Compositions and methods for targeting tumor-associated macrophages

Abstract

The present disclosure relates to compositions that target tumor-associated macrophages. The compositions disclosed herein preferably comprise a glucan backbone, a tumor-associated macrophage targeting moiety, a targeting moiety linker, a payload, and optionally a payload linker. The present disclosure also provides methods for making such compositions. The present disclosure also provides treatment methods using such compositions.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from U.S. Provisional Patent Application No. 63 / 447,626, entitled "COMPOSITIONS AND METHODS FOR TARGETING TUMOR-ASSOCIATED MACROPHAGES," filed February 22, 2023, the contents of which are incorporated by reference in their entirety. [Background technology]

[0002] Soft tissue sarcoma (STS) is a rare but deadly cancer in children and adults. According to estimates by the American Cancer Society, there are approximately 13,000 new cases of STS annually in the United States, with approximately 5,130 expected deaths and a 5-year survival rate of only 16% for metastatic disease. Traditional treatments, including surgery, chemotherapy, and radiation therapy, have limited success in treating STS. For example, in undifferentiated pleomorphic sarcoma (UPS), a highly aggressive adult sarcoma, the median overall survival for metastatic UPS is only 15.5 months. In Ewing's sarcoma / primitive neuroectodermal tumor (PNET), an aggressive sarcoma associated with adolescents, the 5-year survival rate for metastatic cases is 15%. Treatment of solid tumors has improved in recent years with the advent of a wide range of targeted therapies, including small molecules and biologics. While small molecules have excellent solid tumor penetration, many of them act by inhibiting signaling pathways, resulting in growth inhibition, rather than direct tumor cytotoxicity. Unless the entire tumor is killed, cancer cells may develop resistance to small molecules. Biologics such as antibodies and antibody-drug conjugates (ADCs) can have significant efficacy against certain malignancies and have favorable blood stability. However, antibodies have limited penetration into solid tumors, and tumor cells can develop resistance to ADCs through various cellular alterations (Collins et al., "Acquired Resistance to Antibody-Drug Conjugates," Cancers (Basel), 2019, 11(3):394). Therefore, new approaches are needed to overcome the limitations of the current state of the art and further improve the outcomes of STS treatment. Furthermore, STS includes more than 50 different histological and molecular subtypes, each of which exhibits diverse clinical behaviors (Katz et al., "More Than 50 Subtypes of Soft Tissue Sarcoma: Paving the Path for Histology-Driven Treatments" Am Soc Clin Oncol Educ Book, 2018, 38, 925-938).Due in part to this diversity, current STS treatment options are limited in efficacy, with no single agent or combination treatment consistently effective in treating all STS subtypes.

[0003] CD206 + Cells, particularly macrophages, have been targeted with a variety of molecules with the aim of delivering diagnostic and therapeutic agents to sites where such cells congregate. One example of such a molecule can be found in US2017 / 0209584, entitled "Compositions for Targeting Macrophages and Other CD206 High Expressing Cells and Methods of Treating and Diagnosis." The molecules disclosed in this reference and others target the CD206 of interest. + Although capable of targeting cells, these molecules have a number of drawbacks. Summary of the Invention

[0004] In one aspect, a composition is provided comprising: i) a tumor-associated macrophage targeting moiety; ii) a glucan backbone, the glucan backbone comprising a plurality of backbone monomers; iii) an active ingredient comprising a pyrrolobenzodiazepine (PBD) dimer, the active ingredient attached to the glucan backbone; and iv) a targeting linker connecting the targeting moiety to the glucan backbone, the targeting linker comprising a carbamate group and a chain moiety, the carbamate group being connected to the backbone monomer and the chain moiety connecting the carbamate group to the tumor-associated macrophage targeting moiety.

[0005] Also provided is a method of delivering an agent to tumor-associated macrophages, comprising contacting the macrophages with a composition described herein.

[0006] Also provided are methods of treating cancer, a granulomatous disease, or a non-malignant tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition described herein. [Brief explanation of the drawings]

[0007] [Figure 1] This is a morphological image of mouse M1 cells. [Figure 2] This is a morphological image of mouse M2 cells. [Figure 3] 1 is a graph showing the results of viability of mouse M1, M2, and 3T3 cells after treatment with the compound of formula (A-1). [Figure 4] 1 is a graph showing the results of viability of mouse M1, M2, and 3T3 cells after treatment with the compound of formula (A-1). [Figure 5] 1 is a graph showing the results of viability of mouse M1, M2, and 3T3 cells after treatment with the compound of formula (A-2). [Figure 6] 1 is a graph showing the results of viability of mouse M1, M2, and 3T3 cells after treatment with the compound of formula (A-2). [Figure 7] A and B are graphs showing the weight loss of mice administered increasing concentrations of formula (A-1). [Figure 8] 1 is a graph showing food intake of mice administered increasing concentrations of formula (A-1). [Figure 9-1] 1 is a graph showing hematological parameters of blood among groups of mice administered increasing concentrations of Formula (A-1). [Figure 9-2] 1 is a graph showing hematological parameters of blood among groups of mice administered increasing concentrations of Formula (A-1). [Figure 10-1] 1 is a graph showing differences in serum components between mouse groups administered increasing concentrations of Formula (A-1). [Figure 10-2] 1 is a graph showing differences in serum components between mouse groups administered increasing concentrations of Formula (A-1). [Figure 10-3] 1 is a graph showing differences in serum components between mouse groups administered increasing concentrations of Formula (A-1). [Figure 10-4] 1 is a graph showing differences in serum components between mouse groups administered increasing concentrations of Formula (A-1). [Figure 11] 1 shows the reduction in tumor burden in mice administered with formula (A-1) in a PDX myxofibrosarcoma model. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present disclosure relates to compositions that target tumor-associated macrophages. The compositions disclosed herein include a glucan backbone, a tumor-associated macrophage targeting moiety, a targeting moiety linker, a payload, and an optional payload linker. The present disclosure also provides methods of making and using such compositions.

[0009] chemical definition As used herein, unless otherwise specified, "alkyl" refers to an alkyl group having a specified number of carbon atoms (i.e., C-C 10 "C" refers to a monovalent saturated hydrocarbon chain, which may be linear (i.e., unbranched) or branched, or a combination thereof, having from 1 to 20 carbon atoms ("C-C" means 1 to 10 carbon atoms). Particular alkyl groups are those having from 1 to 20 carbon atoms ("C-C" means 1 to 20 carbon atoms). 20 alkyl"), those having 1 to 10 carbon atoms ("C1-C 10 alkyl"), those with 6 to 10 carbon atoms ("C6-C 10 alkyl"), those having 1 to 6 carbon atoms ("C1-C6 alkyl"), those having 2 to 6 carbon atoms ("C2-C6 alkyl"), or those having 1 to 4 carbon atoms ("C1-C4 alkyl"). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0010] As used herein, "alkylene" refers to the same residue as alkyl, but with divalency. Particular alkylene groups are those having 1 to 20 carbon atoms ("C-C 20 alkylene), those having 1 to 10 carbon atoms ("C1-C 10 alkylene), those with 6 to 10 carbon atoms ("C6-C 10 alkylene"), those having 1 to 6 carbon atoms ("C1-C6 alkylene"), those having 1 to 5 carbon atoms ("C1-C5 alkylene"), those having 1 to 4 carbon atoms ("C1-C4 alkylene"), or those having 1 to 3 carbon atoms ("C1-C3 alkylene"). Examples of alkylene include, but are not limited to, groups such as methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), isopropylene (-CHCH(CH)-), butylene (-CH(CH)CH-), isobutylene (-CHCH(CH)CH-), pentylene (-CH(CH)CH-), hexylene (-CH(CH)CH-), heptylene (-CH(CH)CH-), octylene (-CH(CH)CH-), and the like.

[0011] "Halo" or "halogen" refers to Group 17 elements having atomic numbers 9-85. Preferred halo groups include fluorine, chlorine, bromine, and iodine radicals. When a residue is substituted with more than one halogen, it may be designated by using a prefix corresponding to the number of halogen moieties attached; for example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may, but are not necessarily, the same halogen; thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a "perhaloalkyl." A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen replaces each H in the hydrocarbon comprising the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0012] "Carbamate" refers to the group -OC(=O)-NH-. Unless otherwise specified, the nitrogen atom of the carbamate group is understood to be unsubstituted (i.e., bearing a hydrogen atom).

[0013] "Oxo" refers to the =O part.

[0014] Unless otherwise indicated, "aryl," alone or as part of another term, means a substituted or unsubstituted monovalent carbocyclic aromatic hydrocarbon radical of the indicated number of carbon atoms, typically 6 to 20 carbon atoms, derived by removing one hydrogen atom from a carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ar." Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like. An exemplary aryl group is the phenyl group.

[0015] Unless otherwise stated, "arylene," whether alone or as part of another term, refers to an aryl group, as defined above, that has two covalent bonds (i.e., is divalent) and can be in the ortho, meta, or para configuration.

[0016] Unless otherwise stated, "heterocyclyl," alone or as part of another term, refers to a monovalent substituted or unsubstituted, aromatic or non-aromatic, monocyclic or bicyclic ring system having 3 to 9 carbon atoms (also referred to as ring members) and 1 to 4 heteroatom ring members independently selected from N, O, P, or S, derived by the removal of one hydrogen atom from a ring atom of a parent ring system. One or more N, C, or S atoms in the heterocycle can be oxidized. The heteroatom-containing ring can be aromatic or non-aromatic.

[0017] Unless otherwise specified, a heterocyclyl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Thus, a heteroaryl can be attached through an aromatic carbon of its aromatic ring system (referred to as a C-linked heteroaryl) or through a non-double-bonded N atom (i.e., not =N-) in its aromatic ring system (referred to as an N-linked heteroaryl). Thus, nitrogen-containing heterocyclyls can be C-linked or N-linked and include pyrrole moieties, such as pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked), and imidazole moieties, such as imidazol-1-yl and imidazol-3-yl (both N-linked), as well as imidazol-2-yl, imidazol-4-yl, and imidazol-5-yl moieties (all C-linked).

[0018] When explicitly indicated, the size of a heterocyclyl or heteroaryl ring system is indicated by the total number of atoms in the ring. For example, a designation of a 5- or 6-membered heteroaryl indicates the total number of aromatic atoms (i.e., 5 or 6) in the heteroaromatic ring system of the heteroaryl, but does not imply the number of aromatic heteroatoms or aromatic carbons in the ring system. A fused heteroaryl, whether explicitly designated as such or implied by context, is typically designated by the number of aromatic atoms in each aromatic ring fused together to form the fused heteroaromatic ring system. For example, a 5,6-membered heteroaryl is one in which a 5-membered aromatic ring is fused to a 6-membered aromatic ring, and one or both rings have aromatic heteroatom(s) or the two rings share a heteroatom.

[0019] "Optionally substituted" means, unless otherwise specified, that a group can be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of the substituents listed for that group, which may be the same or different. In some embodiments, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In some embodiments, an optionally substituted group is unsubstituted.

[0020] composition The compositions disclosed herein comprise various components, including a glucan backbone, a tumor-associated macrophage targeting moiety, a targeting moiety linker, a payload (e.g., a pyrrolobenzodiazepine), and an optional payload linker. The arrangement of these components results in a composition that targets tumor-associated macrophages (TAMs). The disclosed compositions may use TAMs as receiver cells to pick up, process, and deliver the payload to the tumor environment. For example, sarcomas are characterized by abundant tumor-associated macrophages (TAMs) (Fujiwara et al., 2021). Anti-CD206 immunohistochemistry on a human sarcoma microarray containing 59 specimens encompassing 19 sarcoma subtypes has shown high and relatively uniform expression of this TAM receptor in essentially all specimens. The disclosed compositions target cells (e.g., CD206) present in tumor-associated macrophages. + ) can be internalized into tumor-associated macrophages. Because of their ability to be internalized by cells present in tumor-associated macrophages, the disclosed compositions can deliver a payload (e.g., a pyrrolobenzodiazepine) to disease sites where such cells congregate. This application describes improved compositions and methods for treating cancer, including delivering a drug (e.g., a pyrrolobenzodiazepine) to tumor-associated macrophages by contacting the tumor-associated macrophages with the disclosed compositions. Because the compositions disclosed herein are larger than typical small molecules but smaller than antibody-drug conjugates, they have excellent penetration to targeted sites and minimal leakage into normal tissues, thereby limiting potential toxicity. Furthermore, while rapidly dividing and mutating heterogeneous cancer cells often develop resistance to conventional therapies, terminally differentiated macrophages are not subject to the selective pressure that leads to the development of resistance to the treatment methods disclosed herein.

[0021] The disclosed compositions may enable targeted delivery of payloads to tumors by targeting specific receptors present on or near tumors, such as CD205 (DEC205), CD206, CD207 (Langerin), CD209 (DC-SIGN), CD280 (ENDO180), and CD301 (MGL).

[0022] Glucan skeleton The compounds described herein comprise a glucan backbone, which is a linear, branched, or cyclic oligosaccharide or polysaccharide comprising multiple glucose monomers. In some embodiments, the glucose monomers are primarily linked by C-1→C-6 glycosidic linkages. Other linkages, such as α-1,3 or α-1,4 linkages, may also be present. In some embodiments, the glucose monomers are linked by α-1,6 and α-1,3 glycosidic linkages. In some embodiments, the glucose monomers are linked by a combination of α-1,6 and α-1,4 glycosidic linkages. A glucan backbone can also be defined as a polymer of glucose in which the glycosidic linkages differ in position. The glucan backbone can comprise the alpha or beta isomer of glucose, or a mixture of alpha and beta isomers. Examples of glucan backbones include dextran, a linear or branched compound, and cyclodextrin, a cyclic glucan. It is understood that in some embodiments, the monomers designated, for example, a, b, or c, are interspersed within the construct. It is also understood that in some embodiments, the constructs described herein may be in blocks or may be interspersed, e.g., random.

[0023] The mass and molecular weight of the glucan backbone can vary, depending in part on the number of glucose monomers. In some embodiments, the glucan backbone can have a molecular weight ranging from 1 to 30 kilodaltons (kDa). Preferred embodiments include glucan backbones of approximately 1 kDa, 3 kDa, 6 kDa, 10 kDa, 20 kDa, or 30 kDa. In some embodiments, the glucan backbone can have a molecular mass ranging from 1,000 to 30,000 grams per mole (g / mol). In some embodiments, the glucan backbone can contain a number of glucose monomers ranging from 5 to 167. The glucan backbone can be linear, branched, cyclic, or a combination thereof. For example, dextran is an example of a linear or branched glucan backbone. Cyclodextrin is another example of a glucan backbone. The backbones described herein can be substituted or unsubstituted. For example, a substituted cyclodextrin is a cyclodextrin derivative that is hydrophobic, hydrophilic, ionic, non-ionic, or any other variation thereof.

[0024] In some embodiments, the glucan backbone comprises a plurality of backbone monomers, the plurality of backbone monomers comprising a plurality of D-glucose monomers linked via α-1,6 glycosidic bonds or β-1,4 glycosidic bonds. In some embodiments, the plurality of D-glucose monomers is n, where n=16 to 111. In some embodiments, n=50 to 65. In some embodiments, the glucan backbone is a linear dextran molecule. In some embodiments, the glucan backbone is a cyclodextrin molecule comprising 6 to 16 D-glucose monomers.

[0025] Targeting part The compositions disclosed herein comprise a targeting moiety (e.g., a tumor-associated macrophage targeting moiety) attached to a glucan backbone. In some embodiments, the targeting moiety binds to a receptor including, but not limited to, CD205 (DEC205), CD206, CD207 (Langerin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL). In some embodiments, the targeting moiety is a CD205 targeting moiety. In some embodiments, the targeting moiety is a CD206 targeting moiety. In some embodiments, the targeting moiety is a CD207 targeting moiety. In some embodiments, the targeting moiety is a CD209 targeting moiety. In some embodiments, the targeting moiety is a CD280 targeting moiety. In some embodiments, the targeting moiety is a CD301 targeting moiety. In some embodiments, the target receptor is in a tumor-associated macrophage. In some embodiments, the target receptor is in a cancer or tumor cell. In some embodiments, the targeting moiety comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N-acetylglucosamine, luteinizing hormone, thyroid-stimulating hormone, phospholipase A2 or a fragment thereof, or chondroitin sulfate. In some embodiments, the targeting moiety comprises mannose (including its D- and L-isomers). In some embodiments, the targeting moiety comprises a furanose. In some embodiments, the targeting moiety comprises a pyranose. In some embodiments, the targeting moiety is D-mannose. It should be understood that a tumor-associated macrophage targeting moiety may also be referred to as a targeting moiety.

[0026] In some embodiments, targeting moieties are attached to about 10% to about 50% of the glucose residues on the glucan backbone, or about 20% to about 45% of the glucose residues, or about 25% to about 40% of the glucose residues. (Note that with respect to the collections or populations of compositions described herein, the molecular weights (MW) referred to herein, as well as the number and degree of conjugation of receptor substrates, leashes, and therapeutic moieties attached to the dextran backbone, refer to the average amount of a given amount of carrier molecule, as some variability may occur depending on the synthesis technique.)

[0027] Targeting linker to scaffold ratio The density of targeting moieties per backbone subunit is expressed using the ratio of targeting moieties to backbone subunits for linear, branched, or cyclic polysaccharide backbones. For example, the degree of substitution (ds) is used to express the density of targeting moieties on a glucan backbone. The ratio of targeting moieties to glucan backbone refers to the number of targeting moieties substituting one or more backbone subunits. For example, a ratio of 1:7 means that there is one targeting moiety for every seven glucose subunits in the glucan backbone. ds represents the average number of substitutions or substitution positions per base unit. For example, a ds of 0.9 means that one backbone subunit is substituted with an average of 0.9 targeting moieties. In some embodiments, the ratio of targeting moieties to backbone subunits is about 1:5 to about 1:25. In some embodiments, the ratio of targeting moiety to backbone subunits is at least 1:50 (e.g., at least 1:33, at least 1:35, at least 1:40, or at least 1:45) to about 1:5. In some embodiments, the ratio of targeting moiety to backbone subunits is from about 1:6 to about 1:19. In some embodiments, ds is from about 0.1 to about 7. In some embodiments, ds is from about 0.5 to 5. In some embodiments, in conjunction with the above or below embodiments, the targeting moiety comprises mannose.

[0028] Targeting Linkers The targeting linker is a cleavable or non-cleavable linker that connects the glucan backbone to the targeting moiety. The cleavable linker can be cleaved by an enzyme (e.g., a protease), a change in temperature, a change in pH, a chemical stimulus, or any combination thereof. The cleavable linker can include a protease cleavage site. In some embodiments, the cleavable linker can be cleaved by a lysosomal protease or an endosomal protease.

[0029] The targeting linker may comprise a carbamate group. In some embodiments, the targeting linker comprises a carbamate group and a chain moiety, wherein the carbamate group is connected to the backbone monomer and the chain moiety connects the carbamate group to the targeting moiety. In some embodiments, the chain moiety of the targeting linker comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) units selected from the group consisting of an optionally substituted alkylene chain, an optionally substituted CO-alkylene chain, a peptide chain, a polymer chain, and a heteroatom selected from the group consisting of an O atom, an S atom, and an optionally substituted N atom. In some embodiments, the chain moiety is a C1-C 12 In some embodiments, the chain portion comprises a C3-C7 alkylene chain. In some embodiments, the chain portion comprises a C6 alkylene chain. In some embodiments, the chain portion is a C6 alkylene chain. In some embodiments, the alkylene chain is an oxo, OH, NH2, SH, C1-C 12 Alkyl, C1-C 12 Haloalkyl, O(C1-C 12 alkyl), O(C1-C 12 haloalkyl), NH(C1-C 12 alkyl), NH(C1-C 12 Haloalkyl), N(C1-C 12 alkyl)2, N(C1-C 12 haloalkyl)2, S(C1-C 12 alkyl), S(C1-C 12 haloalkyl), C(O)OH, C(O)O(C1-C12 alkyl), C(O)O(C1-C 12 haloalkyl), C(O)NH(C1-C 12 alkyl), C(O)NH(C1-C 12 haloalkyl), C(O)N(C1-C 12 alkyl), C(O)N(C1-C 12 haloalkyl)2, C(O)S(C1-C 12 alkyl), and C(O)S(C1-C 12 haloalkyl). In some embodiments, the alkylene chain is unsubstituted.

[0030] In some embodiments, one or more targeting moieties are attached to the glucan backbone via a linker. The linker may be attached to about 1 to about 50% of the backbone moieties. In some embodiments, the targeting linker is 1-12 comprising an alkylene chain and a carbamate group, the carbamate group being connected to a backbone monomer; 1-12 An alkylene chain connects the carbamate group and the targeting moiety.

[0031] active ingredient An active ingredient is a molecule or compound that can be used for therapeutic purposes. The active ingredient may also be referred to as a payload. The active ingredient may be or include a cytotoxic or cytostatic drug. In some embodiments, the payload may facilitate targeted delivery of the compositions described herein to macrophages or cancer cells. In some embodiments, the payload is a hydrophobic payload (e.g., topoisomerase inhibitor I, topoisomerase inhibitor II, or temozolomide). In some embodiments, the payload is a hydrophilic payload. In some embodiments, the payload is a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group including, but not limited to, lomustine, epirubicin, topotecan, irinotecan, pemetrexed, docetaxel, oxaliplatin, altretamine, valrubicin, and sarcin.

[0032] In some embodiments, the active ingredient comprises a pyrrolobenzodiazepine (PBD) toxin or a pharmaceutically acceptable salt thereof. In some embodiments, the PBD is a dimer. In some embodiments, the active ingredient is a PBD dimer of formula (I) or a pharmaceutically acceptable salt thereof: [ka] wherein A is C6-C 10 an arylene group, and X is [ka] is selected from the group consisting of where R N is selected from the group consisting of H and C1-C4 alkyl, and the asterisk represents Q 2 indicates the point of attachment to Q 1 and Q 2 are each independently a single bond, -Z-(CH2) n -, or -CH=CH-, where Z is selected from the group consisting of a single bond, O, S, and NH, and the subscript n is 1 to 3; R 12 -OR 12a and -COOR 12b C6-C optionally substituted with one or more substituents selected from the group consisting of 10 an aryl group, where R 12a and R 12b are each independently H or C1-C6 alkyl; R 6 , R 7 , and R 9 are each independently H, R b , -OR b , -SR b , -NR b R c , -NO2, -SnMe3, and halo; where R b and R care each independently C1-C6 alkyl, 4- to 10-membered heterocyclyl, and C5-C 20 aryl, each of which is optionally substituted; R 10 and R 11 are each independently H, -OR 11a , and -SO Z M, where R 11a is H or C1-C6 alkyl, the subscript Z is 2 or 3, and M is a pharmaceutically acceptable cation), or R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen atom and the carbon atom to which they are attached, R” is C3-C 12 alkylene, the chain of which is O, S, and NR N2 (where R N2 is H or C1-C4 alkyl), and / or one or more heteroatoms selected from the group consisting of C5-C 10 optionally interrupted by an arylene; Y and Y' are each independently selected from the group consisting of O, S, and NH; R 6’ , R 7’ , R 9’ , R 10’ , and R 11’ are R 6 , R 7 , and R 9 , R 10 , and R 11 are independently selected from the same group as

[0033] In some embodiments, in conjunction with the above or below embodiments, A is C6-C 10 an arylene group, and X is [ka] where R N is H and the asterisk is Q 2In some embodiments, in conjunction with the above or below embodiments, Q 1 is a single bond. In some embodiments, in conjunction with the above or below embodiments, Q 2 is a single bond. In some embodiments, in conjunction with the above or below embodiments, R 12 is one or more -OR 12a C6-C optionally substituted by 10 an aryl group, where R 12a is H or C1-C6 alkyl. In some embodiments, in conjunction with the above or below embodiments, R 12 is phenyl substituted with -OCH. In some embodiments, in conjunction with the above or below embodiments, R 6 is H. In some embodiments, in conjunction with the above or below embodiments, R 9 is H. In some embodiments, in conjunction with the above or below embodiments, R 7 HA-OR b and R b is C1-C6 alkyl. In some embodiments, in conjunction with the above or below embodiments, R 7 is —OCH. In some embodiments, in conjunction with the above or below embodiments, R 10 and R 11 forms a nitrogen-carbon double bond between the nitrogen atom and the carbon atom to which it is attached. In some embodiments, in conjunction with the above or below embodiments, R" is a C3-C 12 In some embodiments, in conjunction with the above or below embodiments, R" is C alkylene. In some embodiments, in conjunction with the above or below embodiments, Y is O. In some embodiments, in conjunction with the above or below embodiments, Y' is O. In some embodiments, in conjunction with the above or below embodiments, R 6’ , R 7’ , R 9’ , R 10’ , and R 11’ are R 6 , R 7 , and R 9, R 10 , and R 11 is selected from the same group as

[0034] In some embodiments, the active ingredient is a PBD dimer of formula (IA) or a pharmaceutically acceptable salt thereof: [ka] wherein Y, Y', R", R 6 , R 6’ , R 7 , R 7’ , R 9 , R 9’ , and R x is as defined in formula (I).

[0035] In some embodiments, the active ingredient is a PBD dimer of formula (IB) or a pharmaceutically acceptable salt thereof: [ka] wherein Y, Y′, and R″ are as defined in formula (I).

[0036] In some embodiments, the active ingredient is a PBD dimer of formula (IC) or a pharmaceutically acceptable salt thereof: [ka] wherein n=3-12. In some embodiments, n=3. In some embodiments, n=4. In some embodiments, n=5. In some embodiments, n=6. In some embodiments, n=3. In some embodiments, n=7. In some embodiments, n=8. In some embodiments, n=9. In some embodiments, n=10. In some embodiments, n=11. In some embodiments, n=12.

[0037] In some embodiments, the composition comprises a PBD dimer of formula (ID) or a pharmaceutically acceptable salt thereof: [ka] Includes:

[0038] Payload Linker In certain embodiments, the active ingredient or payload is directly linked to the glucan backbone. In some embodiments, the active ingredient is connected to the glucan backbone via a linker. The linker may be cleavable or non-cleavable. In some embodiments, one or more therapeutic agents are linked via a biodegradable linker. In some embodiments, the biodegradable linker is acid-sensitive, for example, a hydrazone linker. The use of an acid-sensitive linker allows for the transport of the drug into cells and the release of the drug substantially inside the cells. In some embodiments, the payload linker is a Val-Cit linker.

[0039] The payload linker can include a carbamate group. In some embodiments, the payload linker includes a carbamate group and a chain portion, wherein the carbamate group is connected to the backbone monomer and the chain portion connects the carbamate group to the active ingredient. In some embodiments, the chain portion of the payload linker includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) units selected from the group consisting of an optionally substituted alkylene chain, an optionally substituted CO-alkylene chain, a peptide chain, a polymer chain, and a heteroatom selected from the group consisting of an O atom, an S atom, and an optionally substituted N atom. In some embodiments, the chain portion is a C1-C 12 In some embodiments, the chain portion comprises a C3-C7 alkylene chain. In some embodiments, the chain portion comprises a C6 alkylene chain. In some embodiments, the chain portion is a C6 alkylene chain. In some embodiments, the alkylene chain is an oxo, OH, NH2, SH, C1-C 12 Alkyl, C1-C 12 Haloalkyl, O(C1-C 12 alkyl), O(C1-C12 haloalkyl), NH(C1-C 12 alkyl), NH(C1-C 12 Haloalkyl), N(C1-C 12 alkyl)2, N(C1-C 12 haloalkyl)2, S(C1-C 12 alkyl), S(C1-C 12 haloalkyl), C(O)OH, C(O)O(C1-C 12 alkyl), C(O)O(C1-C 12 haloalkyl), C(O)NH(C1-C 12 alkyl), C(O)NH(C1-C 12 haloalkyl), C(O)N(C1-C 12 alkyl), C(O)N(C1-C 12 haloalkyl)2, C(O)S(C1-C 12 alkyl), and C(O)S(C1-C 12 haloalkyl). In some embodiments, the alkylene chain is unsubstituted.

[0040] In some embodiments, the molar ratio of targeting moiety (e.g., mannose) to PBD toxin is about 1:10 to about 10:1. In some embodiments, the molar ratio of targeting moiety to PBD toxin is at least about 1:10 (e.g., about 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, and 4:1). In some embodiments, the molar ratio of targeting moiety to PBD toxin is about 1:1. In some embodiments, the molar ratio of targeting moiety to PBD toxin is about 1:2. In some embodiments, the molar ratio of targeting moiety to PBD toxin is about 1:3. In some embodiments, the molar ratio of targeting moiety to PBD toxin is about 1:4.

[0041] In some embodiments, the payload linker is -C(O)-C 1-12 The carbamate group is connected to the backbone monomer and includes an alkylene chain and a carbamate group, and the carbamate group is connected to the backbone monomer and includes a —C(O)—C 1-12An alkylene chain connects the carbamate group to the payload.

[0042] Secondary Payloads and Linkers In addition to the payload, the compounds disclosed herein can include secondary agents that can be attached to the glucan backbone to add additional functional capabilities. Typically, the secondary payload is attached to the linker in any manner similar to that used to attach the targeting moiety to the targeting linker.

[0043] In some embodiments, the secondary payload can facilitate targeted delivery of the compositions described herein to macrophages or cancer cells. In some embodiments, the secondary payload is a hydrophobic payload (e.g., topoisomerase inhibitor I, topoisomerase inhibitor II, or temozolomide). In some embodiments, the secondary payload is a hydrophilic payload.

[0044] The secondary payload can include additional agents, for example, for diagnostic imaging, therapy, or other purposes. Specifically, in some embodiments, a combination of therapeutic and imaging agents can be linked to the glucan backbone to combine diagnostic and therapeutic functions. In other embodiments, various amino acids, such as cysteine ​​or lysine, can be attached to the linker to crosslink the molecule to its target.

[0045] The secondary payload linker is a cleavable or non-cleavable linker that connects the glucan backbone to the secondary payload moiety. The cleavable linker can be cleaved by an enzyme (e.g., a protease), a change in temperature, a change in pH, a chemical stimulus, or any combination thereof. The cleavable linker can include a protease cleavage site. In some embodiments, the cleavable linker can be cleaved by a lysosomal or endosomal protease.

[0046] The secondary payload linker can include a carbamate group. In some embodiments, the secondary payload linker includes a carbamate group and a chain moiety, where the carbamate group is connected to the backbone monomer and the chain moiety connects the carbamate group to the secondary agent. As used herein, the carbamate functional group has its plain and ordinary meaning from the field of organic chemistry. In some embodiments, the chain moiety of the secondary payload linker includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) units selected from the group consisting of an optionally substituted alkylene chain, an optionally substituted CO-alkylene chain, a peptide chain, a polymer chain, and a heteroatom selected from the group consisting of an O atom, an S atom, and an optionally substituted N atom. In some embodiments, the chain moiety is a C1-C 12 In some embodiments, the chain portion comprises a C3-C7 alkylene chain. In some embodiments, the chain portion comprises a C6 alkylene chain. In some embodiments, the chain portion is a C6 alkylene chain. In some embodiments, the alkylene chain is an oxo, OH, NH2, SH, C1-C 12 Alkyl, C1-C 12 Haloalkyl, O(C1-C 12 alkyl), O(C1-C 12 haloalkyl), NH(C1-C 12 alkyl), NH(C1-C 12 Haloalkyl), N(C1-C 12 alkyl)2, N(C1-C 12 haloalkyl)2, S(C1-C 12 alkyl), S(C1-C 12 haloalkyl), C(O)OH, C(O)O(C1-C 12 alkyl), C(O)O(C1-C 12 haloalkyl), C(O)NH(C1-C 12 alkyl), C(O)NH(C1-C 12 haloalkyl), C(O)N(C1-C 12 alkyl), C(O)N(C1-C 12 haloalkyl)2, C(O)S(C1-C 12 alkyl), and C(O)S(C1-C12 haloalkyl). In some embodiments, the alkylene chain is unsubstituted.

[0047] In some embodiments, one or more secondary payload moieties are attached to the glucan backbone via linkers, which may be attached to about 1 to about 50% of the backbone moieties.

[0048] In some embodiments, the compositions described herein comprise a compound of formula (A-1) or a pharmaceutically acceptable salt thereof. [ka]

[0049] In some embodiments, the monomers of the type designated a, b, or c in the compound of Formula (A-1) may be in a block copolymer configuration, interspersed (e.g., randomly arranged) within the polymer, or any combination thereof, unless otherwise specified. In some embodiments, a, b, and c in Formula (A-1) may each independently represent an integer of 0, at least 1, about 1 to about 165, about 16 to about 111, about 50 to about 65, or about 6 to about 6. In some embodiments, the glucan backbone of Formula (A-1) is linear, branched, cyclic, or a combination thereof. In some embodiments, the terminal group of the glucan backbone of Formula (A-1) may be a hydroxyl end group of a monomer. In some embodiments, the terminal group of the glucan backbone of Formula (A-1) may be any terminal group recognizable by one of ordinary skill in the art.

[0050] In some embodiments, the glucan backbone of formula (A-1) is linear, branched, cyclic, or a combination thereof, and a, b, and c are each independently selected from the group consisting of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16, and the terminal groups of the glucan backbone are hydroxy terminal groups of the monomers. In some embodiments, the glucan backbone of formula (A-1) is cyclic, and a, b, and c are each independently selected from the group consisting of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16. In some embodiments, the glucan backbone of formula (A-1) is linear, and a, b, and c are each independently selected from the group consisting of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16, and the terminal groups of the glucan backbone are hydroxyl end groups of the monomers. In some embodiments, the glucan backbone of formula (A-1) is branched, and a, b, and c are each independently selected from the group consisting of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16, and the terminal groups of the glucan backbone are hydroxyl end groups of the monomers.

[0051] In some embodiments in combination with the above or below embodiments, the glucan backbone of Formula (A-1) is about 6 kDa, and the glucan backbone is dextran. In some embodiments in combination with the above or below embodiments, the a, b, and c groups of Formula (A-1) are interspersed. In some embodiments in combination with the above or below embodiments, the terminal groups of the glucan backbone are natural terminal groups of glucose, such as hydroxyl terminal groups. In some embodiments in combination with the above or below embodiments, the ratio of targeting moiety to backbone monomer of Formula (A-1) is about 1:30 to 1:40 (e.g., 1:33) or about 1:33 to 1:40 (e.g., 1:37). In some embodiments in combination with the above or below embodiments, the ratio of PBD to mannose of Formula (A-1) is about 1:1 to 1:3 (e.g., 1:1) or about 1:3 to 1:5 (e.g., 1:4).

[0052] In some embodiments, provided herein are compounds of Formula (A-1), wherein the glucan backbone is dextran, the molecular weight of the glucan backbone is about 6 kDa, the a, b, and c groups are interspersed, the terminal groups of the glucan backbone are natural terminal groups of glucose, such as hydroxyl terminal groups, the ratio of targeting moiety to backbone monomer is about 1:30 to 1:40 (e.g., 1:33), and the ratio of PBD to mannose is about 1:1 to 1:3 (e.g., 1:1).

[0053] In some embodiments, provided herein are compounds of Formula (A-1), wherein the glucan backbone is dextran, the molecular weight of the glucan backbone is about 6 kDa, and the a, c, and d groups are interspersed, the terminal groups of the glucan backbone are natural terminal groups of glucose, such as hydroxyl terminal groups, the ratio of targeting moiety to backbone monomer is about 1:33 to 1:40 (e.g., 1:37), and the ratio of PBD to mannose is about 1:3 to 1:5 (e.g., 1:4).

[0054] In some embodiments, the compositions described herein comprise a compound of formula (A-2) or a pharmaceutically acceptable salt thereof. [ka]

[0055] In some embodiments, the monomers of the type designated a, b, or c in the compound of Formula (A-2) may be in a block copolymer configuration, interspersed (e.g., randomly arranged) within the polymer, or any combination thereof, unless otherwise specified. In some embodiments, a, b, and c in Formula (A-2) may each independently represent an integer of 0, at least 1, about 1 to about 165, about 16 to about 111, about 50 to about 65, or about 6 to about 6. In some embodiments, the glucan backbone of Formula (A-2) is linear, branched, cyclic, or a combination thereof. In some embodiments, the terminal group of the glucan backbone of Formula (A-2) may be a hydroxyl end group of the monomer. In some embodiments, the terminal group of the glucan backbone of Formula (A-2) may be any terminal group recognizable by one of ordinary skill in the art.

[0056] In some embodiments, the glucan backbone of formula (A-2) is linear, branched, cyclic, or a combination thereof, and a, b, and c are each independently selected from the group consisting of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16, and the terminal groups of the glucan backbone are hydroxy terminal groups of the monomers. In some embodiments, the glucan backbone of formula (A-2) is cyclic, and a, b, and c are each independently selected from the group consisting of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16. In some embodiments, the glucan backbone of formula (A-2) is linear, a, b, and c are each independently selected from the group consisting of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16, and the terminal groups of the glucan backbone are hydroxyl end groups of the monomers. In some embodiments, the glucan backbone of formula (A-2) is branched, a, b, and c are each independently selected from the group consisting of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16, and the terminal groups of the glucan backbone are hydroxyl end groups of the monomers.

[0057] In some embodiments in combination with the above or below embodiments, the glucan backbone of Formula (A-2) is about 6 kDa, and the glucan backbone is dextran. In some embodiments in combination with the above or below embodiments, the a, b, and c groups of Formula (A-2) are interspersed. In some embodiments in combination with the above or below embodiments, the terminal groups of the glucan backbone are natural terminal groups of glucose, such as hydroxyl terminal groups. In some embodiments in combination with the above or below embodiments, the ratio of targeting moiety to backbone monomer of Formula (A-2) is about 1:30 to 1:40 (e.g., 1:33) or about 1:33 to 1:40 (e.g., 1:37). In some embodiments in combination with the above or below embodiments, the ratio of PBD to mannose of Formula (A-2) is about 1:1 to 1:3 (e.g., 1:1) or about 1:3 to 1:5 (e.g., 1:4).

[0058] In some embodiments, provided herein are compounds of Formula (A-2), wherein the glucan backbone is dextran, the molecular weight of the glucan backbone is about 6 kDa, the a, b, and c groups are interspersed, the terminal groups of the glucan backbone are natural terminal groups of glucose, such as hydroxyl terminal groups, the ratio of targeting moiety to backbone monomer is about 1:30 to 1:40 (e.g., 1:33), and the ratio of PBD to mannose is about 1:1 to 1:3 (e.g., 1:1).

[0059] In some embodiments, provided herein are compounds of Formula (A-2), wherein the glucan backbone is dextran, the molecular weight of the glucan backbone is about 6 kDa, and the a, c, and d groups are interspersed, the terminal groups of the glucan backbone are natural terminal groups of glucose, such as hydroxyl terminal groups, the ratio of targeting moiety to backbone monomer is about 1:33 to 1:40 (e.g., 1:37), and the ratio of PBD to mannose is about 1:3 to 1:5 (e.g., 1:4).

[0060] Treatment method The compositions disclosed herein can be used to treat cancer or non-malignant tumors (e.g., meningioma, hemangioblastoma, or giant cell tumor) in a subject in need thereof. Treatment involves administering a therapeutically effective amount of a composition disclosed herein to the subject. The compositions disclosed herein can also be used to treat granulomatous diseases (e.g., sarcoidosis) or chronic inflammatory disorders (e.g., rheumatoid arthritis) in a subject in need thereof. The compositions disclosed herein can also be used to treat lysosomal storage diseases. For example, lysosomal storage diseases include, but are not limited to, cholesteryl ester storage disease, Wolman disease, Hunter syndrome, Hurler disease, Fabry disease, Gaucher disease, Krabbe disease (globoid cell leukodystrophy), metachromatic leukodystrophy, Niemann-Pick disease, Sandhoff disease, Tay-Sachs disease, Batten disease, cystinosis, Danon disease, and Pompe disease. The compositions disclosed herein can also be used to treat macrophage-dependent diseases. In some embodiments, non-malignant tumors include, but are not limited to, meningiomas of all grades (e.g., grade 1 meningiomas, grade 2 meningiomas, or grade 3 meningiomas), schwannoma, schwannomatosis, neurofibromas, neurofibromatosis type 1 (NF1), or neurofibromatosis type 2 (NF2).

[0061] In some embodiments, the cancer may be any cell of a subject undergoing unregulated proliferation. The cancer may be any cancer cell with the ability to metastasize. For example, the cancer may be a sarcoma, lymphoma, leukemia, carcinoma, blastoma, or germ cell tumor. In some embodiments, the cancer may be a carcinoma, lymphoma, blastoma, sarcoma, leukemia, lymphoid malignancy, squamous cell carcinoma, squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, gastric cancer, gastrointestinal cancer, esophageal squamous cell, hepatocellular carcinoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer (e.g., HR+ / HER2- breast cancer, HR- / HER2 In some embodiments, the non-malignant tumor is selected from the group consisting of breast cancer, HR+ / HER2+ breast cancer, HR- / HER2+ breast cancer, triple-negative breast cancer, or inflammatory breast cancer), colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal cancer, penile cancer, head and neck cancer, Merkel cell carcinoma, multiple myeloma, acute myeloid leukemia (AML), hemangioblastoma, and Schwannoma. In some embodiments, the non-malignant tumor is meningioma hemangioblastoma or giant cell tumor.

[0062] Methods for treating or preventing diseases or disorders using the disclosed compositions are provided. The disclosed compositions can be used to target CD205 (DEC205), CD206, CD207 (langerin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL) present on or near tumors. The disclosed compounds can be used to target macrophages for the treatment of intracellular pathogens (M. tuberculosis, F. tularensis, S. typhi). The disclosed compounds can be used to target tumor-associated macrophages, for example, to treat cancer. Macrophage-associated diseases and other diseases associated with cells highly expressing CD205 (DEC205), CD206, CD207 (Langerin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL) for which the compositions and methods herein may be used include acute disseminated encephalomyelitis (ADEM), Addison's disease, agammaglobulinemia, allergic diseases, alopecia areata, Alzheimer's disease, amyotrophic lateral sclerosis, ankylosing spondylitis, antiphospholipid syndrome, antisynthetase syndrome, arterial plaque disorders, asthma, atherosclerosis, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune cardiomyopathy, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune hypothyroidism, autoimmune inner ear disease, and autoimmune lymphoproliferative disorders. Syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyglandular syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Barot disease / Barot concentric sclerosis, Behçet's disease, Berger's disease, Bickerstaff encephalitis, Blau syndrome, bullous pemphigoid, Castleman's disease, celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multiple osteomyelitis, chronic obstructive pulmonary disease, chronic venous stasis ulcer, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, complement component 2 deficiency, contact dermatitis, arteritis capitis, CREST syndrome, Crohn's disease, Cushing's syndrome, cutaneous leukocytoclastic vasculitis, Degos disease, Dercum's disease, dermatitis herpetiformis, dermatomyositis, type I diabetes, type II diabetes,Diffuse cutaneous systemic sclerosis, Dressler's syndrome, drug-induced lupus, discoid lupus erythematosus, eczema, emphysema, endometriosis, enthesitis-related arthritis, eosinophilic fasciitis, eosinophilic gastroenteritis, eosinophilic pneumonia, epidermolysis bullosa acquisita, erythema nodosum, erythroblastosis fetalis, essential mixed cryoglobulinemia, Evans' syndrome, fibrodysplasia ossificans progressiva, fibrosing alveolitis (or idiopathic pulmonary fibrosis), gastritis, gastrointestinal pemphigoid, Gaucher's disease, glomerulonephritis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's encephalopathy, Hashimoto's thyroiditis, heart disease, Henoch-Schein syndrome lein purpura, herpes gestationis (also known as pemphigoid gestationis), hidradenitis suppurativa, cellular histiocytosis, Hughes-Stovin syndrome, hypogammaglobulinemia, infections (including bacterial infections), idiopathic inflammatory demyelinating diseases, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, IgA nephropathy, inclusion body myositis, inflammatory arthritis, inflammatory bowel disease, inflammatory dementia, interstitial cystitis, interstitial pneumonia, juvenile idiopathic arthritis (also known as juvenile rheumatoid arthritis), Kawasaki disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, linear immunoglobulin A disease (LAD), lupoid hepatitis (also known as Autoimmune hepatitis), lupus erythematosus, lymphomatoid granulomatosis, Majeed syndrome, malignancies including cancer (e.g., sarcoma, lymphoma, leukemia, carcinoma, and melanoma), Meniere's disease, microscopic polyangiitis, Miller-Fisher syndrome, mixed connective tissue disease, morphea, Much-Habermann disease (also known as acute pityriasis lichenoides), multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (also known as Devic's disease), neuromyotonia, ocular cicatricial pemphigoid, opsoclonus-myoclonus syndrome, Ordo's thyroiditis, relapsing rheumatoid arthritis, PANDAS (severe ulcerative colitis, rheumatoid arthr ... ptococcus-associated pediatric autoimmune neuropsychiatric disorder), paraneoplastic cerebellar degeneration, Parkinson's disease-like disorder, paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Parsonage-Turner syndrome, peripheral uveitis, pemphigus vulgaris, peripheral arterial disease, pernicious anemia, perivenous encephalomyelitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, Rasmussen's encephalitis, Raynaud's phenomenon, relapsing polychondritis,These conditions include, but are not limited to, Reiter's syndrome, restenosis, restless leg syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatic fever, Rosai-Dorfman disease, sarcoidosis, schizophrenia, Schmidt's syndrome, Schnitzler's syndrome, scleritis, scleroderma, sepsis, serum sickness, Sjogren's syndrome, spondyloarthropathy, Still's disease (adult-onset), stiff-person syndrome, stroke, subacute bacterial endocarditis (SBE), Susac's syndrome, Sweet's syndrome, Sydenham's chorea, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis (also known as "giant cell arteritis"), thrombocytopenia, Tolosa-Hunt syndrome, transplant (e.g., heart / lung transplant) rejection, transverse myelitis, tuberculosis, ulcerative colitis, undifferentiated connective tissue disease, undifferentiated spondyloarthropathy, urticarial vasculitis, vasculitis, vitiligo, and Wegener's granulomatosis. ,

[0063] Those skilled in the art will appreciate that the disclosed compounds can be used to deliver a wide variety of molecules and compounds to cells or tissues.

[0064] In one aspect, provided herein is a method of treating tuberculosis, comprising administering to a subject in need thereof a compound described herein.

[0065] In another aspect, provided herein is a method of treating a macrophage-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound described herein, and detecting a detectable label at a predetermined location in the subject.

[0066] In another aspect, provided herein is a method of treating a macrophage-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound described herein.

[0067] In another aspect, provided herein is a method of targeting tumor-associated macrophages, comprising administering to a subject in need thereof an effective amount of a compound described herein.

[0068] In another aspect, provided herein is a method according to any of the methods described herein, wherein a linker is used to attach one or more targeting moieties and one or more therapeutic agents.

[0069] In another aspect, provided herein is a method according to any of the methods described herein, wherein the disease is rheumatoid arthritis.

[0070] In another aspect, provided herein is a method according to any of the methods described herein, wherein the disorder is cancer.

[0071] In another aspect, provided herein is a method according to any of the methods described herein, wherein the cancer is a sarcoma, lymphoma, leukemia, carcinoma, blastoma, melanoma, or germ cell tumor.

[0072] Combination therapy In some embodiments, the compositions disclosed herein can be administered in combination with a second therapeutic agent. In some embodiments, the compositions disclosed herein are co-administered to a patient with a second therapeutic agent, adjuvant therapy, or radiation therapy. In some embodiments, at least two compounds or compositions are administered to a patient simultaneously, such that an effective amount or concentration of each of the two or more compounds can be found in the patient at a given time. Compositions disclosed herein can be co-administered to a patient simultaneously, but co-administration includes both simultaneous administration of two or more agents or administration at different times, provided that all co-administered compounds or compositions are found in effective concentrations in the subject at a given time. In certain preferred aspects of the present disclosure, one or more of the above-described compositions are co-administered in combination with at least one additional bioactive agent.

[0073] Administration The compositions described herein may, in certain embodiments, be administered orally, parenterally, or topically in single or divided unit doses. Administration of the compositions may range from continuous (intravenous infusion) to multiple oral doses per day (e.g., QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain a penetration enhancer), buccal, sublingual, and suppository administration, inhalation spray, rectal, vaginal, or via an implanted reservoir, among other routes of administration. The most effective dosage form will depend on the pharmacokinetics of the particular agent selected and the severity of the patient's disease.

[0074] The disclosed compositions can be administered by any suitable method. The disclosed compositions can be administered parenterally, intraparenchyma or into the circulation, so that the disclosed compounds reach the target tissue (e.g., where cancer cells may reside). The disclosed compositions can be administered directly into or adjacent to a tumor mass. The disclosed compositions can be administered intravenously. In yet other embodiments, the disclosed compositions can be administered orally, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.

[0075] Parenteral administration of compound, when used, is generally characterized by injection.Injection can be prepared in conventional form, either as solution or suspension, solid form suitable for dissolving suspension before injection, or emulsion.The revised method for parenteral administration involves the use of slow-release or sustained-release system to maintain a constant dosage.

[0076] formulation In an additional aspect, the present specification provides therapeutic or pharmaceutical compositions comprising an effective amount of a composition according to the present disclosure, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient.

[0077] A typical formulation is prepared by mixing a composition of the present disclosure with an excipient, such as a carrier and / or diluent. Suitable carriers, diluents, and other excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The particular carrier, diluent, or other excipient used will depend on the means and purpose for which the compound is being applied. Other pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0078] The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives.

[0079] Patients or subjects in need of therapy using the compositions disclosed herein can be treated by administering to the patient (subject) an effective amount of a composition disclosed herein. The composition is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication without causing serious toxic effects in the treated patient. It will be understood that the specific dosage and treatment regimen for a particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease or condition being treated.

[0080] kit In some aspects, kits for use in treating cancer are provided. Such kits may include the compositions described herein.

[0081] In some embodiments, the kit may include instructions for use in any of the therapeutic methods described herein. The included instructions may provide instructions for administering the pharmaceutical composition to a subject to achieve an intended action in the subject (e.g., treatment of a disease or condition such as cancer). In some embodiments, the instructions for use of the pharmaceutical compositions described herein may include information regarding the dosage, dosing schedule, and route of administration for the intended treatment. The container may be a unit dose, bulk package (e.g., a multi-dose package), or sub-unit dose. The instructions provided with the kits of the present disclosure are typically instructions found on a label or package insert. The label or package insert indicates that the pharmaceutical composition is used for treating, delaying the onset of, and / or alleviating a disease or disorder in a subject.

[0082] In some embodiments, the kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, etc. Also contemplated are packages for use in combination with specific devices, such as inhalers, nasal administration devices, or infusion devices. In some embodiments, the kits may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle).

[0083] In some embodiments, the kits provided herein comprise an additional therapeutic agent useful in the treatment of cancer, as described herein.

[0084] General synthesis method The compositions of the present disclosure will now be described with reference to the following exemplary synthetic schemes for their general preparation, followed by specific examples. To obtain the various compositions herein, those skilled in the art will recognize that starting materials can be appropriately selected so that the ultimately desired substituents are retained throughout the reaction scheme, with or without protection as necessary, to yield the desired products. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that is retained throughout the reaction scheme and can be appropriately replaced with the desired substituent. Furthermore, those skilled in the art will recognize that protecting groups can be used to protect certain functional groups (amino, carboxy, or side chain groups) from reaction conditions, and that such groups are appropriately removed under standard conditions.

[0085] Where it is desired to obtain a particular isomer of a compound or to otherwise purify a reaction product, chromatography, recrystallization, and other conventional separation techniques may be used on intermediates or final products.

[0086] General methods for preparing the compositions described herein are illustrated in the following exemplary methods.

[0087] In some embodiments, the compositions described herein can be synthesized according to the procedure shown in Scheme A1.

[0088] Scheme A1 [ka]

[0089] Scheme A2 [ka]

[0090] As seen in the above scheme, a glucan compound (e.g., dextran or cyclodextrin) is reacted with an activating agent. The resulting activated glucan derivative can then be reacted with an appropriate reagent to introduce a targeting moiety attached to the glucan backbone via a targeting linker and an active ingredient linked to the glucan backbone via a payload linker. Those skilled in the art will recognize that the above scheme is illustrative and that the order of the various reagents and synthetic steps can be modified as necessary to achieve the intended final product. For example, a, b, and c can each independently refer to an integer of 0, at least 1, at least 1, about 1 to about 165, about 16 to about 111, about 50 to about 65, or about 6 to about 16. It should be understood that the types of monomers designated a, b, or c may be in a block copolymer configuration, interspersed (e.g., randomly arranged) within the polymer, or any combination thereof, unless otherwise specified. It should also be understood that the glucan backbone in the above scheme can be linear, branched, cyclic, or a combination thereof. Groups not specified in the above scheme, such as any terminal group of the glucan backbone, can be any terminal group recognizable by those skilled in the art. For example, the terminal group of the glucan backbone can be a hydroxyl end group of a monomer. [Example]

[0091] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0092] Example 1. Synthesis of PBD dimer-NH2 (compound X-1) [ka] Model reaction: Attachment of aniline to the potential linker moiety Fmoc-Val-Cit-PAB-PNP [ka] To test the feasibility of connecting the PBD dimer to the potential linker Fmoc-Val-Cit-PAB-PNP to form an active ingredient-payload linker moiety that could serve as a precursor for the compositions described herein, a model reaction was performed according to Scheme 1-0, resulting in the successful synthesis of compound 4, which clearly demonstrated the feasibility of coupling the aniline unit with the Fmoc-Val-Cit-PAB-PNP linker moiety.

[0093] Step 1. Synthesis of 4-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2-nitrobenzoic acid (Compound A) [ka] As shown in Scheme 1-1, 4-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2-nitrobenzoic acid (Compound A) was synthesized from Compound 1.

[0094] Step 2. Synthesis of (3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-3-ol (Compound B) [ka] As shown in Scheme 1-2, (3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-3-ol (Compound B) was synthesized from Compound 2. In particular, steps 1, 2, and 3 of the four steps are further illustrated in Schemes 1-2-1, 1-2-2, and 1-2-3, respectively. [ka] [ka] [ka]

[0095] In step 1, as shown in Scheme 1-2-1, compound 2 was reacted with MeOH and H2SO4 in DCM at 40 °C for 20 hours to give compound 5 (99.4 g, 94% yield). In step 2, as shown in Scheme 1-2-2, 5.00 g of LiCl (1.3 equivalents) and NaBH4 (1.3 equivalents) were mixed in THF / water and stirred at 17 °C for 5 hours. Then, additional LiCl (0.6 equivalents) and NaBH4 (0.6 equivalents) were added and the mixture was stirred at room temperature for 19 hours. After 19 hours, TLC showed no starting material, and compound 6 was formed (3.93 g, 87% yield). In step 3, compound 6 was mixed with TBDMSCl and Et3N in toluene and stirred at 60 °C for 18 hours. Compound 7 was successfully synthesized.

[0096] Step 3. Synthesis of building block (compound C) [ka] The active ingredient -NH2 building block (Compound C) was synthesized from Compound A and Compound B. In particular, steps 5 and 8 of the synthesis are shown in Scheme 1-3-5 and Scheme 1-3-8, respectively. [ka] [ka]

[0097] In step 5, as shown in Scheme 1-3-5, compound 23 was reacted with PTSA in THF / water at room temperature for 1 day to form compound 24 (6.60 g, 68% yield). In step 8, compound 26 was mixed with TfO (9.0 equivalents) and pyridine (11.0 equivalents) at room temperature and stirred for 6 hours. After 6 hours, compound C was successfully synthesized (18 mg, 25% yield).

[0098] Step 4. Synthesis of Compound D and PBD Dimer-NH2 [ka] Starting from compound C, compound D was synthesized. By combining compound C and compound D, PBD dimer -NH2 (compound X-1) was successfully synthesized.

[0099] Example 2. Synthesis of compound of formula (A-1) [ka] Step 1. Synthesis of 2,2,2-trichloroethyl (11S,11aS)-11-acetoxy-8-(3-bromopropoxy)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate (Compound 40) [ka] As shown in Scheme 2-1, compound 31 was mixed with 1,3-dibromopropane (compound 39) and K2CO3, and the mixture was stirred in acetone to successfully obtain compound 40.

[0100] Step 2. Synthesis of compound 63 [ka] As shown in Scheme 2-2, compound 47 was mixed with LiOAc and the mixture was stirred in DMF / water, and compound 63 was successfully obtained.

[0101] Step 3. Synthesis of compound 64 [ka] As shown in Scheme 2-3, compound 40 and compound 63 were mixed with K2CO3 and stirred in acetone, and compound 64 was successfully obtained.

[0102] Step 4. Synthesis of compound 65 [ka] As shown in Scheme 2-4, the -NHBoc group of the linker moiety was successfully deprotected. Compound 64 was reacted with TFA and DCM to give compound 65.

[0103] Step 5. Synthesis of a protected PBD dimer (compound 51) with a protected linker [ka] As shown in Scheme 2-5, compound 65 was reacted with Fmoc-Val-Cit-PNP, DIPEA, and DMF to successfully obtain compound 51 (32 mg in 78% yield).

[0104] Step 6. Synthesis of protected PBD dimer with deprotected linker (compound X-2) [ka] As shown in Scheme 2-6, compound 51 was mixed with piperidine in DMF to successfully obtain compound (X-2) (7 mg in 79% yield).

[0105] Step 7. Connecting compound (X-2) to the framework [ka] According to Scheme 2-7, the as-synthesized compound (X-2) was first reacted with the glucan backbone in DIPEA, HOBt, DMSO, and pyridine at room temperature for 90 minutes (min). Then, the targeting moiety-targeting linker (compound 4) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 hours. 15 mg of compound 69 was successfully obtained. The as-synthesized compound 69 contained 3 mol% PBD dimer and 12 mol% mannose.

[0106] Step 8. Synthesis of Compound of Formula (A-1) [ka] The precursor of the compound of formula (A-1) (compound 69) was first synthesized from compound (X-2) according to Scheme A-1. Compound 69 was then reacted with Zn, AcOH, and DMSO to obtain the compound of formula (A-1) (9 mg). The as-synthesized compound of formula (A-1) contained approximately 3 mol% PBD dimer and approximately 12 mol% mannose as determined by NMR.

[0107] Example 3. Synthesis of compound of formula (A-2) [ka] Compound (A-2) was synthesized using a similar procedure to compound (A-1), but with a non-cleavable linker. Compound 65, a precursor of the active ingredient-payload linker moiety in compound (A-2), was obtained according to steps 1 to 4 of Example 2. Compound 65 was then coupled to the scaffold as illustrated in Scheme A-1. Following coupling, the protecting groups on the PBD dimer were removed according to a procedure similar to step 8 of Example 2. Compound (A-2) was obtained.

[0108] Example 4. Selectivity and toxicity of compounds of formula (A-1) and formula (A-2) to mouse macrophages The synthesized compounds of formula (A-1) and formula (A-2) were tested for selectivity and toxicity to mouse macrophages. Poly-L-lysine-coated 6-well plates (all wells) were prepared by adding 2 mL of sterile water to each well, followed by 20 μL of a 1 mg / mL stock solution of poly-L-lysine, mixing, and leaving the wells at 37°C for 1 hour or overnight. Complete medium was prepared by thawing MaGS, FBS, and P / S (Science II) at 37°C. Once MaGS was completely dissolved, all of these ingredients were added to macrophage medium (MaM). The plate wells were rinsed with sterile water (2x), and 3 mL of complete medium was added to each well. The cells were completely thawed and resuspended in a 37°C water bath, and 150 μL of macrophages were added to each well and gently dispersed by rocking. The cells in the wells were left to settle and adhere for at least 16 hours, after which the medium was replaced.

[0109] Once cells adhered, LPS (6.25 μl of 500x stock) + 50 ng / ml mouse IFN-gamma (1.5 μl of 100 μg / ml stock) was added for M1 differentiation, and 10 ng / ml IL-4 (0.3 μl of 0.1 mg / ml stock) + 10 ng / ml IL-13 (0.3 μl of 0.1 mg / ml stock) was added for M2 differentiation. After 3 days, cells were detached from the dish using 0.05% trypsin at 37°C for less than 10 minutes. The mixture was collected for staining (spun down and resuspended in 100 μl of staining buffer). Isolation was achieved with macrophage isolation solution (promo cell C-41330) (more than 1 hour for isolation). CD206 staining is recommended at 10 μl / cell. 62 μL was used in this experiment. The cells were from Science catalog number M1920-57, and all cell conditions and differentiation protocols were in accordance with the manufacturer's instructions. Polarization occurred using bone marrow. M1 differentiation was achieved with 1×LPS and 50 n / mL mouse IFN-gamma. M2 differentiation was achieved with 10 ng / mL IL-4 and 10 ng / mL IL-13. The differentiation process was carried out for 3 days, and then after an additional 48 hours, the cells were treated with the compound of formula (A-1) and the compound of formula (A-2), as well as 3 μM staurosporine toxicity control, followed by viability measurement using CellTier Flo (Spectramax).

[0110] Images of the morphology of mouse M1 and M2 macrophages are shown in Figures 1 and 2, respectively. The results for mouse cells treated with the compound of Formula (A-1) are summarized in Figures 3 and 4 and Table 4-1. The results for mouse cells treated with the compound of Formula (A-2) are summarized in Figures 5 and 6 and Table 4-2. As can be seen from Table 4-1, M2 macrophages are four times more sensitive to the cytotoxicity of A1 than M1 macrophages and seven times more sensitive than 3T3 cells. This is consistent with the fact that M2 macrophages express higher levels of CD206 (the receptor targeted by A1) than M1 macrophages, and that 3T3 cells do not express the A1 target. This result is consistent with the higher uptake by M2 cells at lower A1 concentrations. The IC50 results in Table 4-2 show that none of the three cell types are significantly affected by A2, indicating that the cleavable linker confers greater biological activity against both dividing and non-dividing cells. [Table 1] [Table 2]

[0111] Example 5. Maximum Tolerated Dose (MTD) of TA in CD-1 Mice Following IV Administration of Compound of Formula (A-1) The maximum tolerated dose of Formula (A-1) was determined in CD-1 mice. Twenty-five female CD-1 mice were divided into five groups, and all animals were monitored for 7 days. After 7 days, animals were weighed and assigned to treatment groups based on weight using a randomization procedure. Day 0 was designated as the start of the study, when randomization and treatment began. Mice were administered a single slow IV bolus of Formula (A-1) at doses of 0.3 mg / kg (G1), 1.0 mg / kg (G2), 3.0 mg / kg (G3), 10.0 mg / kg (G4), or 30.0 mg / kg (G5). After dosing, animals were closely monitored. Body weight and food intake were monitored and recorded for all mice for 7 days. On day 7, mice were sacrificed and necropsied. Serum for clinical chemistry and whole blood for hematology were collected from all mice.

[0112] Figures 7A and 7B show the weight change and percentage weight change in all five treatment groups. Figures 7A and 7B show that animals in all groups lost less than 5% weight and gradually regained weight over the seven-day period. Similarly, Figure 8 shows that there was little difference in food intake among the five treatment groups. During gross necropsy performed on day 7, all organs were observed to be normal.

[0113] Blood hematology and serum clinical chemistry analyses showed no significant differences among all groups. Figures 9A-9L show that none of the treatment groups exhibited differences in hematology parameters. Similarly, Figures 10A-10T show that there were no differences in serum constituents among the treatment groups.

[0114] These data indicate that the compound of formula (A-1) was tolerated over a range of 0.3 mg / kg to 30 mg / kg. In this study, the maximum tolerated dose of formula (A-1) in CD-1 mice was not defined. In the mouse tumor model, it is expected that mice can be treated with 30 mg / kg at least once a week.

[0115] Example 6. In vivo anti-cancer efficacy of compounds of formula (A-1) The initial anticancer efficacy of compound Formula (A-1) was investigated in a PDX myxofibrosarcoma model. Twenty male PDX mice were randomly divided into three different treatment groups according to tumor size and administered either saline, doxorubicin, or Formula (A-1). Mice received three intravenous doses of each treatment at 1 mg / kg once a week for three weeks (days 0, 7, and 14). As can be seen in Figure 11, the tumor volumes of mice treated with Formula (A-1) were comparable to those of mice treated with doxorubicin. Both Formula (A-1)- and doxorubicin-treated mice exhibited lower tumor burdens than mice treated with saline.

Claims

1. 1. A composition comprising: i) a tumor-associated macrophage targeting moiety; and ii) a glucan backbone, the glucan backbone comprising a plurality of backbone monomers; iii) an active ingredient comprising a pyrrolobenzodiazepine (PBD) dimer, said active ingredient being attached to the glucan backbone; and iv) a targeting linker that connects the targeting moiety to the glucan backbone; wherein the targeting linker comprises a carbamate group and a chain moiety, the carbamate group being attached to a backbone monomer, and the chain moiety connecting the carbamate group and the tumor-associated macrophage targeting moiety.

2. The PBD dimer is a compound of formula (I): 【Chemistry 1】 where: A is C ６ -C １０ an arylene group, and X is 【Chemistry 2】 is selected from the group consisting of Here, R Ｎ is H and C １ -C ４ alkyl, and the asterisk represents Q ２ indicates the point of attachment to Q １ and Q ２ are each independently a single bond, -Z-(CH ２ ) ｎ -, or -CH=CH-, where Z is selected from the group consisting of a single bond, O, S, and NH, and the subscript n is 1 to 3; R １２ is -OR １２ａ and -COOR １２ｂ C optionally substituted with one or more substituents selected from the group consisting of ６ -C １０ an aryl group, where R １２ａ and R １２ｂ are each independently H or C １ -C ６ is alkyl, R ６ , R ７ , and R ９ are each independently H, R ｂ , -OR ｂ , -SR ｂ , -NR ｂ R ｃ , -NO ２ , -SnMe ３ and halo; Here, R ｂ and R ｃ are each independently C １ -C ６ Alkyl, 4- to 10-membered heterocyclyl, and C ５ -C ２０ aryl, each of which is optionally substituted; R １０ and R １１ are each independently H, -OR １１ａ , and -SO Ｚ M, where R １１ａ is H or C １ -C ６ alkyl, the subscript Z is 2 or 3, and M is a pharmaceutically acceptable cation; or R １０ and R １１ form a nitrogen-carbon double bond between the nitrogen atom and the carbon atom to which they are attached, R" is C ３ -C １２ alkylene, the chain of which is made up of O, S, and NR Ｎ２ (where R Ｎ２ is H or C １ -C ４ alkyl), and / or C ５ -C １０ optionally interrupted by an arylene; Y and Y′ are each independently selected from the group consisting of O, S, and NH; R ６’ , R ７’ , R ９’ , R １０’ , and R １１’ are respectively R ６ , R ７ , and R ９ , R １０ , and R １１ selected from the same group as The composition of claim 1.

3. 3. The composition of claim 1, wherein the plurality of backbone monomers comprises a plurality of D-glucose monomers linked by α-1,6 glycosidic bonds or β-1,4 glycosidic bonds.

4. 4. The composition of claim 3, wherein the plurality of D-glucose monomers is n, and n=16 to 111.

5. 5. The composition of claim 3, wherein the number of D-glucose monomers is n, and n=50 to 65.

6. The composition of any one of claims 1 to 5, wherein the glucan backbone is a linear dextran molecule.

7. The composition according to any one of claims 1 to 5, wherein the glucan backbone is a cyclodextrin molecule and n = 6 to 16.

8. 8. The composition of any one of claims 1 to 7, wherein the tumor-associated macrophage targeting moiety comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N-acetylglucosamine, luteinizing hormone, thyroid-stimulating hormone, phospholipase A2 or a fragment thereof, or chondroitin sulfate.

9. The composition of any one of claims 1 to 8, wherein the targeting moiety is mannose.

10. 10. The composition of claim 9, wherein the ratio of mannose to backbone monomer is from about 1:5 to about 1:

25.

11. 11. The composition of claim 9 or 10, wherein the ratio of mannose to backbone monomer is from about 1:6 to about 1:

19.

12. The composition according to any one of claims 1 to 8, wherein the degree of substitution of mannose in the cyclodextrin ranges from about 0.1 to about 7.

13. 13. The composition according to any one of claims 1 to 9 or 12, wherein the degree of substitution of mannose in the cyclodextrin is in the range of about 0.5 to 5.

14. The composition of any one of claims 1 to 13, wherein the targeting linker is attached to the glucan backbone via the oxygen atom of the carbamate group.

15. The chain portion of the targeting linker is C ３ -C ７ The composition of any one of claims 1 to 14, comprising an alkylene chain.

16. The chain portion of the targeting linker is C ６ The composition according to any one of claims 1 to 15, comprising an alkylene moiety.

17. The chain portion of the targeting linker is an unsubstituted C ６ The composition according to any one of claims 1 to 16, wherein the aryl group is an alkylene moiety.

18. 18. The composition of any one of claims 1 to 17, wherein the carbon atom of the carbamate group of the targeting linker is the only sp2 hybridized carbon when the linker is attached to mannose.

19. 19. The composition of any one of claims 1 to 18, wherein the tumor-associated macrophage targeting moiety is a moiety that targets CD205 (DEC205), CD206, CD207 (Langerin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL).

20. 20. The compound of claim 19, wherein the tumor-associated macrophage targeting moiety is a CD206 targeting moiety.

21. 21. The composition of any one of claims 1 to 20, wherein the composition has a molar ratio of the TAM targeting moiety to the PBD toxin of about 1:1 to about 1:

10.

22. 21. The composition of any one of claims 1-20, wherein the molar ratio of the TAM targeting moiety to the PBD toxin is about 1:1, about 1:2, or about 1:

3.

23. The composition of claim 1 , wherein the active ingredient is attached to the glucan backbone via a payload linker.

24. 24. The composition of claim 23, wherein the payload linker is a non-cleavable linker.

25. 25. The composition of claim 24, wherein the payload linker comprises a carbamate group and a chain moiety, the carbamate group being connected to the backbone monomer and the chain moiety connecting the carbamate group and the active ingredient.

26. 24. The composition of claim 23, wherein the payload linker is a cleavable linker.

27. 27. The composition of claim 26, wherein the cleavable linker is cleavable by a protease.

28. 28. The composition of claim 27, wherein the protease is a lysosomal or endosomal protease.

29. 27. The composition of claim 26, wherein the cleavable linker is cleavable by a change in pH.

30. The composition of claim 26, wherein the payload linker comprises a Val-Cit moiety.

31. A compound of formula (A-1). 【Transformation 3】

32. A compound of formula (A-2). 【Chemistry 4】

33. 33. A method of delivering a drug to tumor-associated macrophages, comprising contacting said macrophages with a composition according to any one of claims 1 to 30 or a compound according to claim 31 or 32.

34. 33. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition according to any one of claims 1 to 30 or a compound according to claim 31 or 32.

35. 35. The method of claim 34, wherein the cancer is selected from the group consisting of carcinoma, lymphoma, blastoma, sarcoma, leukemia, lymphoid malignancies, squamous cell carcinoma, squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatic cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, anal cancer, penile cancer, and head and neck cancer.

36. 36. The method of claim 34 or 35, wherein the cancer is a sarcoma or glioblastoma.

37. The method of any one of claims 34 to 36, wherein the cancer is a soft tissue sarcoma.

38. 33. A method of treating a non-malignant tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition according to any one of claims 1 to 30 or a compound according to claim 31 or 32.

39. 39. The method of claim 38, wherein the non-malignant tumor is a meningioma hemangioblastoma or giant cell tumor.

40. 38. The method of any one of claims 34 to 37, wherein the subject is administered a second therapeutic agent, adjuvant therapy, or radiation therapy.

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