the anti-KIR antibody IPH2101 and lenalidomide in patients with relapsed/refractory multiple myeloma, Clin Cancer Res., 2015, May 21. pii: clincanres.0304.2015); the contents of which are incorporated by reference in its entirety. [0225] In other embodiments, the antagonist agent may be any compound that can inhibit the inhibitory function of a coinhibitory checkpoint molecule selected from CTLA-4, PD-1, PD-L1, PD-L2, TIM-3, LAG-3(CD223), BTLA, CD160, CD200R, TIGIT, KRLG-1, KIR, 2B4 (CD244), VISTA and A2aR. [0226] In some examples, the antagonist agent may be a non-antibody inhibitor such as LAG-3-Ig fusion protein (IMP321) (Romano et al., J transl. Medicine, 2014, 12:97), and herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of BTLA)/CD160-HVEM) pathways (Lasaro et al., Mol Ther.2011; 19(9): 1727–1736). [0227] In some embodiments, the payload of the conjugate may be an agent that is bispecific or multiple specific. As used herein, the terms “bispecific agent” and “multiple specific agent” refer to any agent that can bind to two targets or multiple targets simultaneously. In some aspects, the bispecific agent may be a bispecific peptide agent that has a first peptide sequence that binds a first target and a second peptide sequence that binds a second different target. The two different targets may be two different inhibitory checkpoint molecules selected from CTLA-4, PD-1 PD-L1, PD-L2, TIM-3, LAG-3(CD223), BTLA, CD160, CD200R, TIGIT, KRLG-1, KIR, 2B4 (CD244), VISTA and A2aR. A non-limiting example of bispecific peptide agents is a bispecific antibody or antigen-binding fragment thereof. Similarly, a multiple specific agent may be a multiple peptide specific agent that has more than one specific binding sequence domain for binding to more than one target. For example, a multiple specific polypeptide can bind at least two, at least three, at least four, at least five, at least six, or more targets. A non-limiting example of multiple- specific peptide agents is a multiple-specific antibody or antigen-binding fragment thereof. [0228] In one example, such bispecific agent is the bispecific polypeptide antibody variants for targeting TIM-3 and PD-1, as disclosed in US publication NO.: 2013/0156774; the content of which is incorporated herein by reference in its entirety. [0229] In some embodiments, one, two or multiple checkpoint antagonists/inhibitors may be connected to the targeting moiety through the linker in one conjugate. [0230] In other embodiments, the conjugate of the present disclosure may comprise two active agents that are connected to the targeting moiety through the linker, in which one active agent is an antagonist agent that specifically binds to an inhibitory molecule selected from CTLA-4, PD-1, PD-L1, PD-L2, TIM-3, LAG-3, BTLA, CD160, C200R, TIGIT, KLRG-1, KIR, 2B4/CD244, VISTA and Ara2R; the other active agent is an agonist agent that specifically binds to a stimulatory molecule selected from CD28, CD80(B7.1), CD86 (B7.2), 4-1BB(CD137), 4-1BBL (CD137L), CD27, CD70, CD40, CD40L, CD226, CD30, CD30L, OX40, OX40L, GITR and its ligand GITRL, LIGHT, LTβR, LTαβ, ICOS(CD278), ICOSL(B7-H2) and NKG2D. 9. Targeting regulatory cells infiltrating the tumor microenvironment [0231] Many regulatory cells with immunosuppressive potential can infiltrate the tumor microenvironment, including Regulatory T cells, microphages (M2) and MDSCs. Suppressive mechanisms employed by these cells involve secretion of cytokines (e.g., IL-10 and TGFβ), Growth factors (e.g., VEGF), secretion of enzymes (e.g., arginase, NOS and IDO), and expression of inhibitory receptors as discussed in the previous section (e.g., CTLA-4 and PD-L1). Depleting or modifying these regulatory cells and targeting each of the mechanisms they use within the tumor microenvironment can reverse immunosuppression. [0232] Regulatory T cells (Tregs): Regulatory T cells (Tregs) have been widely recognized as crucial players in controlling immune responses. CD4+ regulatory T cells can constitutively express CD25 (IL-2 receptor α-chain) and the forkhead box P3 (FOXP3) transcription factor. CD25+ FOXP3+ and Type 1 regulatory T cells (Tr1) are induced in the thymus and IL-2 appears to be fundamental for their survival, expansion, and suppressive function. Activated CD4+CD25+FOXP3+ Tr1cells can suppress CD4+ and CD8+ effector T cell proliferation and cytokine secretion, and inhibit B lymphocytes proliferation. Tr1 cells produce a large amount of IL-10 and TGF-β that inhibit Th1 and Th2 T cell responses. Tregs also maintain immune tolerance by restraining the activation, proliferation, and effector functions of natural killer (NK) and NKT cells, B cells and antigen presenting cells (APCs). [0233] Depleting CD25+ regulatory T cells in the tumor microenvironment is a promising strategy for destructing cancer. Several studies showed that depletion of Treg cells using anti-CD25 antibody can enhance the efficacy of a variety of immunotherapies (Li et al., Complete regression of experimental solid tumors by combination LEC/chTNT-3 immunotherapy and CD25+ T-cell depletion. Cancer Res.2003;63:8384-8392; Klages et al., Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res.2010; 70:7788-7799). [0234] In some embodiments, the payload of the conjugate may be an agent that can reduce or deplete regulatory T cell activity in tumors. [0235] In one example, the agent for reducing or depleting regulatory T cell activity may be an antagonistic antibody that binds to CTLA-4, CD25, CD4, neuropillin. The antibody may be a full length antibody or a functional antibody fragment. The antibodies may include antibodies in US8, 961, 968; the contents of which are incorporated by reference in its entirety. [0236] In one example, the agent for reducing or depleting regulatory T cell activity may include, but are not limited to, bivalent IL-2 fusion toxins as disclosed in PCT publication NO.2014/093240; the contents of which are incorporated by reference herein in its entirety. The bivalent IL-2 fusion toxin comprises a cytotoxic protein (e.g., diphtheria toxin, pseudomonas exotoxin, or cytotoxic portions or variants thereof) fused with at least two Interleukin 2 (IL-2) sequences. [0237] In one example, the agent for reducing or depleting regulatory T cell activity may be a neutralizing antibody that can block CCL-1(chemokine (C-C motif) ligand 1 (CCL1)); the neutralization of CCL-1 can deplete Treg cells and increase anti-cancer cells such as CD8+NKG2D+ T cells and NK cells (Hoelzinger et al., Blockade of CCL1 inhibits T regulatory cell suppressive function enhancing tumor immunity without affecting T effector responses. J Immunol.2010; 184: 6833-6842). [0238] In another example, the agent for reducing or depleting regulatory T cell activity may be a small molecule antagonist of CCR4. It has been shown that Treg recruitment to the tumor microenvironment can be blocked through neutralizing CCL17 and CCL22 using a small molecule antagonist of CCR4, which leads to improved responses to vaccine (CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self-antigens. Blood.2011, 118: 4853-4862). [0239] Myeloid-Derived Suppressor Cells (MDSCs): Myeloid-derived suppressor cells, which have immunosuppressive and pro-angiogenic activity, comprise a mixture of monocytes/macrophages, granulocytes, and dendritic cells (DCs) at different stages of differentiation. MDSCs maintain an immature phenotype when exposed to proinflammatory signals and contribute to a tumor-promoting type 2 phenotype by producing IL-10 and blocking macrophage to product IL-12. MDSCs inhibit the function of effector T cells and decrease NK cells cytotoxicity, cytokine production, and maturation of dendritic cells. It has also been suggested that MDSCs interact with Kuppfer cells to induce PD-L1 expression, which in turn inhibits antigen presentation. [0240] MDSC differentiation can be blocked using cyclooxygenase (COX) inhibitors, which prevent the production of prostaglandin. All-trans retinoic acids (ATRA) have also been shown to reduce the presence of immature MDSC by converting them to non-immunosuppressive mature myeloid cells. [0241] The chemokine CCL2 is an attractant for myeloid derived suppressor cells and its neutralization could augment the antitumor activity of vaccine or adoptive cytotoxic T lymphocytes (CTLs) transfer (Fridlender et al., CCL2 blockade augments cancer immunotherapy. Cancer Res.2010; 70:109-118). [0242] Monoclonal antibodies specific for GR-1 (Myeloid differentiation antigen, also known as Ly-6G) could deplete MDSCs and the depletion, when combined with adoptive T cell therapy can result in an enhancement of immunotherapy and regression of established tumors (Morales et al., Adoptive transfer of HER2/neu- specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells. Cancer Immunol Immunother.2009;58:941-953) [0243] In accordance with the present disclosure, the payload of the conjugate may be an agent that can deplete or reduce MDSCs in the tumor microenvironment. In some embodiments, the active agent may block differentiation and recruitment of MDSCs to the tumor sites. Such an agent may include but is not limited to, a cyclooxygenase (COX) inhibitor, a trans- retinoic acid, a neutralizing antibody specific to CCL-2, or a neutralizing antibody specific to GR-1. In one example, the agent that negative regulates MDSC may be a peptibody disclosed in PCT publication NO.2015/048748; the contents of which are incorporated by reference in its entirety. [0244] Regulatory DC cells: Tumor infiltrating regulatory DCs can suppress T-cell activation through IL-10 and indoleamine 2,3-dioxygenase (IDO) production. The immune tolerance effect contributes to immunosuppression in the tumor microenvironment (Holtzhausen et al., Melanoma-derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy. Cancer Immunol Res, 2015, Jun 3. pii: canimm.0167.2014. [Epub ahead of print]). [0245] Tumor infiltrating macrophages (TAMs): In most tumors, the infiltrated M2 microphages can secrete IL-10, TGF-β, and arginase, which provide an immunosuppressive microenvironment for tumor growth. Furthermore, tumor- associated M2 macrophages secrete many other cytokines, chemokines, and proteases, which promote tumor angiogenesis, growth, metastasis, and immunosuppression (Hao et al., Macrophages in Tumor Microenvironments and the Progression of Tumors, Clin Dev Immunol.2012; 2012: 948098). [0246] Clodronate encapsulated in liposomes is a reagent for the depletion of macrophages in vivo. This reagent can deplete M2 macrophages and increase the efficacy of therapies including anti-angiogenic therapy using anti-VEGF or agonist- CD137 and CpG combination immunotherapy (Zeisberger et al., Clodronate- liposome-mediated depletion of tumor-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer.2006, 95:272-281). [0247] Additionally, Macrophages possess a certain degree of plasticity with regard to phenotype, and it is possible to manipulate tumor-associated immunosuppressive M2 macrophages to become immuno-supportive M1-like macrophage. Agonist anti-CD40 antibodies may be used to re-polarize macrophage in the tumor microenvironment (Buhtoiarov et al., Anti-tumor synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumor-associated macrophages. Immunology.2011, 132: 226-239). [0248] In accordance with the present disclosure, the payload of the conjugate may be an agent that can deplete or reduce tumor infiltrating macrophages (TAMs) activity. In some aspects, the agent for reducing or depleting TAM activity may include, but are not limited to, an anti-VEGF antibody and a functional antibody fragment thereof, [0249] In accordance with the present disclosure, the payload of the conjugate may be an active agent that can block differentiation or recruitments of regulatory cells, or deplete regulatory cells, or reprogram immunosuppressive cells in the tumor microenvironments. It may be an antibody, polypeptide, a fusion protein and/or a small molecule. [0250] In some embodiments, the active agent may be a targeted immunostimulatory antibody and fusion protein that inhibits the development or function of Tregs and MDSCs within the tumor microenvironment, therefore counteract or reverse immune tolerance of tumor cells. The targeted immunostimulatory antibody and fusion protein may bind an immunosuppressive cytokine and molecule expressed by Treg cells and MDSCs, such as CTLA-4/CD152, PD-L1/B7-1, TGF-β, RANKL (Receptor activator of nuclear factor-κB ligand), LAG- 3, GITR/TNFRSF18 (glucocorticoid-induced tumor necrosis factor receptor family- related gene) and IL-10. Such conjugates contain a payload of an immunomodulatory moiety. Some of examples of such conjugates are discussed in US Pat No.8,993,524, which is incorporated herein by reference in its entirety, including a molecule that binds TGF-β and an extracellular ligand-binding domain of TGF-β receptor (e.g. TGF-βRII, TGF-βRIIb, or TGF-βRIII), which can inhibit the function of TGF-β. In other examples, the immunomodulatory moiety may be a molecule that specifically binds to RANKL, or an extracellular ligand-binding domain or ectodomain of RANK. 10. Immunosuppressive enzyme [0251] The catabolism of the amino acids arginine and tryptophan has been associated with the immunosuppressive tumor microenvironment. Arginase (ARG) can deplete arginine, and indoleamine 2,3-dioxygenase (IDO) can degrade tryptophan present in the tumor microenvironment. Inhibitors that can block the activity of these enzymes may be used to enhance immunotherapy efficacy. [0252] N-hydroxy-L-Arg (NOHA) used to target ARG-expressing M2 macrophages can increase the survival of sarcoma tumor bearing mice when combined with agonist OX40 therapy. Nitroaspirin or sildenafil (Viagra®), blocking ARG and nitric oxide synthase (NOS) simultaneously, could reduce function of MDSCs and increase the number of tumor infiltrating lymphocytes. [0253] IDO inhibitors, such as 1-methyl-tryptophan, can improve various kinds of immunotherapies such as vaccines and adoptive T cell transfer. siRNA targeted to IDO, when loaded in DCs, can be directly used as cell vaccine (Zheng et al., Silencing IDO in dendritic cells: a novel approach to enhance cancer immunotherapy in s murine breast cancer model, Int. J Cancer, 2013, 132: 967-977) 11. Chemokines, cytokines and other soluble factors within the tumor microenvironment [0254] Infiltrating regulatory cells and tumor cells secrete many chemokine, cytokines and growth factors to regulate the microenvironment. The cellular compositions in the tumor microenvironment are then further influenced by these factors. Infiltrating immune cells may be attracted in the responses to specific chemokines. Manipulating such profiles and their associated molecules in the tumor microenvironment can change the environment from immunosuppressive to immuno- potentiating with anti-cancer immunity. [0255] As discussed above, IL-10 secreted by TAMs and tumor cells is an important immunosuppressive cytokine that favors tumor to escape from immune surveillance. IL-10 diminishes the production of inflammatory mediators and inhibits antigen presentation (Sabat et al., Biology of Interleukin 10, Cytokine Growth Factor Rev., 2010, 21:331-344). [0256] Similarly, TGF-β in the tumor microenvironment can strengthen the immunosuppression through different mechanisms of inhibiting the cytolytic activity of NKG2D+ natural killer (NK) cells, decreasing dendritic cells (DCs) migration and increasing apoptosis; and promoting tumor growth by the maintenance of Treg cell differentiation. [0257] TGF-β inhibitors can be used to block TGF-β activity and lift immunosuppression, such as peptide inhibitors (Lopez et al., Peptide inhibitors of transforming growth factor beta enhance the efficacy of anti-tumor immunotherapy. Into J cancer, 2009, 125: 2614-2623). [0258] VEGF is another tumor derived soluble factor that contributes to the immune tolerance in the tumor microenvironment by regulating dendritic cell (Johnson et al., Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy.2007, Expert Opin Biol Ther., 7(4): 449-460). [0259] Studies also showed that some chemokines are specific to tumors and changes to the microenvironment can increase efficacy of additional immunotherapy agents, for example, adoptive T cell transfer. CCL21-secreting tumors recruited more CD11b⁺CD11c⁻F4/80-Grl^high myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells (Shields, et al., Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21, Science, 2010, 328:749-752). [0260] Accordingly, in some embodiments of the present disclosure, the payload of the conjugate may be an antagonistic agent that binds specifically to a cytokine, a chemokine or a soluble factor that make a contribution to the immunosuppression in cancer, including those that are presently known and those yet to be identified as one of skill in the art will appreciate. In some aspects, the molecule may include, including IL-10, TGF-β, CCL-21, andVEGF. The antagonistic agent may be antibodies, functional antibody fragments, polypeptides, peptides, nucleic acids, aptamers, and small molecule compounds that bind specifically to the soluble factors. In some examples. The antagonistic agent may neutralize the activity of the targeted cytokine, chemokine, growth factor and other soluble factors. 12. Other tumor associated negative factors [0261] In addition to induce immunosuppressive TGF-β, PD-L1/B7-H1,VEGF and IL-10 to inhibit the differentiation and maturation of antigen-presenting dendritic cells and to promote the development of immunosuppressive CD4⁺ regulatory T cells and MDSCs, in some cancers, particularly B cell cancers and B hematological malignancies, tumor cell also express HLA-G, a non-classical MHC class I human leukocyte antigen-G (HLA-G), which is a crucial tumor-driven immune escape molecule involved in immune tolerance. HLA-G and soluble counterparts are able to exert inhibitory functions by direct interactions with inhibitory receptors present on both innate cells such as natural killer cells, and adaptive immune cells as cytotoxic T and B lymphocytes. Another non-classical MHC molecule HLA-E is also reported recently in several human cancer types. HLA-E overexpression in tumor cells can restrain tumor specific cytotoxic T lymphocytes (Gooden et al., HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8⁺ T lymphocytes, Proc Natl Acad Sci USA, 2011, 108(26): 10656-10661). [0262] In some embodiments, the payload of the conjugate may be an antagonistic agent that can block HLA-G. The blocker may be soluble HLA-G peptides from US publication NO.2011/0189238; the contents of which are incorporated herein by reference in its entirety. In other examples, the antagonistic agent may be antibodies and functional fragments thereof against the alpha3 domain of HLA-G protein as disclosed in PCT publication NO.2014/072534; the contents of which are incorporated herein by reference in its entirety. [0263] In some embodiments, the payload of the conjugate may be an antagonistic agent that can block HLA-E. In some examples, the antagonistic agent may be antibodies specific to the heavy chain of HLA-E disclosed in PCT publication NO. 2012/094252, and anti-HLA-E antibodies in PCT publication NO.2014/008206; the contents of each of which are incorporated herein by reference in their entirety. [0264] In some embodiments, the payload of the conjugate may be any molecule secreted by tumor cells including: growth factors, tumor antigens, cytokines, angiogenic factors, adhesion molecules, sialoproteins (e.g. osteopontin), integrins, carbohydrate structures, cell surface molecules, intra-cellular molecules, polynucleotides, oligonucleotides, proteins, peptides or receptors thereof. Secreted molecules such as, growth factors, cytokines and angiogenic factors comprise: VEGF, tumor necrosis factors (TNF) transforming growth factors (TGF), colony stimulating factors (CSF), Fibroblast growth factors (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), interferons (IFN), interleukins, endostatins, osteopontin (bone sialoprotein (BSP)), or fragments thereof. [0265] In some embodiments, the payload of the conjugate may comprise an active agent that is specific to other immune cell specific molecules that can modulate immune cell activity, including but not limited to, CD2, CD3, CD4, CD8a, CD11a, CD11b, CD11c, CD19, CD20, CD25 (IL-2Rα), CD26, CD44, CD54, CD56, CD62L (L-Selectin), CD69 (VEA), CD83, CD95 (Fas), TNFRSF14, ATAR, TR2, CD150 (SLAM), CD178 (FasL), CD209 (DC-SIGN), CD277, AITR, AITRL, HLA-A, HLA- B, HLA-C, HLA-D, HLA-R, HLA-Q, TCR-α, TCR-β, TCR-γ, TCR-δ, ZAP-70, NK1.1, T Cell receptor αβ (TCRαβ), T Cell receptor γδ (TCRγδ), T cell receptor ζ (TCRζ), TGFβRII, TNF receptor, CD1-339, Foxp3, mannose receptor, or DEC205, or variants thereof. [0266] In some embodiments, the conjugate of the present disclosure may comprise two different payloads of which one agent is specific to a soluble factor in the tumor microenvironment such as IL-10, TGF-β, VEGF, CC chemokines such as CCL-21 and CCL-19, and the other active agent that is specific to a co-stimulatory molecule such as 4-1BB (CD137), 4-1BBL (CD137L), CD27, CD70, CD28, CD80 (B7-1), CD86 (B7-2), CD226, CD30 and CD30 ligand, CD40, CD154(CD40 ligand), GITR and GITR ligands, OX40 (CD134), OX40L, LIGHT, HVEM (CD270), NKG2D, RANK, LTβ (lymphotoxin receptor), LTαβ (ligand), or variants thereof. [0267] In some embodiments, the conjugate of the present disclosure may comprise two different payloads of which one agent is specific to a soluble factor in the tumor microenvironment such as IL-10, TGF-β, VEGF, CC chemokines such as CCL-21 and CCL-19, and the other active agent that is specific to a co-inhibitory molecule such as CTLA-4 (CD152), PD-1(CD279), PD-L1 (B7-H1), PD-L2 (B7- DC), B7-H2 (ICOS), ICOSL (B7RP-1), B7-H3, B7-H4, TIM-3, LAG-3, BTLA, A2aR, CD200R, TIGIT, or variants thereof. [0268] In some embodiments, the conjugate of the present disclosure may comprise two different payloads of which one agent is specific to a costimulatory molecule such as 4-1BB (CD137), 4-1BBL (CD137L), CD27, CD70, CD28, CD80 (B7-1), CD86 (B7-2), CD226, CD30 and CD30 ligand, CD40, CD154(CD40 ligand), GITR and GITR ligands, OX40 (CD134), OX40L, LIGHT, HVEM (CD270), NKG2D, RANK, LTβ (lymphotoxin receptor), LTαβ (ligand), or variants thereof, and the other active agent is specific to a co-inhibitory factor such as CTLA-4 (CD152), PD-1(CD279), PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H2 (ICOS), ICOSL (B7RP-1), B7-H3, B7-H4, TIM-3, LAG-3, BTLA, A2aR, CD200R, TIGIT, or variants thereof. [0269] In addition to antagonistic antibodies, the payloads of the conjugates that are specific to an immunoregulator may be aptamers, for example aptamer specifically binding to a soluble immunosuppressive factor and a co-modulating molecule. In one example, the aptamer may be a bispecific aptamer that binds to VEGF and 4-1BB, or a bispecific aptamer that binds to osteopontin and 4-1BB, as disclosed in US publication No.2015/0086584; the content of which is incorporated by reference in its entirety. B. Chelators and Radioactive Agents [0270] In some embodiments, the conjugate further comprises a chemical moiety that binds to a radionuclide (such as a radioisotope), such as a chelating agent (also known as a chelator). [0271] The chelating agent or chelator may be a metal chelating agent that binds to a metal including a metallic nuclide. The chelating agent may also be a moiety that binds to a non-metal active agent. The chelating agent may be acyclic or macrocyclic. Non-limiting examples of chelating agents include 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid (DOTA); DOTA derivative: DO3A; diethylenetriamine- N,N,N',N'',N''-pentaacetic acid (DTPA); DTPA derivatives: 2-(p-SCN-Bz)-6-methyl- DTPA, CHX-A''-DTPA, and the cyclic anhydride of DTPA (CA-DTPA); 1,4,7- triazacyclononane-1,4-7-triacetic acid (NOTA); NOTA derivatives (e.g., BCNOTA, p-NCS-Bz-NOTA, BCNOT); 6-hydrazinonicotinamide (HYNIC); ethylenediamine tetraacetic acid (EDTA); N,N′-ethylene-di-L-cysteine; N,N′-bis(2,2-dimethyl-2- mercaptoethyl)ethylenediamine-N,N′-diacetic acid (6SS); 1-(4- carboxymethoxybenzyl)-N-N'-bis[(2-mercapto-2,2-dimethyl)ethyl]-1,2- ethylenediamine-N,N'-diacetic acid (B6SS); Deferoxamine (DFO); 1,1,1- tris(aminomethyl)ethane (TAME); tris(aminomethyl)ethane-N,N,N’,N’,N’’,N’’- hexaacetic acid (TAME Hex); O-hydroxybenzyl iminodiacetic acid; 1,4,7- triazacyclononane (TACN); 1,4,7,10-tretraazacyclododecane (cyclen); 1,4,7- triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA); 1-(1-carboxy-3- carboxypropyl)-4,7-bis-(carboxymethyl)-1,4,7-triazacyclononane (NODAGA); 1,4,7- tris(2-mercaptoethyl)-1,4,7-triazacylclonane (triazacyclononane−TM); 1,4,7- triazacyclononane-N,N′,N′′-tris(methylenephosphonic)acid (NOTP); 1, 4, 8, 11- tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA); 1,4,7,10,13- pentaazacyclopentadecane-N,N′,N″,N''',N″″-pentaacetic acid (PEPA), 1,4,7,10,13,16- hexaazacyclohexadecane-N,N',N'',N''',N'''',N'''''-hexaacetic acid (HEHA); 1,4,7,10- tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (TCMC); and derivatives or analogs thereof. [0272] In some embodiments, the chelating agents are polyaminocarboxylate agents, such as ethylenediamine tetraacetic acid (EDTA), diethylenetriamine pentaacetic acid (DTPA), 1,4,7,10-tetra-azacylcododecane-N,N′,N″,N‴-tetraacetic acid (DOTA), or derivatives thereof. They can coordinate with metals such as Fe, In, Ga, Zr, Y, Bi, Pb, or Ac.

[0273] In some embodiments, the cheating agents are macrocyclic agents: 1,4,7- Triazacyclononane-N,N′,N″-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane- N,N′,N″,N‴-tetraacetic acid (TETA), 1,4,7,10,13-pentaazacyclopentadecane- N,N',N",N"',N""-pentaacetic acid (PEPA), 1,4,7,10,13,16- hexaazacyclohexadecane- N,N',N",N"',N"",N""'-hexaacetic acid (HEHA), or derivatives thereof. [0274] Non-limiting examples of DTPA and derivatives thereof are:

glu-DTPA [0275] Non-limiting examples of DOTA and derivatives thereof are:

[0276] In some embodiments, the conjugates of the present disclosure comprise DOTA, DOTAGA, or any derivative/analog thereof as a chelating agent. Any chelating agent disclosed in Eisenwiener et al., Bioorg Med Chem Lett., vol.10(18):2133 (2000), the contents of which are incorporated herein by reference in their entirety, may be used as a chelating agent, such as 1,4,7,10- Tetraazacyclododecane-1,4,7,10-tetraacetic acid, α-(2-carboxyethyl) (DOTAGA) or 1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid, 10-(1,2-dicarboxyethyl) (DOTASA).

DOTASA n=1 DOTAGA n=2 [0277] Other non-limiting examples of chelating agents are:

2C-TETA 6C-TETA

[0278] In some embodiments, the chelators bind to a radionuclide (such as a radioisotope). A variety of radionuclides have emission properties, including α, β, γ, and Auger emissions, that may be used for therapeutic and/or diagnostic purposes. For example, the chelator may bind to a radioisotope, such as Y-90, Y-86, I-131, Re-186, Re-188, Y-90, Bi-212, At-211, Zr-89, Sr-89, Ho-166, Sm-153, Cu-67, Cu-64, Lu-177, Ac-225, Pb-203, Bi-213, Th-227, Pb-212, Ra-223, P-32, Sc-47, Br-77, Rh-105, Pd- 103, Ag-111, Pr-142, Pm-149, Gd-159, Ir-194 and Pt-199. [0279] In some embodiments, the chelator binds to an imaging probe, such as a radiolabel (e.g., a radioisotope). Non-limiting examples of radioisotopes for imaging include I-124, I-131, In-111, Re-186, Re-188, Y-90, Bi-212, At-211, Sr-89, Ho-166, Sm-153, Cu-60, Cu-67, Cu-64, Lu-177, Ac-225, Bi-213, Th-227, Pb-212, Ra-223, P- 32, Sc-47, Br-76, Br-77, Rh-105, Pd-103, Ag-111, Pr-142, Pm-149, Gd-159, In-111, Ir-194, Pt-199, Tc-99m, Co-57, Ga-66, Ga-67, Ga-68, Kr-81m, Rb-82, Sr-92, Tl- 201,Y-86, Zr-89, C-11, N-13, O-15 and F-18. [0280] In some embodiments, the chelator binds to a radioactive agent. A conjugate comprising a chelator attached to a radioactive agent (e.g., a radioisotope) is a radioactive analog of a conjugate with a chelator agent alone or with a chelator attached to a non-radioactive isotope. [0281] In some embodiments, the chelator binds to Lu-177. For example, the chelator may be DOTA or DOTAGA. [0282] In some embodiments, the chelator binds to Ac-225. For example, the chelator may be macropa or macropa-NCS. C. Linkers and Spacers [0283] The conjugates contain one or more linkers attaching the active agents, chelators, and targeting moieties. The linkers, Y, are bound to one or more active agents, one or more chelators, and/or one or more targeting ligands to form a conjugate. The linker Y is attached to the targeting moiety X, the chelator, and/or the active agent Z by functional groups independently selected from an ester bond, disulfide, amide, acylhydrazone, ether, carbamate, carbonate, sulfonamide, alkyl, aryl, heteroaryl, thioether, and urea. Alternatively the linker can be attached to the targeting moiety, the chelator, and/or the active agent by a group such as provided by the conjugation between a thiol and a maleimide, an azide and an alkyne. In some embodiments, the linker is a small molecule. In some embodiments, the linker is independently selected from the group consisting alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups optionally is substituted with one or more groups, each independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, wherein each of the carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups, each independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, carbamoyl, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl. [0284] In some embodiments, the linker comprises a cleavable functionality that is cleavable. The linker can be cleaved to release the active agent. The cleavable functionality may be hydrolyzed in vivo or may be designed to be hydrolyzed enzymatically, for example by Cathepsin B. A “cleavable” linker, as used herein, refers to any linker which can be cleaved physically or chemically. Examples for physical cleavage may be cleavage by light, radioactive emission or heat, while examples for chemical cleavage include cleavage by re- dox-reactions, hydrolysis, pH-dependent cleavage or cleavage by enzymes. For example, the cleavable functionality may be a disulfide bond, an amide bond, a carbamate group, or a urea group [0285] In some embodiments, the linker comprises an alkyl chain. The alkyl chain of the linker may optionally be interrupted by one or more atoms or groups selected from –O-, -C(=O)-, -NR, -O-C(=O)-NR-, -S-, -S-S-. The linker may be selected from dicarboxylate derivatives of succinic acid, glutaric acid or diglycolic acid. [0286] In some embodiments, the linker Y may be X’-R¹-Y’-R²-Z’ and the conjugate can be a compound according to Formula Ia: Ia wherein X is a targeting moiety defined above; Z is an active agent; X’, R¹, Y’, R² and Z’ are as defined herein. [0287] X’ is either absent or independently selected from carbonyl, amide, urea, amino, ester, aryl, arylcarbonyl, aryloxy, arylamino, one or more natural or unnatural amino acids, thio or succinimido; R¹ and R² are either absent or comprised of alkyl, substituted alkyl, aryl, substituted aryl, polyethylene glycol (2-30 units); Y’ is absent, substituted or unsubstituted 1,2-diaminoethane, polyethylene glycol (2-30 units) or an amide; Z’ is either absent or independently selected from carbonyl, amide, urea, amino, ester, aryl, arylcarbonyl, aryloxy, arylamino, thio or succinimido. In some embodiments, the linker can allow one active agent molecule to be linked to two or more ligands, or one ligand to be linked to two or more active agent molecule. [0288] In some embodiments, the linker Y may be A_m and the conjugate can be a compound according to Formula Ib:

Ib wherein A is defined herein, m=0-20. [0289] A in Formula Ia is a spacer unit, either absent or independently selected from the following substituents. For each substituent, the dashed lines represent substitution sites with X, Z or another independently selected unit of A wherein the X, Z, or A can be attached on either side of the substituent:

wherein z = 0-40, R is H or an optionally substituted alkyl group, and R’ is any side chain found in either natural or unnatural amino acids. [0290] In some embodiments, the conjugate may be a compound according to Formula Ic:

Ic wherein A is defined above, m=0-40, n=0-40, x=1-5, y=1-5, and C is a branching element defined herein. [0291] C in Formula Ic is a branched unit containing three to six functionalities for covalently attaching spacer units, ligands, or active drugs, selected from amines, carboxylic acids, thiols, or succinimides, including amino acids such as lysine, 2,3- diaminopropanoic acid, 2,4-diaminobutyric acid, glutamic acid, aspartic acid, and cysteine. [0292] In some embodiments, the conjugates may comprise a spacer. The spacer is a chemical group that is non-cleavable. When a linker is non-cleavable, it can also be referred to a spacer. [0293] In some embodiments, the spacer comprises at least one amino acid or analog(s) thereof, such as 2 amino acids or analogs thereof, 3 amino acids or analogs thereof, 4 amino acids or analogs thereof, or 5 amino acids or analogs thereof. The amino acids or analogs thereof may be D amino acids. The amino acids or analogs thereof may be anionic (e.g., DGlu), cationic (e.g., DLys), or uncharged (e.g., Sar, where Sar=N-methyl glycine). The spacer may be DGlu-DGlu-DLys, DLys-DLys- DGlu, DGlu-DGlu-DGlu, DLys-DLys-DLys, Sar-DLys-Sar, Sar-Sar-Sar, Sar-DGlu- Sar, Ala-Asp-D-Ser, Ala-Asp-L-Ser, or Glu. Not willing to be bound by any theory, the spacer affects biodistribution of the conjugates and may reduce liver uptake of the conjugates. HSP90 binding affinity is maintained regardless of what charges are present on the spacer. [0294] In some embodiments, the spacer comprises polyethylene glycol (PEG). The PEG spacers can be constructed from (PEG)_n, wherein n is an integer between 1 to 20. In some embodiments, the PEG spacer is (PEG)4. In some embodiments, the PEG spacer is (PEG)12. HSP90 binding affinity is maintained regardless of what charges are present on the spacer. D. HSP90 Targeting Moieties [0295] Targeting ligands (also referred to as targeting moieties) as described herein include any molecule that can bind one or more HSP90 proteins. Such targeting ligands can be peptides, antibody mimetics, nucleic acids (e.g., aptamers), polypeptides (e.g., antibodies), glycoproteins, small molecules, carbohydrates, or lipids. [0296] The targeting moiety, X, can be any HSP90 binding moiety such as, but not limited to, natural compounds (e.g., geldanamycin and radicicol), and synthetic compounds such as geldanamycin analogue 17-AAG (i.e., 17- allylaminogeldanamycin), a purine-scaffold HSP90 inhibitor series including PU24FC1 (He H., et al, J. Med. Chem., vol.49:381 (2006), the contents of which are incorporated herein by reference in their entirety), BIIB021 (Lundgren K., et al, Mol. Cancer Ther., vol.8(4):921 (2009), the contents of which are incorporated herein by reference in their entirety), 4,5- diarylpyrazoles (Cheung K.M., et al, Bioorg. Med. Chem. Lett., vol.15:3338 (2005), the contents of which are incorporated herein by reference in their entirety), 3- aryl,4-carboxamide pyrazoles (Brough P.A., et al, Bioorg. Med. Chem. Lett., vol.15: 5197 (2005), the contents of which are incorporated herein by reference in their entirety), 4,5-diarylisoxazoles (Brough P.A., et al, J. Med. Chem., vol.51:196 (2008), the contents of which are incorporated herein by reference in their entirety), 3,4-diaryl pyrazole resorcinol derivative (Dymock B.W., et al, J. Med. Chem., vol.48:4212 (2005), the contents of which are incorporated herein by reference in their entirety), thieno[2,3- d]pyrimidine (WO2005034950 to VERNALIS et al., the contents of which are incorporated herein by reference in their entirety), aryl triazole derivatives of Formula I in EP2655345 to Giannini et al., the contents of which are incorporated herein by reference in their entirety, or any other example of HSP90 binding ligands or their derivatives/analogs. [0297] In some embodiments, the HSP90 binding moiety may be heterocyclic derivatives containing three heteroatoms. WO2009134110 to MATULIS et al., the contents of which are incorporated herein by reference in their entirety, discloses 4,5- diaryl thiadiazoles which demonstrate good HSP90 binding affinity. Even though they have rather modest cell growth inhibition, they may be used as HSP90 binding moiety in conjugates of the present invention. Another class of aza-heterocyclic adducts, namely triazole derivatives or their analogs, may be used as HSP90 binding moiety in conjugates of the present invention. For example, the 1,2,4-triazole scaffold has been profusely documented as possessing HSP90 inhibiting properties. WO2009139916 to BURLISON et al. (Synta Pharmaceuticals Corp.), the contents of which are incorporated herein by reference in their entirety, discloses tricyclic 1,2,4-triazole derivatives inhibiting HSP90 at high micromolar concentrations. Any tricyclic 1,2,4- triazole derivatives disclosed in WO2009139916 or their derivatives/analogs may be used as HSP90 binding moiety in conjugates of the present invention. Any trisubstituted 1,2,4- triazole derivatives disclosed in WO 2010017479 and WO 2010017545 (Synta Pharmaceuticals Corp.) or their derivatives/analogs, the contents of which are incorporated herein by reference in their entirety, may be used as HSP90 binding moiety in conjugates of the present invention. In another example, a triazolone-containing HSP90 inhibitor named ganetespib (previously referred as to STA-9090, or as its highly soluble phosphate prodrug STA- 1474) disclosed in WO2006055760 (Synta Pharmaceuticals Corp.), the contents of which are incorporated herein by reference in their entirety, or its derivatives/analogs may be used as HSP90 binding moiety in conjugates of the present invention.

[0298] In some embodiments, ganetespib or its derivatives/analogs may be used a targeting moiety. Non-limiting examples of ganetespib derivatives/analogs are shown below.

[0299] In some embodiments, Onalespib (AT13387) or its derivatives/analogs may be used as a targeting moiety in the conjugates of the present invention. Onalespib and non-limiting examples of Onalespib derivatives/analogs are shown below.

Onalespib

[0300] In some embodiments, the targeting moiety comprises AUY-922, or an analog/derivative/fragment thereof. In one embodiment, the targeting moiety has a structure of

. [0301] Any HSP90 ligand or HSP90 inhibitor disclosed in WO2013158644, WO2015038649, WO2015066053, WO2015116774, WO2015134464, WO2015143004, WO2015184246, the contents of which are incorporated herein by reference in their entirety, or their derivatives/analogs may be used as HSP90 binding moiety in the conjugates of the present invention, such as: [0302] Formula

, wherein R1 may be alkyl, aryl, halide, carboxamide or sulfonamide; R2 may be alkyl, cycloalkyl, aryl or heteroaryl, wherein when R2 is a 6 membered aryl or heteroaryl, R2 is substituted at the 3- and 4- positions relative to the connection point on the triazole ring, through which a linker L is attached; and R3 may be SH, OH, -CONHR4, aryl or heteroaryl, wherein when R3 is a 6 membered aryl or heteroaryl, R3 is substituted at the 3 or 4 position;

Formula II , wherein R1 may be alkyl, aryl, halo, carboxamido, sulfonamido; and R2 may be optionally substituted alkyl, cycloalkyl, aryl or heteroaryl. Examples of such compounds include 5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2-morpholinoethyl)-4-(4-(morpholinomethyl)phenyl)-4H-1,2,4- triazole-3-carboxamide and 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(4- methylpiperazin-1-yl)phenyl)-N-(2,2,2-trifluoroethyl)-4H-1,2,4-triazole-3- carboxamide;

, wherein X, Y, and Z may independently be CH, N, O or S (with appropriate substitutions and satisfying the valency of the corresponding atoms and aromaticity of the ring); R1 may be alkyl, aryl, halide, carboxamido or sulfonamido; R2 may be substituted alkyl, cycloalkyl, aryl or heteroaryl, where a linker L is connected directly or to the extended substitutions on these rings; R3 may be SH, OH, NR4R5 AND -CONHR6, to which an effector moiety may be connected; R4 and R5 may independently be H, alkyl, aryl, or heteroaryl; and R6 may be alkyl, aryl, or heteroaryl, having a minimum of one functional group to which an effector moiety may be connected; or Formula I

, wherein R1 may be alkyl, aryl, halo, carboxamido or sulfonamido; R2 and R3 are independently C1-C5 hydrocarbyl groups optionally substituted with one or more of hydroxy, halogen, C1-C2 alkoxy, amino, mono- and di-C1-C2 alkylamino; 5- to 12- membered aryl or heteroaryl groups; or, R2 and R3, taken together with the nitrogen atom to which they are attached, form a 4- to 8- membered monocyclic heterocyclic group, of which up to 5 ring members are selected from O, N and S. Examples of such compounds include AT-13387. [0303] The HSP90 targeting moiety may be Ganetespib, Luminespib (AUY-922, NVP-AUY922), Debio-0932, MPC-3100, Onalespib (AT-13387), SNX-2112, 17- amino-geldanamycin hydroquinone, PU-H71, or derivatives/analogs thereof.

3100

[0304] The HSP90 targeting moiety may be SNX5422 (PF-04929113), or any other HSP90 inhibitors disclosed in US 8080556 (Pfizer), WO2008096218 (Pfizer), WO2006117669 (Pfizer), WO2008059368 (Pfizer), WO2008053319 (Pfizer), WO2006117669 (Pfizer), EP1885701 (Novartis), EP1776110 (Novartis), EP2572709 (Novartis), WO2012131413 (Debiopharm), or WO2012131468 (Debiopharm), the contents of each of which are incorporated herein by reference in their entirety.

SNX5422 [0305] The HSP90 targeting moiety may also be PU-H71, an HSP90 inhibitor that is ¹²⁴I radiolabeled for PET imaging or its derivatives/analogs. [0306] Conjugates comprising SNX-2112, 17-amino-geldanamycin hydroquinone, PU-H71, or AT13387 may have a structure of:

. [0307] In some embodiments, the targeting moiety comprises an imaging probe, such as a radiolabel (e.g., a radioisotope). Non-limiting examples of radioisotopes include I-131, Re-186, Re-188, Y-90, Bi-212, At-211, Sr-89, Ho-166, Sm-153, Cu-67, Cu-64, Lu-177, Ac-225, Bi-213, Th-227, Pb-212, Ra-223, P-32, Sc-47, Br-77, Rh- 105, Pd-103, Ag-111, Pr-142, Pm-149, Gd-159, Ir-194, Pt-199, Tc-99m, Co-57, Ga- 67, Kr-81m, Rb-82, Sr-92, Tl-201, C-11, N-13, O-15 and F-18. [0308] In some embodiments, the conjugates of the present disclosure comprise more than one targeting moiety. For example, the conjugate may comprise 2, 3, 4, or 5 HSP90 targeting moieties. Extracellular HSP90 (eHSP90) [0309] In normal cells, secretion of HSP90 occurs when cells are under environmental stress such as heat, drugs, cytokines, UV, and/or gamma rays. The main function of the extracellular HSP90 (eHSP90) is to help tissue repair by promoting the cells at the edge of damaged tissue to migrate into the damaged area. However, in tumors, constitutively activated oncogenes trigger HSP90 secretion even without any environmental stress. Secreted Hsp90 by tumors eHSP90α promotes both tumor and tumor stroma cell migration during invasion and metastasis. The extracellular promotility function of HSP90α depends on a 115-amino acid fragment (F-5) on the surface of HSP90 (Li et al., Int Rev Cell Mol Biol., vol.303:203-235 (2013), the contents of which are incorporated herein by reference in their entirety). eHSP90 has been shown to be present on the surface of tumor cells and to also be capable of being internalized (Crowe et al., ACS Chem. Biol., vol.12:1047-1055 (2017)). The surface expression of eHSP90 in tumor cells thus represents a target for directing therapies selectively to tumors over healthy cells. Therefore, eHSP90 (eHSP90α in particular) may be a good target for treating tumors. [0310] In some embodiments, the targeting moiety selectively binds to eHSP90. In some embodiments, the targeting moiety binds to F-5 region of eHSP90. [0311] In some embodiments, the targeting moiety has low cell-permeability and prefers to bind to cell surface eHSP90. In some embodiments, the targeting moiety is cell-impermeable and binds exclusive to eHSP90. In some embodiments, the conjugates comprising the targeting moieties have a low cell permeability or is cell- impermeable. [0312] In some embodiments, the targeting moieties comprise HS-23, HS-131, (disclosed in Crowe et al., ACS Chem. Biol., vol.12:1047-1055 (2017), the contents of which are incorporated herein by reference in their entirety) or DMAG-N-oxide (a cell-impermeable for of 17-AAG disclosed in Tsutsumi et al., Oncogene, vol.27(17):2478-2487 (2008), the contents of which are incorporated herein by reference in their entirety), or analog/derivative thereof, the structures shown below.

[0313] In certain embodiments, the targeting moiety or moieties of the conjugate are present at a predetermined molar weight percentage from about 0.1 % to about 10%, or about 1% to about 10%, or about 10% to about 20%, or about 20% to about 30%, or about 30% to about 40%, or about 40% to about 50%, or about 50% to about 60%, or about 60% to about 70%, or about 70% to about 80%, or about 80% to about 90%, or about 90% to about 99% such that the sum of the molar weight percentages of the components of the conjugate is 100%. The amount of targeting moieties of the conjugate may also be expressed in terms of proportion to the active agent(s), for example, in a ratio of ligand to active agent of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4; 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. E. Pharmacokinetic Modulating Unit [0314] The conjugates of the present invention may further comprise at least one external linker connected to a reacting group that reacts with a functional group on a protein or an engineered protein or derivatives/analogs/mimics thereof, or comprise at least one external linker connected to a pharmacokinetic modulating unit (PMU). The external linkers connecting the conjugates and the reacting group or the pharmacokinetic modulating units may be cleavable linkers that allow release of the conjugates. Hence, the conjugates may be separated from the protein or pharmacokinetic modulating units as needed. [0315] Any reacting group or PMU (such as PMUs comprising polymers) disclosed in WO2017/197241, the contents of which are incorporated herein by reference in their entirety, may be attached to the conjugates of the present disclosure. [0316] In some embodiments, the conjugate comprises a protein-binding reacting group attached to its active agent. In some embodiments, the conjugate comprises a protein-binding reacting group attached to its targeting moiety. In some embodiments, the conjugate comprises a protein-binding reacting group attached to its linker. The reacting group binds to a protein reversibly or irreversibly. The protein may be a naturally occurring protein, such as a serum or plasma protein, or a fragment thereof. Particular examples include Fc neonatal receptor (FcRn), thyroxine-binding protein, transthyretin, α1-acid glycoprotein (AAG), transferrin, fibrinogen, albumin, an immunoglobulin, α-2-macroglobulin, a lipoprotein, or fragments thereof. The reacting group may bind to such a protein via covalent bonds or non-covalent interactions, such as hydrogen bonds, ionic bonds, van der Waals interactions, and hydrophobic bonds. [0317] In some embodiments, the protein-binding reacting group may bind to a serum protein via non-covalent interactions. For example, the reacting group may be saturated fatty acids that bind to albumin with weak affinities (10^-4 to 10^-5 M). Non- limiting examples of such fatty acids may include myristic acid (a fatty acid with 14 carbon atoms) and palmitic acid (a fatty acid with 16 carbon atoms). Other non- limiting examples of the reacting groups include a naphthalene acylsulfonamide group, a diphenylcyclohexanol phosphate ester group, a 6-(4-(4-iodophenyl) butanamido)hexanoate group (‘Albu’-tag), a series of peptides having the core sequence of DICLPRWGCLW including SA21 (a cyclic peptide with 18 amino acids Ac-RLIEDICLPRWGCLWEDD-NH₂) disclosed by Dennis et al. in J. Biol. Chem., vol.277:35035 (2002), the contents of which are incorporated herein by reference in their entirety. [0318] A protein-binding reacting group may comprise a structure of:

(4-(4-iodophenyl) butanamido group), or

(a 6-(4-(4-iodophenyl) butanamido)hexanoate group). [0319] In some embodiments, the protein-binding reacting group may comprise any peptide-fatty acid albumin-binding ligand disclosed in Zorzi et al., Nature Communications, vol.8:16092, (2017), the contents of which are incorporated herein by reference in their entirety. These peptide-fatty acid albumin-binding ligands comprise a fatty acid connected to a short peptide, e.g., a heptapeptide, via an amino acid side chain. The fatty acid may be linked to the short peptide via its carboxylic group to the side chain of lysine. The fatty acid binds to albumin with an affinity in the micromolar range and the short peptide enhances the affinity by forming additional contacts to albumin. The peptide-fatty acid ligands may have a general structure of:

, wherein X = any amino acid (such as Gly or Ser), K = Lys, n=12 (myristic acid), 14 (palmitic acid), or 16 (stearic acid). [0320] In some embodiments, any albumin-binding functional group disclosed in US 9670482 (Bicycle Therapeutics), the contents of which are incorporated herein in their entirety, may be used as a protein-binding reacting group in the present application. In some embodiments, the protein-binding reacting group comprises a fluorene ring and binds to albumin non-covalently and/or reversibly. As a non- limiting example, the protein-binding reacting group comprises a fluorenylmethyloxycarbonyl (FMOC) group. Optionally, the protein-binding reacting group comprises at least one amino acid attached to FMOC, such as Lys, Trp, Gly, or Phe. For example, the small molecule may comprise Fmoc-Lys-, Fmoc-Gly-, Fmoc- Phe-, Fmoc-GGSGD-, Fmoc-FGGGD-, Fmoc-FGSGD-, Fmoc-WGSGD-, Fmoc- WGGGA, or Fmoc-Trp-GGG.

Non-Limiting Examples of Conjugates [0321] In some embodiments, the conjugate comprises at least one HSP90 targeting moiety (TM), an active agent moiety, a chelating agent moiety (chelator), wherein each moiety is covalently attached to another moiety via a linker or a spacer. [0322] In some embodiments, the HSP90 targeting moiety may be a ganetespib analog or derivative (such as TM1, TM2, TM3, TM4, TM5, TM8, TM9, TM10, TM11, TM12, TM13, or TM14), an onalespib analog or derivative (such as TM6 or TM7), or TM15. [0323] The active agent may be any suitable active agent. In some embodiments, the active agent comprises a PI3K inhibitor, or an analog, derivative or fragment thereof. [0324] The chelating agent may be any suitable chelating agent. In some embodiments, the chelating agent is DOTA or DOTAGA. The chelating agent can be free (no metal attached), with an active metal (therapeutic or imaging) attached to it, or with an inactive metal attached to it. [0325] In some embodiments, the linker is small molecule. The linker may be cleavable. In some embodiments, the linker comprises an amide bond. [0326] In some embodiments, the spacer may comprise at least one amino acid. The spacer may comprise PEG, such as (PEG)4 or (PEG)12. [0327] The molecular weight of the conjugates may be less than 5000 Da, such as between about 1000 Da and about 3000 Da, or between about 1500 Da and 2500 Da. [0328] In some embodiments, the conjugate has a structure of Formula A:

[0329] In some embodiments, the conjugate has a structure of Formula B:

(B). [0330] In some embodiments, the conjugate has a structure of Formula C:

(C). [0331] In some embodiments, the conjugate comprises TM10, a PEG spacer, a DOTA chelator, a cleavable linker, and a PI3K inhibitor analog. As PI3K inhibitor analog comprises a structure of:

. As a non-limiting example, the conjugate is Compound 100, which has a structure of:

(100). II. Formulations [0332] In some embodiments, compositions are administered to humans, human patients or subjects. For the purposes of the present disclosure, the phrase “active ingredient” generally refers to the conjugate as described herein. [0333] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g. non-human mammals. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and/or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and/or rats; and/or birds, including commercially relevant birds such as poultry, chickens, ducks, geese, and/or turkeys. [0334] Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, dividing, shaping and/or packaging the product into a desired single- or multi-dose unit. [0335] A pharmaceutical composition in accordance with the invention may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. [0336] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100%, e.g., between .5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient. [0337] The conjugates of the present invention can be formulated using one or more excipients to: (1) increase stability; (2) permit the sustained or delayed release (e.g., from a depot formulation of the monomaleimide); (3) alter the biodistribution (e.g., target the monomaleimide compounds to specific tissues or cell types); (4) alter the release profile of the monomaleimide compounds in vivo. Non-limiting examples of the excipients include any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, and preservatives. Excipients of the present invention may also include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, hyaluronidase, nanoparticle mimics and combinations thereof. Accordingly, the formulations of the invention may include one or more excipients, each in an amount that together increases the stability of the monomaleimide compounds. Excipients [0338] Pharmaceutical formulations may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional excipient medium is incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. [0339] In some embodiments, a pharmaceutically acceptable excipient is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some embodiments, an excipient is approved for use in humans and for veterinary use. In some embodiments, an excipient is approved by United States Food and Drug Administration. In some embodiments, an excipient is pharmaceutical grade. In some embodiments, an excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and/or the International Pharmacopoeia. [0340] Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in pharmaceutical compositions. [0341] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and/or combinations thereof. [0342] Exemplary granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross- linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM®), sodium lauryl sulfate, quaternary ammonium compounds, etc., and/or combinations thereof. [0343] Exemplary surface active agents and/or emulsifiers include, but are not limited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and VEEGUM® [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [TWEEN®20], polyoxyethylene sorbitan [TWEEN®60], polyoxyethylene sorbitan monooleate [TWEEN®80], sorbitan monopalmitate [SPAN®40], sorbitan monostearate [SPAN®60], sorbitan tristearate [SPAN®65], glyceryl monooleate, sorbitan monooleate [SPAN®80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [MYRJ®45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Kolliphor® (SOLUTOL®)), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. CREMOPHOR®), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [BRIJ®30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, PLUORINC®F 68, POLOXAMER®188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof. [0344] Exemplary binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol,); natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylates; waxes; water; alcohol; etc.; and combinations thereof. [0345] Exemplary preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and/or other preservatives. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and/or sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/or thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, GLYDANT PLUS®, PHENONIP®, methylparaben, GERMALL®115, GERMABEN®II, NEOLONE™, KATHON™, and/or EUXYL®. [0346] Exemplary buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, etc., and/or combinations thereof. [0347] Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof. [0348] Exemplary oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and/or combinations thereof. [0349] Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents can be present in the composition, according to the judgment of the formulator. Administration [0350] The conjugates of the present invention may be administered by any route which results in a therapeutically effective outcome. These include, but are not limited to enteral, gastroenteral, epidural, oral, transdermal, epidural (peridural), intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal, (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intraarterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraperitoneal, (infusion or injection into the peritoneum), intravesical infusion, intravitreal, (through the eye), intracavernous injection, ( into the base of the penis), intravaginal administration, intrauterine, extra-amniotic administration, transdermal (diffusion through the intact skin for systemic distribution), transmucosal (diffusion through a mucous membrane), insufflation (snorting), sublingual, sublabial, enema, eye drops (onto the conjunctiva), or in ear drops. In specific embodiments, compositions may be administered in a way which allows them to cross the blood- brain barrier, vascular barrier, or other epithelial barrier. [0351] The formulations described herein contain an effective amount of conjugates in a pharmaceutical carrier appropriate for administration to an individual in need thereof. The formulations may be administered parenterally (e.g., by injection or infusion). The formulations or variations thereof may be administered in any manner including enterally, topically (e.g., to the eye), or via pulmonary administration. In some embodiments the formulations are administered topically. Dosing [0352] The present invention provides methods comprising administering conjugates as described herein to a subject in need thereof. Conjugates as described herein may be administered to a subject using any amount and any route of administration effective for preventing or treating or imaging a disease, disorder, and/or condition (e.g., a disease, disorder, and/or condition relating to working memory deficits). The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like. [0353] Compositions in accordance with the invention are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective, prophylactically effective, or appropriate imaging dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. [0354] In some embodiments, compositions in accordance with the present invention may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg to about 0.05 mg/kg, from about 0.005 mg/kg to about 0.05 mg/kg, from about 0.001 mg/kg to about 0.005 mg/kg, from about 0.05 mg/kg to about 0.5 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, from about 25 mg/kg to about 50 mg/kg, from about 50 mg/kg to about 100 mg/kg, from about 100 mg/kg to about 125 mg/kg, from about 125 mg/kg to about 150 mg/kg, from about 150 mg/ to about 175 mg/kg, from about 175 mg/kg to about 200 mg/kg, from about 200 mg/kg to about 250 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic, diagnostic, prophylactic, or imaging effect. The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In some embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). When multiple administrations are employed, split dosing regimens such as those described herein may be used. [0355] The concentration of the conjugates may be between about 0.01 mg/mL to about 50 mg/mL, about 0.1 mg/mL to about 25 mg/mL, about 0.5 mg/mL to about 10 mg/mL, or about 1 mg/mL to about 5 mg/mL in the pharmaceutical composition. [0356] As used herein, a “split dose” is the division of single unit dose or total daily dose into two or more doses, e.g, two or more administrations of the single unit dose. As used herein, a “single unit dose” is a dose of any therapeutic administered in one dose/at one time/single route/single point of contact, i.e., single administration event. As used herein, a “total daily dose” is an amount given or prescribed in 24 hr period. It may be administered as a single unit dose. Dosage Forms [0357] A pharmaceutical composition described herein can be formulated into a dosage form described herein, such as a topical, intranasal, intratracheal, or injectable (e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, and subcutaneous). VI. Methods of Using the Conjugates [0358] The conjugates as described herein can be administered to treat any hyperproliferative disease, metabolic disease, infectious disease, or cancer, as appropriate. Formulations may be administered by injection, orally, or topically, typically to a mucosal surface (lung, nasal, oral, buccal, sublingual, vaginally, rectally) or to the eye (intraocularly or transocularly). [0359] In various embodiments, methods for treating a subject having a cancer are provided, wherein the method comprises administering a therapeutically-effective amount of the conjugates, salt forms thereof, as described herein, to a subject having a cancer, suspected of having cancer, or having a predisposition to a cancer. According to the present invention, cancer embraces any disease or malady characterized by uncontrolled cell proliferation, e.g., hyperproliferation. Cancers may be characterized by tumors, e.g., solid tumors or any neoplasm. [0360] In some embodiments, the cancer is a solid tumor. Large drug molecules have limited penetration in solid tumors. The penetration of large drug molecules is slow. On the other hand, small molecules such as conjugates of the present invention may penetrate solid tumors rapidly and more deeply. Regarding penetration depth of the drugs, larger molecules penetrate less, despite having more durable pharmacokinetics. Small molecules such as conjugates of the present invention penetrate deeper. Dreher et al. (Dreher et al., JNCI, vol.98(5):335 (2006), the contents of which are incorporated herein by reference in their entirety) studied penetration of dextrans with different sizes into a tumor xenograft. [0361] In one embodiment, conjugates of the present invention reach at least about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 75 µm, about 100 µm, about 150 µm, about 200 µm, about 250 µm, about 300 µm, about 400 µm, about 500 µm, about 600 µm, about 700 µm, about 800 µm, about 900 µm, about 1000 µm, about 1100 µm, about 1200 µm, about 1300 µm, about 1400 µm or about 1500 µm into the solid tumor from the vascular surface of the tumor. Zero distance is defined as the vascular surface of the tumor, and every distance greater than zero is defined as the distance measured in three dimensions to the nearest vascular surface. [0362] In another embodiment, conjugates of the present invention penetrate to the core of the tumor. “Core” of the tumor, as used herein, refers to the central area of the tumor. The distance from any part of the core area of the tumor to the vascular surface of the tumor is between about 30% to about 50% of the length or width of the tumor. The distance from any part of the core area of the tumor to the center point of the tumor is less than about 20% of the length or width of the tumor. The core area of the tumor is roughly the center 1/3 of the tumor. [0363] In another embodiment, conjugates of the present invention conjugates of the present invention penetrate to the middle of the solid tumor. “Middle” of the tumor, as sued herein, refers to the middle area of the tumor. The distance from any part of the middle area of the tumor to the vascular surface of the tumor is between about 15% and about 30% of the length or the width of the tumor. The distance from any part of the middle area of the tumor to the center point of the tumor is between about 20% to about 35% of the length or width of the tumor. The middle area of the tumor is roughly between the center 1/3 of the tumor and the outer 1/3 of the tumor. [0364] In some embodiments, the subject may be otherwise free of indications for treatment with the conjugates. In some embodiments, methods include use of cancer cells, including but not limited to mammalian cancer cells. In some instances, the mammalian cancer cells are human cancer cells. [0365] In some embodiments, the conjugates of the present teachings have been found to inhibit cancer and/or tumor growth. They may also reduce, including cell proliferation, invasiveness, and/or metastasis, thereby rendering them useful for the treatment of a cancer. [0366] In some embodiments, the conjugates of the present teachings may be used to prevent the growth of a tumor or cancer, and/or to prevent the metastasis of a tumor or cancer. In some embodiments, compositions of the present teachings may be used to shrink or destroy a cancer. [0367] In some embodiments, the conjugates provided herein are useful for inhibiting proliferation of a cancer cell. In some embodiments, the conjugates provided herein are useful for inhibiting cellular proliferation, e.g., inhibiting the rate of cellular proliferation, preventing cellular proliferation, and/or inducing cell death. In general, the conjugates as described herein can inhibit cellular proliferation of a cancer cell or both inhibiting proliferation and/or inducing cell death of a cancer cell. In some embodiments, cell proliferation is reduced by at least about 25%, about 50%, about 75%, or about 90% after treatment with conjugates of the present invention compared with cells with no treatment. In some embodiments, cell cycle arrest marker phospho histone H3 (PH3 or PHH3) is increased by at least about 50%, about 75%, about 100%, about 200%, about 400% or about 600% after treatment with conjugates of the present invention compared with cells with no treatment. In some embodiments, cell apoptosis marker cleaved caspase-3 (CC3) is increased by at least 50%, about 75%, about 100%, about 200%, about 400% or about 600% after treatment with conjugates of the present invention compared with cells with no treatment. [0368] Furthermore, in some embodiments, conjugates of the present invention are effective for inhibiting tumor growth, whether measured as a net value of size (weight, surface area or volume) or as a rate over time, in multiple types of tumors. [0369] In some embodiments the size of a tumor is reduced by about 60 % or more after treatment with conjugates of the present invention. In some embodiments, the size of a tumor is reduced by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, by a measure of weight, and/or area and/or volume. [0370] The cancers treatable by methods of the present teachings generally occur in mammals. Mammals include, for example, humans, non-human primates, dogs, cats, rats, mice, rabbits, ferrets, guinea pigs horses, pigs, sheep, goats, and cattle. In various embodiments, Cancers include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt’s lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin’s and non-Hodgkin’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom’s macroglobulinemia, testicular tumors, uterine cancer, and Wilms’ tumor. Other cancers include primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gall bladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, kidney cancer, urothelium cancer, female genital tract cancer, uterine cancer, gestational trophoblastic disease, male genital tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary gland cancer, hemangioma, sarcoma arising from bone and soft tissues, Kaposi’s sarcoma, nerve cancer, ocular cancer, meningial cancer, glioblastomas, neuromas, neuroblastomas, Schwannomas, solid tumors arising from hematopoietic malignancies such as leukemias, metastatic melanoma, recurrent or persistent ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumors, colorectal cancer, gastric cancer, melanoma, glioblastoma multiforme, non-squamous non-small-cell lung cancer, malignant glioma, epithelial ovarian cancer, primary peritoneal serous cancer, metastatic liver cancer, neuroendocrine carcinoma, refractory malignancy, triple negative breast cancer, HER2- amplified breast cancer, nasopharageal cancer, oral cancer, biliary tract, hepatocellular carcinoma, squamous cell carcinomas of the head and neck (SCCHN), non-medullary thyroid carcinoma, recurrent glioblastoma multiforme, neurofibromatosis type 1, CNS cancer, liposarcoma, leiomyosarcoma, salivary gland cancer, mucosal melanoma, acral/ lentiginous melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumor, triple negative breast cancer, colorectal cancer, sarcoma, melanoma, renal carcinoma, endometrial cancer, thyroid cancer, rhabdomysarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancy. [0371] In one embodiment, the conjugates as described herein or formulations containing the conjugates as described herein are used to treat small cell lung cancer. About 12%-15% of patients having lung cancer have small cell lung cancer. Survival in metastatic small cell lung cancer is poor. Survival rate is below 5% five years after diagnosis. US incidence of small cell lung cancer is about 26K-30K. [0372] In some embodiments, the conjugates as described herein or formulations containing the conjugates as described herein are used to treat patients with tumors that express or over-express the HSP90. [0373] A feature of conjugates of the present invention is relatively low toxicity to an organism while maintaining efficacy at inhibiting, e.g. slowing or stopping tumor growth. As used herein, “toxicity” refers to the capacity of a substance or composition to be harmful or poisonous to a cell, tissue organism or cellular environment. Low toxicity refers to a reduced capacity of a substance or composition to be harmful or poisonous to a cell, tissue organism or cellular environment. Such reduced or low toxicity may be relative to a standard measure, relative to a treatment or relative to the absence of a treatment. For example, conjugates of the present invention may have lower toxicity than the active agent moiety Z administered alone. For conjugates comprising DM1, their toxicity is lower than DM1 administered alone. [0374] Toxicity may further be measured relative to a subject’s weight loss where weight loss over 15%, over 20% or over 30% of the body weight is indicative of toxicity. Other metrics of toxicity may also be measured such as patient presentation metrics including lethargy and general malaise. Neutropenia, thrombocytopenia, white blood cell (WBC) count, complete blood cell (CBC) count may also be metrics of toxicity. Pharmacologic indicators of toxicity include elevated aminotransferases (AST/ALT) levels, neurotoxicity, kidney damage, GI damage and the like. In one embodiment, conjugates of the present invention do not cause a significant change of a subject’s body weight. The body weight loss of a subject is less about 30%, about 20%, about 15%, about 10%, or about 5% after treatment with conjugates of the present invention. In another embodiment, conjugates of the present invention do not cause a significant increase of a subject’s AST/ALT levels. The AST or ALT level of a subject is increased by less than about 30%, about 20%, about 15%, about 10%, or about 5% after treatment with conjugates of the present invention. In yet another embodiment, conjugates of the present invention do not cause a significant change of a subject’s CBC or WBC count after treatment with conjugates of the present invention. The CBC or WBC level of a subject is decreased by less than about 30%, about 20%, about 15%, about 10%, or about 5% after treatment with conjugates of the present invention. Combination Therapies [0375] In some embodiments, conjugates of the present invention are combined with at least one additional active agent. The active agent may be any suitable drug. The conjugates and the at least one additional active agent may be administered simultaneously, sequentially, or at any order. The conjugates and the at least one additional active agent may be administered at different dosages, with different dosing frequencies, or via different routes, whichever is suitable. [0376] In some embodiments, the additional active agents affect the biodistribution (i.e., tissue distribution) of the conjugates of the current invention. For example, radioactive agents may accumulate in kidneys and may pose a potential radiotoxicity problem to kidneys and surrounding organs. The additional active agent may reduce renal accumulation or retention time. Preferably, kidney update of the conjugates is reduced, while tumor uptake of the conjugates is not affected. Kidney and surrounding organs are protected without reducing the efficacy of the conjugates. In one non-limiting example, conjugates of the current invention may be administered in combination with at least one amino acid or analog(s) thereof. The amino acid or analog(s) thereof may be positively charged basic amino acids such as lysine (L- lysine or D-lysine) or arginine, or a combination thereof. In another non-limiting example, conjugates of the current invention may be administered in combination with an active agent that binds to HSP90, such as an HSP90 inhibitor. Any ligand discussed in the “HSP90 Targeting Moieties” section, such as ganetespib or its derivative/analog thereof, may be used. In another non-limiting example, conjugates of the current invention may be administered in combination with monosodium glutamate (MSG) or glutamic acid. In yet another non-limiting example, conjugates of the current invention may be administered in combination with amifostine (Ethyol, WR-2721), the bovine gelatin-containing solution Gelofusine or albumin fragments. The albumin fragments may have a molecular weight between 3 and 50 kDa. [0377] The additional active agent may also be selected from any active agent described herein such as a drug for treating cancer. It may also be a cancer symptom relief drug. Non-limiting examples of symptom relief drugs include: octreotide or lanreotide; interferon, cypoheptadine or any other antihistamines. In some embodiments, conjugates of the present invention do not have drug-drug interference with the additional active agent. In one embodiment, conjugates of the present invention do not inhibit cytochrome P450 (CYP) isozymes. CYP isozymes may include CYP3A4 Midazolam, CYP3A4 Testosterone, CYP2C9, CYP2D6, CYP1A2, CYP2C8, CYP2B6, and CYP2C19. The additional active agent may be administered concomitantly with conjugates of the present invention. [0378] In another example, conjugates of the present invention may be combined with a moderate dose of chemotherapy agents such as mitomycin C, vinblastine and cisplatin (see Ellis et al., Br J Cancer, vol.71(2): 366–370 (1995), the contents of which are incorporated herein by reference in their entirety). [0379] In yet another example, a patient may first receive a pharmaceutically effective dose of an unconjugated active agent, followed by a pharmaceutically effective dose of a conjugate comprising the same active agent. [0380] In some embodiments, a non-radioactive conjugate of the present invention may be combined with an radioactive analog of this conjugate. For example, the non- radioactive conjugate can be administered prior to the radioactive analog. In another example, a subject may receive a mixture of the non-radioactive conjugate and its radioactive analog. In yet another example, a subject may receive the non-radioactive conjugate treatment first, followed by a mixture of the non-radioactive conjugate and its radioactive analog. [0381] In some embodiments, a conjugate of the present invention comprising one radiolabel may be combined with at least one other conjugate of the present invention comprising one or more different radiolabels. For example, conjugates comprising an imaging radiolabel may be combined with conjugates comprising a non-imaging radiolabel. In one embodiment, conjugates comprising lutetium (Lu) may be combined with conjugates comprising gallium (Ga). [0382] The conjugates as described herein or formulations containing the conjugates as described herein can be used for the selective tissue delivery of a therapeutic, prophylactic, or diagnostic agent to an individual or patient in need thereof. For example, conjugates of the present invention are used to deliver radioactive agents to selective tissues. These tissues may be tumor tissues. Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic. V. Kits and Devices [0383] The invention provides a variety of kits and devices for conveniently and/or effectively carrying out methods of the present invention. Typically kits will comprise sufficient amounts and/or numbers of components to allow a user to perform multiple treatments of a subject(s) and/or to perform multiple experiments. [0384] In one embodiment, the present invention provides kits for inhibiting tumor cell growth in vitro or in vivo, comprising a conjugate of the present invention or a combination of conjugates of the present invention, optionally in combination with any other active agents. [0385] The kit may further comprise packaging and instructions and/or a delivery agent to form a formulation composition. The delivery agent may comprise a saline, a buffered solution, or any delivery agent disclosed herein. The amount of each component may be varied to enable consistent, reproducible higher concentration saline or simple buffer formulations. The components may also be varied in order to increase the stability of the conjugates in the buffer solution over a period of time and/or under a variety of conditions. [0386] The present invention provides for devices which may incorporate conjugates of the present invention. These devices contain in a stable formulation available to be immediately delivered to a subject in need thereof, such as a human patient. In some embodiments, the subject has cancer. [0387] Non-limiting examples of the devices include a pump, a catheter, a needle, a transdermal patch, a pressurized olfactory delivery device, iontophoresis devices, multi-layered microfluidic devices. The devices may be employed to deliver conjugates of the present invention according to single, multi- or split-dosing regiments. The devices may be employed to deliver conjugates of the present invention across biological tissue, intradermal, subcutaneously, or intramuscularly. VI. Definitions [0388] The term “compound”, as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. In the present application, compound is used interchangeably with conjugate. Therefore, conjugate, as used herein, is also meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. [0389] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. [0390] Compounds of the present disclosure also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples prototropic tautomers include ketone – enol pairs, amide – imidic acid pairs, lactam – lactim pairs, amide – imidic acid pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. [0391] Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium. [0392] The compounds and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods. [0393] The terms "subject" or "patient", as used herein, refer to any organism to which the conjugates may be administered, e.g., for experimental, therapeutic, diagnostic, and/or prophylactic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, guinea pigs, cattle, pigs, sheep, horses, dogs, cats, hamsters, lamas, non-human primates, and humans). [0394] The terms "treating" or “preventing”, as used herein, can include preventing a disease, disorder or condition from occurring in an animal that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder or condition; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain. [0395] A “target”, as used herein, shall mean a site to which targeted constructs bind. A target may be either in vivo or in vitro. In certain embodiments, a target may be cancer cells found in leukemias or tumors (e.g., tumors of the brain, lung (small cell and non-small cell), ovary, prostate, breast and colon as well as other carcinomas and sarcomas). In still other embodiments, a target may refer to a molecular structure to which a targeting moiety or ligand binds, such as a hapten, epitope, receptor, dsDNA fragment, carbohydrate or enzyme. A target may be a type of tissue, e.g., neuronal tissue, intestinal tissue, pancreatic tissue, liver, kidney, prostate, ovary, lung, bone marrow, or breast tissue. [0396] The “target cells” that may serve as the target for the method or conjugates, are generally animal cells, e.g., mammalian cells. The present method may be used to modify cellular function of living cells in vitro, i.e., in cell culture, or in vivo, in which the cells form part of or otherwise exist in animal tissue. Thus, the target cells may include, for example, the blood, lymph tissue, cells lining the alimentary canal, such as the oral and pharyngeal mucosa, cells forming the villi of the small intestine, cells lining the large intestine, cells lining the respiratory system (nasal passages/lungs) of an animal (which may be contacted by inhalation of the subject invention), dermal/epidermal cells, cells of the vagina and rectum, cells of internal organs including cells of the placenta and the so-called blood/brain barrier, etc. In general, a target cell expresses at least one type of HSP90. In some embodiments, a target cell can be a cell that expresses an HSP90 and is targeted by a conjugate described herein, and is near a cell that is affected by release of the active agent of the conjugate. For example, a blood vessel expressing an HSP90 that is in proximity to a tumor may be the target, while the active agent released at the site will affect the tumor. [0397] The term "therapeutic effect" is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease, disorder or condition in the enhancement of desirable physical or mental development and conditions in an animal, e.g., a human. [0398] The term “modulation” is art-recognized and refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart. The modulation is generally compared to a baseline or reference that can be internal or external to the treated entity. [0399] “Parenteral administration”, as used herein, means administration by any method other than through the digestive tract (enteral) or non-invasive topical routes. For example, parenteral administration may include administration to a patient intravenously, intradermally, intraperitoneally, intrapleurally, intratracheally, intraossiously, intracerebrally, intrathecally, intramuscularly, subcutaneously, subjunctivally, by injection, and by infusion. [0400] “Topical administration”, as used herein, means the non-invasive administration to the skin, orifices, or mucosa. Topical administration can be delivered locally, i.e., the therapeutic can provide a local effect in the region of delivery without systemic exposure or with minimal systemic exposure. Some topical formulations can provide a systemic effect, e.g., via adsorption into the blood stream of the individual. Topical administration can include, but is not limited to, cutaneous and transdermal administration, buccal administration, intranasal administration, intravaginal administration, intravesical administration, ophthalmic administration, and rectal administration. [0401] “Enteral administration”, as used herein, means administration via absorption through the gastrointestinal tract. Enteral administration can include oral and sublingual administration, gastric administration, or rectal administration. [0402] “Pulmonary administration”, as used herein, means administration into the lungs by inhalation or endotracheal administration. As used herein, the term “inhalation” refers to intake of air to the alveoli. The intake of air can occur through the mouth or nose. [0403] The terms “sufficient” and “effective”, as used interchangeably herein, refer to an amount (e.g., mass, volume, dosage, concentration, and/or time period) needed to achieve one or more desired result(s). A “therapeutically effective amount” is at least the minimum concentration required to effect a measurable improvement or prevention of at least one symptom or a particular condition or disorder, to effect a measurable enhancement of life expectancy, or to generally improve patient quality of life. The therapeutically effective amount is thus dependent upon the specific biologically active molecule and the specific condition or disorder to be treated. Therapeutically effective amounts of many active agents, such as antibodies, are known in the art. The therapeutically effective amounts of compounds and compositions described herein, e.g., for treating specific disorders may be determined by techniques that are well within the craft of a skilled artisan, such as a physician. [0404] The terms “bioactive agent” and “active agent”, as used interchangeably herein, include, without limitation, physiologically or pharmacologically active substances that act locally or systemically in the body. A bioactive agent is a substance used for the treatment (e.g., therapeutic agent), prevention (e.g., prophylactic agent), diagnosis (e.g., diagnostic agent), cure or mitigation of disease or illness, a substance which affects the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment. [0405] The term "prodrug" refers to an agent, including a small organic molecule, peptide, nucleic acid or protein, that is converted into a biologically active form in vitro and/or in vivo. Prodrugs can be useful because, in some situations, they may be easier to administer than the parent compound (the active compound). For example, a prodrug may be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. A prodrug may also be less toxic than the parent. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Harper, N.J. (1962) Drug Latentiation in Jucker, ed. Progress in Drug Research, 4:221-294; Morozowich et al. (1977) Application of Physical Organic Principles to Prodrug Design in E. B. Roche ed. Design of Biopharmaceutical Properties through Prodrugs and Analogs, APhA; Acad. Pharm. Sci.; E. B. Roche, ed. (1977) Bioreversible Carriers in Drug in Drug Design, Theory and Application, APhA; H. Bundgaard, ed. (1985) Design of Prodrugs, Elsevier; Wang et al. (1999) Prodrug approaches to the improved delivery of peptide drug, Curr. Pharm. Design.5(4):265-287; Pauletti et al. (1997) Improvement in peptide bioavailability: Peptidomimetics and Prodrug Strategies, Adv. Drug. Delivery Rev.27:235-256; Mizen et al. (1998). The Use of Esters as Prodrugs for Oral Delivery of β-Lactam antibiotics, Pharm. Biotech.11:345-365; Gaignault et al. (1996) Designing Prodrugs and Bioprecursors I. Carrier Prodrugs, Pract. Med. Chem.671-696; M. Asgharnejad (2000). Improving Oral Drug Transport Via Prodrugs, in G. L. Amidon, P. I. Lee and E. M. Topp, Eds., Transport Processes in Pharmaceutical Systems, Marcell Dekker, p.185-218; Balant et al. (1990) Prodrugs for the improvement of drug absorption via different routes of administration, Eur. J. Drug Metab. Pharmacokinet., 15(2): 143-53; Balimane and Sinko (1999). Involvement of multiple transporters in the oral absorption of nucleoside analogues, Adv. Drug Delivery Rev., 39(1-3):183-209; Browne (1997). Fosphenytoin (Cerebyx), Clin. Neuropharmacol.20(1): 1-12; Bundgaard (1979). Bioreversible derivatization of drugs--principle and applicability to improve the therapeutic effects of drugs, Arch. Pharm. Chemi.86(1): 1-39; H. Bundgaard, ed. (1985) Design of Prodrugs, New York: Elsevier; Fleisher et al. (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs, Adv. Drug Delivery Rev.19(2): 115-130; Fleisher et al. (1985) Design of prodrugs for improved gastrointestinal absorption by intestinal enzyme targeting, Methods Enzymol.112: 360-81; Farquhar D, et al. (1983) Biologically Reversible Phosphate-Protective Groups, J. Pharm. Sci., 72(3): 324-325; Han, H.K. et al. (2000) Targeted prodrug design to optimize drug delivery, AAPS PharmSci., 2(1): E6; Sadzuka Y. (2000) Effective prodrug liposome and conversion to active metabolite, Curr. Drug Metab., 1(1):31-48; D.M. Lambert (2000) Rationale and applications of lipids as prodrug carriers, Eur. J. Pharm. Sci., 11 Suppl.2:S15-27; Wang, W. et al. (1999) Prodrug approaches to the improved delivery of peptide drugs. Curr. Pharm. Des., 5(4):265-87. [0406] The term “biocompatible”, as used herein, refers to a material that along with any metabolites or degradation products thereof that are generally non-toxic to the recipient and do not cause any significant adverse effects to the recipient. Generally speaking, biocompatible materials are materials which do not elicit a significant inflammatory or immune response when administered to a patient. [0407] The term “biodegradable” as used herein, generally refers to a material that will degrade or erode under physiologic conditions to smaller units or chemical species that are capable of being metabolized, eliminated, or excreted by the subject. The degradation time is a function of composition and morphology. Degradation times can be from hours to weeks. [0408] The term “pharmaceutically acceptable”, as used herein, refers to compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio, in accordance with the guidelines of agencies such as the U.S. Food and Drug Administration. A “pharmaceutically acceptable carrier”, as used herein, refers to all components of a pharmaceutical formulation that facilitate the delivery of the composition in vivo. Pharmaceutically acceptable carriers include, but are not limited to, diluents, preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof. [0409] The term “molecular weight”, as used herein, generally refers to the mass or average mass of a material. If a polymer or oligomer, the molecular weight can refer to the relative average chain length or relative chain mass of the bulk polymer. In practice, the molecular weight of polymers and oligomers can be estimated or characterized in various ways including gel permeation chromatography (GPC) or capillary viscometry. GPC molecular weights are reported as the weight-average molecular weight (Mw) as opposed to the number-average molecular weight (Mn). Capillary viscometry provides estimates of molecular weight as the inherent viscosity determined from a dilute polymer solution using a particular set of concentration, temperature, and solvent conditions. [0410] The term “small molecule”, as used herein, generally refers to an organic molecule that is less than 2000 g/mol in molecular weight, less than 1500 g/mol, less than 1000 g/mol, less than 800 g/mol, or less than 500 g/mol. Small molecules are non-polymeric and/or non-oligomeric. [0411] The term “hydrophilic”, as used herein, refers to substances that have strongly polar groups that readily interact with water. [0412] The term “hydrophobic”, as used herein, refers to substances that lack an affinity for water; tending to repel and not absorb water as well as not dissolve in or mix with water. [0413] The term “lipophilic”, as used herein, refers to compounds having an affinity for lipids. [0414] The term “amphiphilic”, as used herein, refers to a molecule combining hydrophilic and lipophilic (hydrophobic) properties. “Amphiphilic material” as used herein refers to a material containing a hydrophobic or more hydrophobic oligomer or polymer (e.g., biodegradable oligomer or polymer) and a hydrophilic or more hydrophilic oligomer or polymer. [0415] The term "targeting moiety", as used herein, refers to a moiety that binds to or localizes to a specific locale. The moiety may be, for example, a protein, nucleic acid, nucleic acid analog, carbohydrate, or small molecule. The locale may be a tissue, a particular cell type, or a subcellular compartment. In some embodiments, a targeting moiety can specifically bind to a selected molecule. [0416] The term “reactive coupling group”, as used herein, refers to any chemical functional group capable of reacting with a second functional group to form a covalent bond. The selection of reactive coupling groups is within the ability of those in the art. Examples of reactive coupling groups can include primary amines (-NH₂) and amine-reactive linking groups such as isothiocyanates, isocyanates, acyl azides, NHS esters, sulfonyl chlorides, aldehydes, glyoxals, epoxides, oxiranes, carbonates, aryl halides, imidoesters, carbodiimides, anhydrides, and fluorophenyl esters. Most of these conjugate to amines by either acylation or alkylation. Examples of reactive coupling groups can include aldehydes (-COH) and aldehyde reactive linking groups such as hydrazides, alkoxyamines, and primary amines. Examples of reactive coupling groups can include thiol groups (-SH) and sulfhydryl reactive groups such as maleimides, haloacetyls, and pyridyl disulfides. Examples of reactive coupling groups can include photoreactive coupling groups such as aryl azides or diazirines. The coupling reaction may include the use of a catalyst, heat, pH buffers, light, or a combination thereof. [0417] The term “protective group”, as used herein, refers to a functional group that can be added to and/or substituted for another desired functional group to protect the desired functional group from certain reaction conditions and selectively removed and/or replaced to deprotect or expose the desired functional group. Protective groups are known to the skilled artisan. Suitable protective groups may include those described in Greene and Wuts, Protective Groups in Organic Synthesis, (1991). Acid sensitive protective groups include dimethoxytrityl (DMT), tert- butylcarbamate (tBoc) and trifluoroacetyl (tFA). Base sensitive protective groups include 9- fluorenylmethoxycarbonyl (Fmoc), isobutyrl (iBu), benzoyl (Bz) and phenoxyacetyl (pac). Other protective groups include acetamidomethyl, acetyl, tert- amyloxycarbonyl, benzyl, benzyloxycarbonyl, 2-(4-biphεnylyl)-2-propy!oxycarbonyl, 2- bromobenzyloxycarbonyl, tert-butyl₇ tert-butyloxycarbonyl, l-carbobenzoxamido- 2,2.2- trifluoroethyl, 2,6-dichlorobenzyl, 2-(3,5-dimethoxyphenyl)-2- propyloxycarbonyl, 2,4- dinitrophenyl, dithiasuccinyl, formyl, 4- methoxybenzenesulfonyl, 4-methoxybenzyl, 4- methylbenzyl, o-nitrophenylsulfenyl, 2-phenyl-2-propyloxycarbonyl, α-2,4,5- tetramethylbenzyloxycarbonyl, p- toluenesulfonyl, xanthenyl, benzyl ester, N- hydroxysuccinimide ester, p-nitrobenzyl ester, p-nitrophenyl ester, phenyl ester, p- nitrocarbonate, p-nitrobenzylcarbonate, trimethylsilyl and pentachlorophenyl ester. [0418] The term “activated ester”, as used herein, refers to alkyl esters of carboxylic acids where the alkyl is a good leaving group rendering the carbonyl susceptible to nucleophilic attack by molecules bearing amino groups. Activated esters are therefore susceptible to aminolysis and react with amines to form amides. Activated esters contain a carboxylic acid ester group -CO₂R where R is the leaving group. [0419] The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. [0420] In some embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), 20 or fewer, 12 or fewer, or 7 or fewer. Likewise, in some embodiments cycloalkyls have from 3-10 carbon atoms in their ring structure, e.g., have 5, 6 or 7 carbons in the ring structure. The term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, a hosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. [0421] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, or from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. In some embodiments, alkyl groups are lower alkyls. In some embodiments, a substituent designated herein as alkyl is a lower alkyl. [0422] It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Cycloalkyls can be substituted in the same manner. [0423] The term “heteroalkyl”, as used herein, refers to straight or branched chain, or cyclic carbon-containing radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, Se, B, and S, wherein the phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups. [0424] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In some embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, and -S-alkynyl. Representative alkylthio groups include methylthio, and ethylthio. The term “alkylthio” also encompasses cycloalkyl groups, alkene and cycloalkene groups, and alkyne groups. “Arylthio” refers to aryl or heteroaryl groups. Alkylthio groups can be substituted as defined above for alkyl groups. [0425] The terms "alkenyl" and "alkynyl", refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. [0426] The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, and tert-butoxy. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl. Aroxy can be represented by –O-aryl or O-heteroaryl, wherein aryl and heteroaryl are as defined below. The alkoxy and aroxy groups can be substituted as described above for alkyl. [0427] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:

wherein R₉, R₁₀, and R'₁₀ each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R8 or R9 and R10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In some embodiments, only one of R₉ or R₁₀ can be a carbonyl, e.g., R9, R10 and the nitrogen together do not form an imide. In still other embodiments, the term “amine” does not encompass amides, e.g., wherein one of R₉ and R₁₀ represents a carbonyl. In additional embodiments, R₉ and R₁₀ (and optionally R’10) each independently represent a hydrogen, an alkyl or cycloalkly, an alkenyl or cycloalkenyl, or alkynyl. Thus, the term "alkylamine" as used herein means an amine group, as defined above, having a substituted (as described above for alkyl) or unsubstituted alkyl attached thereto, i.e., at least one of R9 and R10 is an alkyl group. [0428] The term "amido" is art-recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:

wherein R9 and R10 are as defined above. [0429] “Aryl”, as used herein, refers to C₅-C₁₀-membered aromatic, heterocyclic, fused aromatic, fused heterocyclic, biaromatic, or bihetereocyclic ring systems. Broadly defined, “aryl”, as used herein, includes 5-, 6-, 7-, 8-, 9-, and 10-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles” or “heteroaromatics”. The aromatic ring can be substituted at one or more ring positions with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino (or quaternized amino), nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN; and combinations thereof. [0430] The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e., “fused rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles. Examples of heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or more of the rings can be substituted as defined above for “aryl”. [0431] The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). [0432] The term "carbocycle", as used herein, refers to an aromatic or non- aromatic ring in which each atom of the ring is carbon. [0433] “Heterocycle” or “heterocyclic”, as used herein, refers to a cyclic radical attached via a ring carbon or nitrogen of a monocyclic or bicyclic ring containing 3-10 ring atoms, for example, from 5-6 ring atoms, consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, (C1-C10) alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents. Examples of heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxepanyl, oxetanyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. Heterocyclic groups can optionally be substituted with one or more substituents at one or more positions as defined above for alkyl and aryl, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, and -CN. [0434] The term "carbonyl" is art-recognized and includes such moieties as can be represented by the general formula:

wherein X is a bond or represents an oxygen or a sulfur, and R₁₁ represents a hydrogen, an alkyl, a cycloalkyl, an alkenyl, a cycloalkenyl, or an alkynyl, R'11 represents a hydrogen, an alkyl, a cycloalkyl, an alkenyl, a cycloalkenyl, or an alkynyl. Where X is an oxygen and R₁₁ or R’₁₁ is not hydrogen, the formula represents an "ester". Where X is an oxygen and R₁₁ is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R11 is a hydrogen, the formula represents a "carboxylic acid". Where X is an oxygen and R'₁₁ is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. Where X is a sulfur and R11 or R'11 is not hydrogen, the formula represents a "thioester." Where X is a sulfur and R₁₁ is hydrogen, the formula represents a "thiocarboxylic acid." Where X is a sulfur and R’11 is hydrogen, the formula represents a "thioformate." On the other hand, where X is a bond, and R11 is not hydrogen, the above formula represents a "ketone" group. Where X is a bond, and R₁₁ is hydrogen, the above formula represents an "aldehyde" group. [0435] The term “monoester” as used herein refers to an analog of a dicarboxylic acid wherein one of the carboxylic acids is functionalized as an ester and the other carboxylic acid is a free carboxylic acid or salt of a carboxylic acid. Examples of monoesters include, but are not limited to, to monoesters of succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, oxalic and maleic acid. [0436] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Examples of heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium. Other useful heteroatoms include silicon and arsenic. [0437] As used herein, the term "nitro" means -NO2; the term "halogen" designates -F, -Cl, -Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -SO₂-. [0438] The term “substituted” as used herein, refers to all permissible substituents of the compounds described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, for example, 1-14 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats. Representative substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C3-C20 cyclic, substituted C3-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups. [0439] 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. It is understood that “substitution” or “substituted” 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, i.e., a compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, or elimination. [0440] In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein. The permissible substituents can be one or more and the same or different for appropriate organic compounds. The heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. [0441] In various embodiments, the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, each of which optionally is substituted with one or more suitable substituents. In some embodiments, the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, wherein each of the alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone can be further substituted with one or more suitable substituents. [0442] Examples of substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, thioketone, ester, heterocyclyl, – CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, alkylthio, oxo, acylalkyl, carboxy esters, carboxamido, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl, carboxamidoalkylaryl, carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy, aminocarboxamidoalkyl, cyano, alkoxyalkyl, perhaloalkyl, arylalkyloxyalkyl, and the like. In some embodiments, the substituent is selected from cyano, halogen, hydroxyl, and nitro. [0443] The term “copolymer” as used herein, generally refers to a single polymeric material that is comprised of two or more different monomers. The copolymer can be of any form, for example, random, block, or graft. The copolymers can have any end- group, including capped or acid end groups. [0444] The terms "polypeptide," "peptide" and "protein" generally refer to a polymer of amino acid residues. As used herein, the term also applies to amino acid polymers in which one or more amino acids are chemical analogs or modified derivatives of corresponding naturally-occurring amino acids or are unnatural amino acids. The term "protein", as generally used herein, refers to a polymer of amino acids linked to each other by peptide bonds to form a polypeptide for which the chain length is sufficient to produce tertiary and/or quaternary structure. The term “protein” excludes small peptides by definition, the small peptides lacking the requisite higher- order structure necessary to be considered a protein. [0445] The terms "nucleic acid," "polynucleotide," and "oligonucleotide" are used interchangeably to refer to a deoxyribonucleotide or ribonucleotide polymer, in linear or circular conformation, and in either single- or double-stranded form. These terms are not to be construed as limiting with respect to the length of a polymer. The terms can encompass known analogs of natural nucleotides, as well as nucleotides that are modified in the base, sugar and/or phosphate moieties (e.g., phosphorothioate backbones). In general and unless otherwise specified, an analog of a particular nucleotide has the same base-pairing specificity; i.e., an analog of A will base-pair with T. The term “nucleic acid” is a term of art that refers to a string of at least two base-sugar-phosphate monomeric units. Nucleotides are the monomeric units of nucleic acid polymers. The term includes deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in the form of a messenger RNA, antisense, plasmid DNA, parts of a plasmid DNA or genetic material derived from a virus. An antisense nucleic acid is a polynucleotide that interferes with the expression of a DNA and/or RNA sequence. The term nucleic acids refer to a string of at least two base-sugar-phosphate combinations. Natural nucleic acids have a phosphate backbone. Artificial nucleic acids may contain other types of backbones, but contain the same bases as natural nucleic acids. The term also includes PNAs (peptide nucleic acids), phosphorothioates, and other variants of the phosphate backbone of native nucleic acids. [0446] A "functional fragment" of a protein, polypeptide or nucleic acid is a protein, polypeptide or nucleic acid whose sequence is not identical to the full-length protein, polypeptide or nucleic acid, yet retains at least one function as the full-length protein, polypeptide or nucleic acid. A functional fragment can possess more, fewer, or the same number of residues as the corresponding native molecule, and/or can contain one or more amino acid or nucleotide substitutions. Methods for determining the function of a nucleic acid (e.g., coding function, ability to hybridize to another nucleic acid) are well-known in the art. Similarly, methods for determining protein function are well-known. For example, the DNA binding function of a polypeptide can be determined, for example, by filter-binding, electrophoretic mobility shift, or immunoprecipitation assays. DNA cleavage can be assayed by gel electrophoresis. The ability of a protein to interact with another protein can be determined, for example, by co-immunoprecipitation, two-hybrid assays or complementation, e.g., genetic or biochemical. See, for example, Fields et al. (1989) Nature 340:245-246; U.S. Patent No.5,585,245 and PCT WO 98/44350. [0447] As used herein, the term “linker” refers to a carbon chain that can contain heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.) and which may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 atoms long. Linkers may be substituted with various substituents including, but not limited to, hydrogen atoms, alkyl, alkenyl, alkynl, amino, alkylamino, dialkylamino, trialkylamino, hydroxyl, alkoxy, halogen, aryl, heterocyclic, aromatic heterocyclic, cyano, amide, carbamoyl, carboxylic acid, ester, thioether, alkylthioether, thiol, and ureido groups. Those of skill in the art will recognize that each of these groups may in turn be substituted. Examples of linkers include, but are not limited to, pH-sensitive linkers, protease cleavable peptide linkers, nuclease sensitive nucleic acid linkers, lipase sensitive lipid linkers, glycosidase sensitive carbohydrate linkers, hypoxia sensitive linkers, photo-cleavable linkers, heat-labile linkers, enzyme cleavable linkers (e.g., esterase cleavable linker), ultrasound-sensitive linkers, and x-ray cleavable linkers. [0448] The term “pharmaceutically acceptable counter ion” refers to a pharmaceutically acceptable anion or cation. In various embodiments, the pharmaceutically acceptable counter ion is a pharmaceutically acceptable ion. For example, the pharmaceutically acceptable counter ion is selected from citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)). In some embodiments, the pharmaceutically acceptable counter ion is selected from chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, citrate, malate, acetate, oxalate, acetate, and lactate. In particular embodiments, the pharmaceutically acceptable counter ion is selected from chloride, bromide, iodide, nitrate, sulfate, bisulfate, and phosphate. [0449] The term “pharmaceutically acceptable salt(s)” refers to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. [0450] If the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts. [0451] A pharmaceutically acceptable salt can be derived from an acid selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, trifluoroacetic, and undecylenic acid. [0452] The term “bioavailable” is art-recognized and refers to a form of the subject invention that allows for it, or a portion of the amount administered, to be absorbed by, incorporated to, or otherwise physiologically available to a subject or patient to whom it is administered. [0453] It will be appreciated that the following examples are intended to illustrate but not to limit the present invention. Various other examples and modifications of the foregoing description and examples will be apparent to a person skilled in the art after reading the disclosure without departing from the spirit and scope of the invention, and it is intended that all such examples or modifications be included within the scope of the appended claims. All publications and patents referenced herein are hereby incorporated by reference in their entirety. [0454] It will be appreciated that in the following examples, some conjugates were prepared and characterized using non-radioactive metals such as Lu-175. It will be apparent to a person skilled in that art that the corresponding radioactive Lu-177 analogs can be readily prepared using known methods and that the distribution data for the Lu-175 conjugates may be representative of the Lu-177 analogs. EXAMPLES EXAMPLE 1: Synthesis of the Conjugates [0455] The conjugates of the invention may be prepared using any convenient methodology. In a rational approach, the conjugates are constructed from their individual components, targeting moiety, in some cases a linker, and active agent moiety. The components can be covalently bonded to one another through functional groups, as is known in the art, where such functional groups may be present on the components or introduced onto the components using one or more steps, e.g., oxidation reactions, reduction reactions, cleavage reactions and the like. Functional groups that may be used in covalently bonding the components together to produce the pharmaceutical conjugate include: hydroxy, sulfhydryl, amino, and the like. The particular portion of the different components that are modified to provide for covalent linkage will be chosen so as not to substantially adversely interfere with that components desired binding activity, e.g., for the active agent moiety, a region that does not affect the target binding activity will be modified, such that a sufficient amount of the desired drug activity is preserved. Where necessary and/or desired, certain moieties on the components may be protected using blocking groups, as is known in the art, see, e.g., Green & Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons) (1991). [0456] Alternatively, the conjugate can be produced using known combinatorial methods to produce large libraries of potential conjugates which may then be screened for identification of a bifunctional, molecule with the pharmacokinetic profile. Alternatively, the conjugates may be produced using medicinal chemistry and known structure-activity relationships for the targeting moiety and the active agent moiety. In particular, this approach will provide insight as to where to join the two moieties to the linker. EXAMPLE 2: Biodistribution studies [0457] In some embodiments, Compound 100 comprises Lutetium, wherein Lutetium is attached to DOTA. Lutetium accumulation is measured in tumor, plasma and healthy tissues of NCI-H460 tumor-bearing mice (lung cancer). NCI-H460 tumor bearing mice are dosed with 0.5 mg/kg of Compound 100 with Lutetium. At the time points indicated, mice are sacrificed and tumor, liver, kidneys and plasma are taken. All tissues are analyzed for lutetium content by ICP-MS, and lutetium uptake in %ID/g determined by the following equation: %ID/g = ((tissue lutetium in ppb) / 175) * (molecular weight of conjugate))/(0.5 * (mouse weight in grams) * 10) [0458] Biodistribution at 24 h and 72 h, Tumor/Kidney ratio (T/K), Tumor/Liver ratio (T/L), and Tumor/Plasma ratio (T/P) are calculated. EXAMPLE 3: In vitro HSP90 Binding Studies Using the Conjugates [0459] HSP90 binding is determined by a competitive fluorescence polarization assay with purified N-terminal HSP90 ^. A series of dilutions of the test compounds are prepared with 10% DMSO in assay buffer and 10µl of the dilution is added to a 100µl reaction so that the final concentration of DMSO is 1% in all reactions. The reactions are conducted at room temperature for 3 hours in a 100µl mixture containing assay buffer, 5nM FITC Labeled Geldanamycin, 350 ng of N-terminal HSP90 ^, and the test compound. Fluorescence intensity is measured at an excitation of 485 nm and an emission of 530 nm using a Tecan Infinite M1000 microplate reader. Fluorescence intensity is converted to fluorescence polarization using the Tecan Magellan6 software. The fluorescence polarization data are analyzed using the computer software, Graphpad Prism. The fluorescence polarization (FPt) in absence of the compound in each data set is defined as 100% activity. In the absence of protein and the compound, the value of fluorescent polarization (FPb) in each data set is defined as 0% activity. The percent activity in the presence of the compound is calculated according to the following equation: % activity = (FP-FPb)/(FPt-FPb)×100%, where FP= the fluorescence polarization in the presence of the compound. EXAMPLE 4: Determining the Permeability of Conjugates [0460] In order to test the ability of the conjugates to enter cells, an artificial membrane permeability assay (“PAMPA”) is used. PAMPAs are useful tool for predicting in vivo drug permeability for drugs that enter cells by passive transport mechanisms. LC/MS is used in conjunction with PAMPA assays to determine the ability of the conjugates to permeate cells. [0461] Pre-coated PAMPA plates are warmed to room temperature for at least 30 minutes prior to adding assay components. [0462] Stock solutions are prepared with the conjugates to be tested. In order to make a working solution, either 50 µL of 100 µM Stock in DMSO + 950 µL of PBS or 50 µL of 200 µM stock is added to 96 deep well plate, resulting in a 5 µM final concentration or a 10 µM final concentration, respectively. 300µL of the working solution containing each conjugate to be tested is added to the appropriate well of a donor PAMPA plate. 200 µL of PBS is added into the corresponding wells of an acceptor PAMPA plates. [0463] The acceptor plate is lowered onto the donor plate and allowed to incubate for five hours. After five hours, a 50 µL aliquot is removed from each well of each plate and added into a new 96 deep-well plate. [0464] 100 µL of methanol containing a predetermined internal standard control compound is added to each aliquot and analyzed by LC/MS. The permeability of each conjugate is calculated.

Claims

CLAIMS We claim: 1. A conjugate comprising at least one active agent, at least one targeting moiety (TM), at least one chelator, wherein the chelator is covalently attached to the TM via a spacer, wherein the active agent is covalently attached to the chelator or the TM via a linker, and wherein the TM binds to HSP90.

2. The conjugate of claim 1, wherein the conjugate has a structure of Formula A:

3. The conjugate of any one of claims 1-2, wherein the TM is a small molecule, a peptide, an antibody, an antibody mimetic, an aptamer, a glycoprotein, a carbohydrate, or a lipid.

4. The conjugate of claim 3, wherein the TM is a small molecule.

5. The conjugate of any one of claims 1-2, wherein the TM is Ganetespib, Luminespib, Debio-0932, MPC-3100, Onalespib, SNX-2112, 17-amino- geldanamycin hydroquinone, PU-H71, AT13387, or an analog/derivative/fragment thereof.

6. The conjugate of any one of claims 1-2, wherein the TM is TM1, TM2, TM3, TM4, TM5, TM8, TM9, TM10, TM11, TM12, TM13, TM14, TM6, TM7, or TM15.

7. The conjugate of any one of claims 1-6, wherein the active agent is a small molecule, a protein, a peptide, a lipid, or a carbohydrate.

8. The conjugate of any one of claims 1-6, wherein the active agent is a small molecule therapeutic agent.

9. The conjugate of any one of claims 1-6, wherein the active agent comprises a PI3K inhibitor, or an analog/derivative/fragment thereof. 10. The conjugate of any one of claims 1-9, wherein the chelator is 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), DO3A, diethylenetriamine- N,N,N',N'',N''-pentaacetic acid (DTPA), 2-(p-SCN-Bz)-6-methyl-DTPA, CHX-A''- DTPA, CA-DTPA, 1,4,7-triazacyclononane-1,4-7-triacetic acid (NOTA), 6- hydrazinonicotinamide (HYNIC), ethylenediamine tetraacetic acid (EDTA), N,N′- ethylene-di-L-cysteine, N,N′-bis(2,2-dimethyl-2-mercaptoethyl)ethylenediamine-N,N′- diacetic acid (6SS), 1-(4-carboxymethoxybenzyl)-N-N'-bis[(2-mercapto-2,2- dimethyl)ethyl]-1,2-ethylenediamine-N,N'-diacetic acid (B6SS), Deferoxamine (DFO); 1,1,1-tris(aminomethyl)ethane (TAME), tris(aminomethyl)ethane- N,N,N’,N’,N’’,N’’-hexaacetic acid (TAME Hex), O-hydroxybenzyl iminodiacetic acid; 1,4,7-triazacyclononane (TACN), 1,4,7,10-tretraazacyclododecane (cyclen), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy- 3-carboxypropyl)-4,7-bis-(carboxymethyl)-1,4,7-triazacyclononane (NODAGA), 1,4,7-tris(2-mercaptoethyl)-1,4,7-triazacylclonane (triazacyclononane−TM), 1,4,7- triazacyclononane-N,N′,N′′-tris(methylenephosphonic)acid (NOTP), 1, 4, 8, 11- tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA), 1,4,7,10,13- pentaazacyclopentadecane-N,N′,N″,N''',N″″-pentaacetic acid (PEPA), 1,4,7,10,13,16- hexaazacyclohexadecane-N,N',N'',N''',N'''',N'''''-hexaacetic acid (HEHA), 1,4,7,10- tetrakis(carbamoylmethyl)-1,4,7,

10-tetraazacyclododecane (TCMC), or a derivative or analog thereof.

11. The conjugate of any one of claims 1-9, wherein the chelator is DOTA or DOTAGA.

12. The conjugate of any one of claims 1-11, wherein the linker is a cleavable linker.

13. The conjugate of claim 12, wherein the linker is a small molecule.

14. The conjugate of claim 13, wherein the linker comprises an ester bond, disulfide, amide, acylhydrazone, ether, carbamate, carbonate, or urea.

15. The conjugate of any one of claims 1-14, wherein the spacer comprises at least one amino acid or analog thereof.

16. The conjugate of claim 15, wherein the spacer comprises 2 amino acids or analogs thereof, 3 amino acids or analogs thereof, 4 amino acids or analogs thereof, or 5 amino acids or analogs thereof.

17. The conjugate of any one of claims 1-14, wherein the spacer between the chelator and the TM comprises polyethylene glycol (PEG).

18. The conjugate of claim 17, wherein the spacer comprises (PEG)4 or (PEG)12.

19. The conjugate of any one of claims 1-18, wherein the molecule weight of the conjugate is less than 5000 Da, less than 4000 Da, less than 3000 Da, or less than 2000 Da.

20. The conjugate of any one of claims 1-19, wherein the conjugate further comprises at least one pharmacokinetic modulating unit (PMU).

21. The conjugate of claim 20, wherein the PMU binds to albumin.

22. The conjugate of claim 21, wherein the PMU comprises

.

23. The conjugate of claim 1, wherein the conjugate is Compound 100 or a pharmaceutically acceptable salt thereof.

24. The conjugate of any one of claims 1-23, wherein the chelator binds to a radionuclide.

25. The conjugate of claim 24, wherein the radionuclide is Y-90, Y-86, I-131, Re- 186, Re-188, Y-90, Bi-212, At-211, Zr-89, Sr-89, Ho-166, Sm-153, Cu-67, Cu-64, Lu-177, Ac-225, Pb-203, Bi-213, Th-227, Pb-212, Ra-223, P-32, Sc-47, Br-77, Rh- 105, Pd-103, Ag-111, Pr-142, Pm-149, Gd-159, Ir-194, or Pt-199.

26. A pharmaceutical composition comprising the conjugate of any one of claims 1-25 and at least one pharmaceutically acceptable excipient.

27. A method of reducing cell proliferation comprising administering a therapeutically effective amount of the conjugate of any one of claims 1-25 to the cell.

28. The method of claim 27, wherein the cell is a cancer cell.

29. The method of claim 28, wherein the cancer cell is a small-cell lung cancer cell, a non-small-cell lung cancer cell, a sarcoma cell, a pancreatic cancer cell, a breast cancer cell, or a colon cancer cell.

30. A method of treating cancer, comprising administering the pharmaceutical composition of claim 26.

31. The method of claim 30, wherein the cancer is small-cell lung cancer, non- small-cell lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer.