Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/07—Tetrapeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present disclosure also provides methods of targeting monocytes, macrophages, dendritic cells, and other cells which assemble at disease sites comprising administration of a composition comprising a compound to a subject, wherein the compound comprises a targeting moiety, a glucan backbone, and an active component.
• a composition comprising a compound to a subject, wherein the compound comprises a targeting moiety, a glucan backbone, and an active component.
• Biologics such as antibody and antibody-drug conjugates (ADC) can have profound potency for certain malignancies and have favorable stability in blood.
• ADC antibody and antibody-drug conjugates
• antibodies have limited penetrance into solid tumors, and tumor cells can develop resistance to ADCs through a variety of cellular modifications (Collins, et.al. Acquired Resistance to Antibody-Drug Conjugates. Cancers (Basel) 11, (2019)).
• Improved methods to target, penetrate and kill cancer cells of a solid tumor are needed. Provided are embodiments that meet such needs.
• a method of treatment of a cancer in a subject comprising administering to the subject having the cancer, a composition comprising a compound comprising: i) a tumor-associated macrophage (TAM)-targeting moiety; ii) a glucan 1 sf-5754346 16547-20003.40 backbone, wherein the glucan backbone comprises a plurality of backbone monomers; iii) an active component, wherein the active component is coupled to the glucan backbone; and iv) a targeting linker that links the targeting moiety to the glucan backbone, wherein the targeting linker comprises a carbamate group and a chain moiety, and wherein the carbamate group is connected to a backbone monomer and the chain moiety connects the carbamate group and the tumor-associated macrophage-targeting moiety.
• TAM tumor-associated macrophage
• the plurality of backbone monomers comprises a plurality of D-glucose monomers in a ⁇ -1,6 glycosidic linkage or beta-1,4 glycosidic linkage.
• the glucan backbone is a linear dextran molecule.
• the tumor-associated macrophage-targeting moiety comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N- acetylglucosamine, luteinizing hormone, thyroid stimulating hormone, phospholipase A2 or fragments thereof, or a chondroitin sulfate.
• the targeting moiety is a mannose.
• the ratio of mannose to backbone monomers is about 1 to 5 to about 1 to 33. In some of any embodiments, the ratio of mannose to backbone monomers is about 1 to 6 to about 1 to 19.
• the degree of substitution of mannose on a cyclodextrin ranges from about 0.1 to about 7. In some of any embodiments, the degree of substitution of mannose on a cyclodextrin ranges from about 0.5 to 5.
• the targeting linker is connected to the glucan backbone through the oxygen atom of the carbamate group.
• the chain moiety of the targeting linker comprises a C 3 -C 7 alkylene chain. In some of any embodiments, the chain moiety of the targeting linker comprises a C6-alkylene moiety. In some of any embodiments, the chain moiety of the targeting linker is an unsubstituted C6-alkylene moiety.
• the carbon atom of the carbamate group of the targeting linker is the only sp2-hybridized carbon when said linker is attached to mannose.
• the tumor-associated macrophage-targeting moiety is a moiety targeting CD205 (DEC205), CD206, CD207 (langerin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 2 sf-5754346 16547-20003.40 (MGL).
• the tumor-associated macrophage-targeting moiety is a CD206 targeting moiety.
• the compound has a molar ratio between the TAM- targeting moiety and the active component from about 1:1 to about 1:10.
• the molar ratio between the TAM-targeting moiety and the active component is about 1:1, about 1:2, or about 1:3.
• the active component is coupled to the glucan backbone via a payload linker.
• the active component is cytotoxic agent.
• the cytotoxic agent is selected from the group consisting of an auristatin, a dolastatin, auristatin E, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), dimethylvaline-valine-dolaisoleuine-dolaproine- phenylalanine-p-phenylenediamine (AFP), 5-benzoylvaleric acid-auristatin E ester (AEVB), auristatin EB (AEB), ansamitocin, ivlertansine/emtansine (DMI), ravtansine/soravtansine (DM4), duocarmycins, calicheamicins, and pyrrolobenzodiazepines.
• auristatin a dolastatin
• auristatin E monomethyl auristatin E
• MMAF monomethyl auristatin F
• AFP 5-benzoylvaleric acid-auristatin
• the cytotoxic agent is MMAE.
• the payload linker is a non-cleavable linker.
• the payload 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 and the active component.
• the payload linker is a cleavable linker.
• the cleavable linker is capable of being cleaved by a protease.
• the protease is a lysosomal protease or an endosomal protease.
• the cleavable linker is capable of being cleaved by a pH change.
• the payload linker comprises a Val-Cit moiety.
• the cancer is a solid tumor selected from the group consisting of: carcinoma, lymphoma, blastoma, sarcoma, glioma, leukemia, lymphoid malignancies, squamous cell cancer, epithelial squamous cell cancer, lung cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, gall bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma
• the solid tumor is sarcoma or 3 sf-5754346 16547-20003.40 glioblastoma.
• the cancer is a soft tissue sarcoma.
• the cancer is undifferentiated pleomorphic sarcoma (UPS).
• the subject and/or the cancer (a) is resistant to temozolomide (TMZ) and/or doxorubicin and/or (b) comprises a population of cells that are resistant to inhibition by TMZ and/or doxorubicin.
• the composition is administered to the subject six times daily, five times daily, four times daily, three times daily, twice daily, once daily, every other day, three times a week, two times a week, at least once a week, once a week, once every two weeks, once every three weeks, once every month, once every two months, or once every three months. In some embodiments, the composition is administered to the subject once every two weeks, once every three weeks, or once every month. [0012] In some of any embodiments, the method further comprises administering one or more additional therapeutic agent(s), an adjuvant therapy, and/or radiation therapy to the subject.
• the one or more additional active agent is selected from the group consisting of chemotherapeutic agents, DNA hypomethylating agents, alkylating agents, topoisomerase inhibitors, therapeutic antibodies that specifically bind to cancer antigens, hematopoietic growth factors, cytokines, antibiotics, cox-2 inhibitors, CDK inhibitors, immunomodulators, anti-thymocyte globulin, immunosuppressants, and corticosteroids or pharmacological derivatives thereof.
• the one or more additional active agent(s) is a chemotherapeutic agent.
• the chemotherapeutic agent is TMZ, doxorubicin, and/or paclitaxel.
• the chemotherapeutic agent is administered prior to, concurrently with, and/or subsequently to initiation of administration of the composition to the subject.
• the adjuvant therapy and/or radiation therapy is administered prior to, concurrently with, and/or subsequently to initiation of administration of the composition to the subject.
• the composition is administered intravenously, intraperitoneally, subcutaneously, intramuscularly, intracranially, or by pump infusion to the subject. In some embodiments, the composition is administered intravenously or by pump infusion to the subject.
• a method of treating glioblastoma in a subject comprising administering to the subject having glioblastoma a composition comprising: i) a tumor-associated macrophage (TAM)-targeting moiety; ii) a glucan backbone, wherein the glucan backbone comprises a plurality of backbone monomers; iii) an active component 4 sf-5754346 16547-20003.40 comprising MMAE, wherein the active component is coupled to the glucan backbone; and iv) a targeting linker that links the targeting moiety to the glucan backbone, wherein the targeting linker comprises a carbamate group and a chain moiety, and wherein the carbamate group is connected to a backbone monomer and the chain moiety connects the carbamate group and the tumor-associated macrophage-targeting moiety, wherein the subject and/or the glioblastoma (a) is resistant to TM
• a method of treating brain metastases in a subject comprising administering to the subject having the brain metastases a composition comprising: i) a tumor-associated macrophage (TAM)-targeting moiety; ii) a glucan backbone, wherein the glucan backbone comprises a plurality of backbone monomers; iii) an active component comprising MMAE, wherein the active component is coupled to the glucan backbone; and iv) a targeting linker that links the targeting moiety to the glucan backbone, wherein the targeting linker comprises a carbamate group and a chain moiety, and wherein the carbamate group is connected to a backbone monomer and the chain moiety connects the carbamate group and the tumor-associated macrophage-targeting moiety, wherein the subject and/or the brain metastases (a) is resistant to TMZ and/or (b) comprises a population of cells that are resistant to inhibition by TMZ.
• TAM tumor-associated macrophage
• a method of treating UPS in a subject comprising administering to the subject having UPS a composition comprising: i) a tumor-associated macrophage (TAM)-targeting moiety; ii) a glucan backbone, wherein the glucan backbone comprises a plurality of backbone monomers; iii) an active component comprising MMAE, wherein the active component is coupled to the glucan backbone; and iv) a targeting linker that links the targeting moiety to the glucan backbone, wherein the targeting linker comprises a carbamate group and a chain moiety, and wherein the carbamate group is connected to a backbone monomer and the chain moiety connects the carbamate group and the tumor-associated macrophage-targeting moiety, wherein the subject and/or the UPS (a) is resistant to doxorubicin and/or (b) comprises a population of cells that are resistant to doxorubicin.
• TAM tumor-associated macrophage
• the plurality of backbone monomers comprises a plurality of D-glucose monomers in a ⁇ -1,6 glycosidic linkage or beta-1,4 glycosidic linkage.
• the glucan backbone is a linear dextran molecule.
• the tumor-associated macrophage-targeting moiety comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N- acetylglucosamine, luteinizing hormone, thyroid stimulating hormone, phospholipase A2 or fragments thereof, or a chondroitin sulfate.
• the targeting moiety is a mannose.
• the ratio of mannose to backbone monomers is about 1 to 5 to about 1 to 33.
• the ratio of mannose to backbone monomers is about 1 to 6 to about 1 to 33.
• the degree of substitution of mannose on a cyclodextrin ranges from about 0.1 to about 7. In some of any embodiments, the degree of substitution of mannose on a cyclodextrin ranges from about 0.5 to 5.
• the targeting linker is connected to the glucan backbone through the oxygen atom of the carbamate group.
• the chain moiety of the targeting linker comprises a C 3 -C 7 alkylene chain. In some of any embodiments, the chain moiety of the targeting linker comprises a C6-alkylene moiety.
• the chain moiety of the targeting linker is an unsubstituted C6-alkylene moiety.
• the carbon atom of the carbamate group of the targeting linker is the only sp2-hybridized carbon when said linker is attached to mannose.
• the tumor-associated macrophage-targeting moiety is a moiety targeting CD205 (DEC205), CD206, CD207 (langerin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL).
• the tumor-associated macrophage-targeting moiety is a CD206 targeting moiety.
• the compound has a molar ratio between the TAM-targeting moiety and the active component from about 1:1 to about 1:10. In some of any embodiments, the molar ratio between the TAM-targeting moiety and the active component is about 1:1, about 1:2, or about 1:3.
• the active component is coupled to the glucan backbone via a payload linker. In some embodiments, the payload linker is a non-cleavable linker. In some embodiments, the payload 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 and the active component.
• the payload linker is a cleavable linker.
• the cleavable linker is capable of being cleaved by a protease.
• the protease is a lysosomal protease or an 6 sf-5754346 16547-20003.40 endosomal protease.
• the cleavable linker is capable of being cleaved by a pH change.
• the payload linker comprises a Val-Cit moiety. [0021] In some of any embodiments, the method further comprises administering radiation therapy to the subject.
• the method further comprises administering TMZ and/or doxorubicin to the subject.
• the method attenuates tumor growth in the subject.
• the subject is immunocompetent or immunocompromised.
• the method comprises: i) the tumor-associated macrophage (TAM)-targeting moiety is a CD206 targeting moiety; and ii) the active component is coupled to the glucan backbone via a payload linker, wherein the active component is MMAE and the payload linker is a Val-Cit linker.
• TAM tumor-associated macrophage
• the method comprises: i) the tumor-associated macrophage (TAM)-targeting moiety is a CD206 targeting moiety; and ii) the active component is coupled to the glucan backbone via a payload linker, wherein the active component is MMAE and the payload linker is a Val-Cit linker.
• the method comprises administration of Compound A to the subject.
• kits comprising a composition comprising a compound, wherein the compound comprises: i) a tumor-associated macrophage (TAM)-targeting moiety; ii) a glucan backbone, wherein the glucan backbone comprises a plurality of backbone monomers; iii) an active component, wherein the active component is coupled to the glucan backbone; and iv) a targeting linker that links the targeting moiety to the glucan backbone, wherein the targeting linker comprises a carbamate group and a chain moiety, and wherein the carbamate group is connected to a backbone monomer and the chain moiety connects the carbamate group and the tumor-associated macrophage-targeting moiety; and instructions for administering, to a subject for treating a cancer.
• TAM tumor-associated macrophage
• FIG. 1 is a graphic representation of a candidate compound, wherein a tumor- associated macrophage (TAM)-targeting moiety molecule is labeled with MMAE.
• FIGs. 2A, B depicts the therapeutic effect of Target 5 on tumor volume (FIG. 2A) and body weight (FIG. 2B) in a subcutaneous HT1080 fibrosarcoma model.
• FIG. 3 depicts the therapeutic effect of Target 5 on tumor size (as measured by bioluminescence) in an intracranial challenge with HT1080 cells in a STS brain metastasis model. 7 sf-5754346 16547-20003.40 [0026] FIGs.
• FIGs. 4A-D depicts the efficacy of Target 5 in doxorubicin-resistant UPS PDX model.
• FIGs. 4A and 4B show the effect of Target-5 on tumor volume.
• FIG. 4C shows the effect of Target-5 on tumor volume as compared to doxorubicin. Representative tumors from mice in each treatment group were excised (FIG. 4D).
• FIGs. 5A, B depicts the efficacy of Target 5 on tumor volume (FIG. 5A) and body weight (FIG. 5B) in a subcutaneous glioma model (U87MG cell line).
• FIGs. 6A-6C depicts the efficacy of Target 5 on tumor volume (FIG. 6A and FIG. 6C) and body weight (FIG.
• FIG. 7 depicts the plasma concentration of free MMAE in mice following administration of Target-5.
• FIG. 10 depicts the anti-cancer efficacy of Target-5 in a myxofibrosarcoma PDX model as compared to doxorubicin.
• the method comprises administration of a composition comprising a compound to a subject, wherein the compound comprises a targeting moiety, a glucan backbone, and an active component.
• the targeting moiety is a tumor-associated macrophage-targeting moiety.
• the method comprises administration of the compound to target monocytes, macrophages and other cells (such as dendritic cells), particularly those cells that are assembled at a site of disease.
• the targeting moiety e.g., a tumor-associated macrophage-targeting moiety
• the method comprises administration of a composition comprising a compound, wherein the 8 sf-5754346 16547-20003.40 compound comprises a glucan backbone, a targeting moiety, a targeting moiety linker, a payload, and optionally a payload linker.
• CD206 + cells have been targeted by various molecules in the hopes of delivering diagnostic and therapeutic agents to sites where such cells assemble.
• One example of such molecules is found in US 2017/0209584, entitled, “Compositions for Targeting Macrophages and Other CD206 High Expressing Cells and Methods of Treating and Diagnosis.” While the molecules disclosed in this reference and others may target CD206 + cells of interest, the molecules suffer from a number of short-comings.
• Soft tissue sarcomas STS are rare but deadly cancers of children and adults. The American Cancer Society estimates about 13,000 new STS cases per year in the United States with about 5,130 expected deaths and a 5-year survival for metastatic disease of only 16%.
• Doxorubicin is one of the most active drugs available for the treatment of sarcoma and is often the first-line treatment of undifferentiated/unclassified STS, although cardiotoxicity of doxorubicin can be dose-limiting. Response rates to single doxorubicin treatment significantly decrease after exposure to the drug, indicating that growing resistance to doxorubicin can lead to treatment failure (Das, B. et al. Commun Biol 4, 1312 (2021)).
• GBM Glioblastoma multiforme
• Treatment involves surgery, radiation with concomitant temozolomide (TMZ), followed by 6-12 months of maintenance TMZ.
• STS encompass over 50 different histologic and molecular subtypes, with each displaying variable clinical behavior (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 partly to this variability, current treatment options have yielded limited efficacy, and there are no single or combination treatments that can consistently and effectively treat all STS subtypes. [0040] Tumors are often characterized by a high proportion of tumor-associated mcarophages (TAMs); often representing 30-50% or greater of the total cells in a tumor (Vinogradov et al., Nanomedicine (Lond).
• TAMs tumor-associated mcarophages
• Targeting TAMs as a receiver cell for delivering tumor-killing payloads has the advantage of allowing local delivery of anti-cancer therapy while not adversely affecting the TAMs. This approach also bypasses the difficulties of targeting heterogenous cancer cells as well as circumventing most types of evolved cancer cell resistance .
• Provided herein are methods of treatment that bypass concerns of tumor heterogeneity and evolved drug resistance associated with current therapeutics (e.g. doxorubicin, temozolomide).
• Provided herein are methods of treatment that bypass specific properties of each cancer type.
• the methods comprise administration of a composition comprising a compound.
• the compound comprises a glucan backbone, a targeting moiety, a targeting moiety linker, a payload and optionally a payload linker.
• the arrangement of these components provides a compound that targets tumor-associated macrophages (TAMs).
• TAMs tumor-associated macrophages
• the methods disclosed herein utilize the TAMs as receiver cells to pick up, process, and deliver payloads to the tumor environment.
• sarcomas are characterized by abundant tumor-associated macrophages (TAMs) (Fujiwara et al., “Role of tumor-associated macrophages in sarcomas” Cancers (Basel), 2021, 13(5):1086).
• TAMs tumor-associated macrophages
• the method comprises the internalization of the administered compound by cells (e.g., CD206 + cells) present in tumor-associated macrophages.
• the ability to be internalized by cells present in tumor-associated macrophages allows for the administered compounds and compositions to deliver payloads to disease sites where such cells assemble, such as solid tumor cancers and granulomatous diseases.
• the methods disclosed herein comprise the administration of a composition comprising a compound wherein the compound is larger than typical small molecules but smaller than antibody drug conjugates, allowing excellent penetration into targeted locations and minimal leakage to normal tissues, thereby limiting potential toxicities.
• terminally-differentiated macrophages are under no selective pressures to develop resistance to methods of treatment disclosed herein. A.
• the methods described herein comprise the administration of a compound comprising a glucan backbone, which is a linear, branched, or circular 11 sf-5754346 16547-20003.40 oligosaccharide or polysaccharide comprising a plurality of glucose monomers linked predominantly by C-1 ⁇ C-6 glycosidic bonds. In certain embodiments, other glycosidic bonds such as ⁇ -1,3 or ⁇ -1,4 linkages may also be present. In some embodiments, the plurality of glucose monomers are linked by ⁇ -1,6 and ⁇ -1,3 glycosidic bonds.
• the plurality of glucose monomers are linked by a mixture of ⁇ -1,6 and ⁇ -1,4 glycosidic bonds.
• a glucan backbone may also be defined as a polymer of glucose wherein the position of glycosidic bonds is varied.
• a glucan backbone may also be defined as a polymer of glucose wherein the position of glycosidic bonds is varied.
• a glucan backbone may comprise the alpha or the beta isomer of glucose.
• Glucan backbones include, but are not limited to, dextran, a linear or branched compound, and cyclodextrin, a circular glucan.
• a glucan backbone may vary in mass and molecular weight, as determined in part by the number of glucose monomers.
• a glucan backbone may range in molecular weight from 1-30 kilodaltons (kDa). Preferred embodiments include glucan backbones of approximately 1 kDa, 3 kDa, 6 kDa, 10 kDa, 20 kDa, or 30 kDa.
• the glucan backbone may range in molecular mass from 1,000 to 30,000 grams per mole (g/mol).
• the glucan backbone may contain glucose monomers ranging from 5 to 167 in number.
• the glucan backbone can be linear, branched, circular, or combinations thereof.
• dextran is an example of a linear or branched glucan backbone.
• Cyclodextrin is another example of a glucan backbone.
• the backbones described here can be substituted or unsubstituted.
• a substituted cyclodextrin is a cyclodextrin derivative that is hydrophobic, hydrophilic, ionized, non-ionized, or any other variation thereof.
• the glucan backbone comprises a plurality of backbone monomers, wherein the plurality of backbone monomers comprises a plurality of D-glucose monomers in a ⁇ -1,6 glycosidic linkage or beta-1,4 glycosidic linkage.
• the plurality of backbone monomers comprises a plurality of D-glucose monomers in a beta-1,4 glycosidic linkage.
• 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.
• 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) which are present on a tumor or near a tumor, allowing targeted delivery of payloads to the tumor.
• the targeting moiety is a CD205 targeting moiety.
• the targeting moiety is a CD206 targeting moiety.
• the targeting moiety is a CD207 targeting moiety.
• the targeting moiety is a CD209 targeting moiety.
• the targeting moiety is a CD280 targeting moiety.
• the targeting moiety is a CD301 targeting moiety. In some embodiments, the targeting moiety is a CD206 ligand. [0051] In some embodiments, the target receptor is on a tumor-associated macrophage. In some embodiments, the target receptor is on a cancer or tumor cell.
• a targeting moiety may be a molecule, a compound, a structure, or any combination thereof that targets one or more pattern recognition receptors on tumor-associated macrophage or a cancer or tumor cell.
• the targeting moiety may target a pattern recognition receptor that is also be characterized as a C-type lectin receptor. In a specific embodiment, the targeting moiety targets CD206, a mannose receptor.
• the targeting moiety comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N-acetylglucosamine, luteinizing hormone, thyroid stimulating hormone, phospholipase A2 or fragments thereof, or a chondroitin sulfate.
• the targeting moiety comprises a mannose, including D- and L-isomers thereof.
• the targeting moiety comprises a furanose.
• the targeting moiety comprises a pyranose.
• the targeting moiety is D- mannose.
• the tumor-associated macrophage-targeting moiety may be referred to as the targeting moiety.
• the targeting moieties are attached to between about 10% and about 50% of the glucose residues of the glucan backbone, or between about 20% and about 45% of the glucose residues, or between about 25% and about 40% of the glucose residues.
• C. Ratio of targeting linker to backbone [0054] The density of a targeting moiety relative to backbone subunits is presented using a targeting moiety to backbone subunit ratio for linear, branched, or circular polysaccharide 13 sf-5754346 16547-20003.40 backbones.
• degree of substitution is used to communicate the density of targeting moieties on a glucan backbone.
• the ratio of a targeting moiety to a glucan backbone refers to the number of targeting moieties that substitute a backbone subunit or subunits. For example, a ratio of 1:7 or 1 to 7 means that there is one targeting moiety for every seven glucose subunits in a glucan backbone.
• the d.s. describes the average number of substituents or substituted positions per unit base. For example, a d.s. of 0.9 means that one backbone subunit is substituted with an average of 0.9 targeting moieties.
• the targeting moiety to backbone subunit ratio is from about 1:5 to about 1:25.
• the targeting moiety to backbone subunit ratio is from 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 targeting moiety to backbone subunit ratio is from about 1:6 to about 1:19. In some embodiments, the targeting moiety to backbone subunit ratio is or is about 1:1. In some embodiments, the targeting moiety to backbone subunit ratio is or is about 2:1. In some embodiments, the targeting moiety to backbone subunit ratio is or is about 3:1. In some embodiments, the d.s. is from about 0.1 to about 7. In some embodiments, the d.s. is from about 0.5 to 5.
• the targeting moiety comprises a mannose.
• the method described herein comprises the administration of a compound comprising a targeting moiety coupled to the glucan backbone by a targeting linker.
• the targeting linker is a cleavable or a non-cleavable linker.
• a cleavable linker is capable of being 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 may comprise a protease cleavage site.
• the cleavable linker is capable of cleavage by a lysosomal protease or an endosomal protease.
• the targeting linker may comprise a carbamate group.
• the targeting linker comprises a carbamate group and a chain moiety, wherein the carbamate group is connected to a backbone monomer and the chain moiety connects the carbamate group and the targeting moiety.
• a carbamate functional group takes the plain and ordinary meaning derived from the field of organic chemistry.
• 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 14 sf-5754346 16547-20003.40 chain, an optionally substituted CO-alkylene chain, a peptide chain, a polymeric chain, and a heteroatom selected from the group consisting of an O atom, a S atom, and an optionally substituted N atom.
• the chain moiety comprises a C1-C12 alkylene chain.
• the chain moiety comprises a C 3 -C 7 alkylene chain.
• the chain moiety comprises a C6 alkylene chain.
• the chain moiety is a C6 alkylene chain.
• the alkylene chain is substituted by one or more substituents selected from the group consisting of oxo, OH, NH 2 , SH, C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, O(C1-C12 alkyl), O(C1-C12 haloalkyl), NH(C1-C12 alkyl), NH(C1-C12 haloalkyl), N(C1- C12 alkyl)2, N(C1-C12 haloalkyl)2, , S(C1-C12 alkyl), S(C1-C12 haloalkyl), C(O)OH, C(O)O(C1-C12 alkyl), C(O)O(C 1 -C 12 haloalkyl), C(O)NH(C 1 -C 12 alkyl), C(O)NH(C 1 -C 12 alkyl),
• the alkylene chain is unsubstituted.
• one or more targeting moieties are attached to the glucan backbone through a linker.
• the linker may be attached at from about 1 to about 50% of the backbone moieties.
• the targeting linker comprises a C1-12 alkylene chain and a carbamate group, wherein the carbamate group is connected to the backbone monomer and the C 1-12 alkylene chain connects the carbamate group and the targeting moiety.
• the method described herein comprises the administration of a compound comprising an active component.
• an active component is a molecule or a compound that may be used for diagnostic purposes, therapeutic purposes, or a combination thereof.
• An active component is also referred to as a payload.
• an active component may be or comprise a cytotoxic agent, an imaging agent, or a combination thereof.
• a payload may facilitate targeted delivery of the compounds described herein to the tumor-associated macrophages or cancer cells.
• the payload is a hydrophobic payload (e.g., topoisomerase inhibitor I, topoisomerase inhibitor II, or temozolomide).
• the payload is a hydrophilic payload.
• the active component is a therapeutic agent.
• the therapeutic agent may be any compound known to be useful for the treatment of a macrophage-mediated disease.
• Therapeutic agents include, but are not limited to, chemotherapeutic agents, such as doxorubicin; alkylating agents, such as temozolomide; anti-infective agents, such as antibiotics 15 sf-5754346 16547-20003.40 (e.g.
• tetracycline tetracycline, streptomycin, rifampin, and isoniazid
• anti-virals anti-fungals
• anti- parasitics immunological adjuvants
• steroids nucleotides, such as DNA, RNA, RNAi, siRNA, CpG or Poly (I:C); peptides; proteins; antibody-drug conjugates (e.g. trastuzumab deruxtecan) or metals such as silver, gallium or gadolinium.
• nucleotides such as DNA, RNA, RNAi, siRNA, CpG or Poly (I:C)
• peptides proteins
• antibody-drug conjugates e.g. trastuzumab deruxtecan
• metals such as silver, gallium or gadolinium.
• the therapeutic agent is selected from a group including, but not limited to, cytostatic agents, alkylating agents, antimetabolites, anti-proliferative agents, tubulin binding agents, hormones and hormone antagonists, anthracycline drugs, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, pteridine drugs, diynenes, podophyllotoxins, toxic enzymes, and radiosensitizing drugs.
• the therapeutic agent is selected from the group consisting of lomustine, epirubicin, topotecan, irinotecan, pemetrexed, docetaxel, oxaliplatin, altretamine, valrubicin, sarcin, temozolomide, mechlorethamine, triethylenephosphoramide, cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, triaziquone, nitrosourea compounds, adriamycin, carminomycin, daunorubicin (daunomycin), doxorubicin, isoniazid, rifampin, indomethacin, gallium(III), 68gallium(III), aminopterin, methotrexate, methopterin, mithramycin, streptonigrin, dichloromethotrexate, mitomycin C, actinomycin-D, porfir
• the active component is a cytotoxic agent or comprises a cytotoxic agent.
• the cytotoxic agent is a chemotherapeutic agent, an antitubulin agent, a DNA modifying agent, or a small interfering ribonucleic acid.
• the cytotoxic agent is selected from the group consisting of an auristatin, a dolastatin, auristatin E, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), dimethylvaline-valine-dolaisoleuine-dolaproine-phenylalanine-p-phenylenediamine (AFP), 5- benzoylvaleric acid-auristatin E ester (AEVB), auristatin EB (AEB), ansamitocin, ivlertansine/emtansine (DMI), ravtansine/soravtansine (DM4), duocarmycins, calicheamicins, and pyrrolobenzodiazepines.
• auristatin a dolastatin
• auristatin E monomethyl auristatin E
• MMAF monomethyl auristatin F
• AFP dimethylvaline-valine-dolaisoleuine
• the active component is MMAE. 16 sf-5754346 16547-20003.40 F. Payload Linker [0063]
• the active component or payload is coupled directly to the glucan backbone.
• the active component is connected to a glucan backbone via a linker.
• the linker can be cleavable or non-cleavable.
• the one or more therapeutic agent is attached via a biodegradable linker.
• the biodegradable linker is acid sensitive, such as a hydrazone linker. The use of an acid sensitive linker enables the drug to be transported into the cell and allows for the release of the drug substantially inside of the cell.
• the payload linker is a Val-Cit linker.
• the payload linker may comprise a carbamate group.
• the payload linker comprises a carbamate group and a chain moiety, wherein the carbamate group is connected to a backbone monomer and the chain moiety connects the carbamate group and the active component.
• a carbamate functional group takes the plain and ordinary meaning derived from the field of organic chemistry.
• the chain moiety of the payload 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 polymeric chain, and a heteroatom selected from the group consisting of an O atom, a S atom, and an optionally substituted N atom.
• the chain moiety comprises a C1-C12 alkylene chain.
• the chain moiety comprises a C3-C7 alkylene chain.
• the chain moiety comprises a C 6 alkylene chain.
• the chain moiety is a C 6 alkylene chain.
• the alkylene chain is substituted by one or more substituents selected from the group consisting of oxo, OH, NH2, SH, C1-C12 alkyl, C1-C12 haloalkyl, O(C1-C12 alkyl), O(C1-C12 haloalkyl), NH(C1-C12 alkyl), NH(C1-C12 haloalkyl), N(C1-C12 alkyl)2, N(C1-C12 haloalkyl) 2, , S(C 1 -C 12 alkyl), S(C 1 -C 12 haloalkyl), C(O)OH, C(O)O(C 1 -C 12 alkyl), C(O)O(C 1 -C 12 haloalkyl), C(O)NH(C1-C12 alkyl), C(O)NH(C1-C12 alkyl), C(O
• the alkylene chain is unsubstituted.
• the molar ratio between the targeting moiety (e.g., mannose) and the payload is from about 1:10 to about 10:1. In some embodiments, the molar ratio between the targeting moiety and the payload 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 between the targeting moiety and the payload is about 1:1. In some embodiments, the molar ratio between the targeting moiety and the payload is about 1:2.
• the molar ratio 17 sf-5754346 16547-20003.40 between the targeting moiety and the payload is about 1:3. In some embodiments, the molar ratio between the targeting moiety and the payload is about 1:4.
• the payload linker comprises a -C(O)-C1-12 alkylene chain and a carbamate group, wherein the carbamate group is connected to the backbone monomer and the -C(O)-C1-12 alkylene chain connects the carbamate group and the payload.
• the compounds used in the methods disclosed here can encompass the inclusion of secondary agents that can be coupled to the glucan backbone to add additional functional capabilities.
• the secondary payload is coupled to the linker in a manner similar to that used to couple the targeting moiety to the targeting linker.
• a secondary payload may facilitate targeted delivery of the compositions described herein to the macrophages or cancer cells.
• the secondary payload is a hydrophobic payload (e.g., topoisomerase inhibitor I, topoisomerase inhibitor II, or temozolomide).
• the secondary payload is a hydrophilic payload.
• a secondary payload may be a radiosensitizer. See, e.g., Zhang et al., “Application of Radiosensitizers in Cancer Radiotherapy” Int J Nanomedicine, 2021, 16:1083-1102.
• the radiosensitizer is a small molecule radiosensitizer including, but not limited to, monomethyl auristatin E (MMAE), mitomycin C, misonidazole, curcumin, or paclitaxel.
• MMAE monomethyl auristatin E
• mitomycin C mitomycin C
• misonidazole misonidazole
• curcumin curcumin
• paclitaxel paclitaxel
• a secondary payload may be an anti-tuberculosis medicine (e.g., rifampin or isoniazid).
• a secondary payload can encompass, for example, additional agents for imaging, therapy, or for other purposes. Specifically, in one embodiment, combinations of therapeutic and imaging agents can be linked to the glucan backbone to combine diagnostic and therapeutic functionalities. In another embodiment, various amino acids, such as cysteine or lysine can be coupled to the linker to crosslink the molecule to a target.
• a secondary payload linker is a cleavable or a non-cleavable linker that connects a glucan backbone to a secondary payload moiety.
• a cleavable linker is capable of being 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 may comprise a protease cleavage site.
• the cleavable linker is capable of cleavage by a lysosomal protease or an endosomal protease. 18 sf-5754346 16547-20003.40 [0071]
• the secondary payload linker may comprise a carbamate group.
• the secondary payload linker comprises a carbamate group and a chain moiety, wherein the carbamate group is connected to a backbone monomer and the chain moiety connects the carbamate group and the secondary agent.
• a carbamate functional group takes the plain and ordinary meaning derived from the field of organic chemistry.
• the chain moiety of the secondary payload 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 polymeric chain, and a heteroatom selected from the group consisting of an O atom, a S atom, and an optionally substituted N atom.
• the chain moiety comprises a C 1 -C 12 alkylene chain.
• the chain moiety comprises a C 3 -C 7 alkylene chain.
• the chain moiety comprises a C6 alkylene chain.
• the chain moiety is a C6 alkylene chain.
• the alkylene chain is substituted by one or more substituents selected from the group consisting of oxo, OH, NH 2 , SH, C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, O(C1-C12 alkyl), O(C1-C12 haloalkyl), NH(C1-C12 alkyl), NH(C1-C12 haloalkyl), N(C1- C12 alkyl)2, N(C1-C12 haloalkyl)2, , S(C1-C12 alkyl), S(C1-C12 haloalkyl), C(O)OH, C(O)O(C1-C12 alkyl), C(O)O(C 1 -C 12 haloalkyl), C(O)NH(C 1 -C 12 alkyl), C(O)NH(C 1 -C 12 alkyl),
• the alkylene chain is unsubstituted.
• the one or more secondary payload moieties are attached to the glucan backbone through a linker.
• the linker may be attached at from about 1 to about 50% of the backbone moieties.
• the composition described herein comprises Compound A or a pharmaceutically acceptable salt thereof: 19 sf-5754346 16547-20003.40 Compound A.
• monomers of the types labelled with a, c, or d in Compound A may be in a block co-polymer arrangement or may be randomly arranged within the polymer or any combination thereof unless otherwise indicated.
• a, c, and d of Compound A may each independently refer to an integer of 0, at least 1, from about 1 to about 165, from about 16 to about 111, from about 50 to about 65, from about 5 to about 167, or from about 6 to about 16.
• the glucan backbone of Compound A is linear, branched, circular, or combinations thereof.
• an end group of the glucan backbone of Compound A may be a hydroxy end group of the monomer.
• an end group of the glucan backbone of Compound A may be any end groups recognizable by one skilled in the art.
• the glucan backbone of Compound A is linear, branched, circular, or combinations thereof; a, c, and d is each independently elected from the group consisting of: an integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 5 to about 167, an integer from about 50 to about 65, and an integer from about 6 to about 16; and the end group of the glucan backbone is a hydroxy end group of the monomer.
• the glucan backbone of Compound A is circular, and a, c, and d is each independently elected from the group consisting of: an integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 5 to about 167, an integer from about 20 sf-5754346 16547-20003.40 50 to about 65, and an integer from about 6 to about 16.
• the glucan backbone of Compound A is linear; a, c, and d is each independently elected from the group consisting of: an integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 5 to about 167, an integer from about 50 to about 65, and an integer from about 6 to about 16; and the end group of the glucan backbone is a hydroxy end group of the monomer.
• the glucan backbone of Compound A is branched; a, c, and d is each independently elected from the group consisting of: an integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 5 to about 167, an integer from about 50 to about 65, and an integer from about 6 to about 16; and the end group of the glucan backbone is a hydroxy end group of the monomer.
• the glucan backbone of Compound A is about 6 kDa, wherein the glucan backbone is a dextran.
• the a, c, and d groups of Compound A are interspersed.
• the end groups of the glucan backbone is a natural end group of glucose, such as a hydroxy end group.
• the ratio of the targeting moiety to backbone monomers of Compound A is about 1:30 to 1:40 (e.g., 1:33).
• the ratio of the MMAE to mannose of Compound A is about 1:1 to 1:3 (e.g., 1:1) or about 1:3 to 1:5 (e.g., 1:4).
• glucan backbone is a dextran; the molecular weight of the glucan backbone is about 6 kDa; the a, c, and d groups are interspersed; the end groups of the glucan backbone is a natural end group of glucose, such as a hydroxy end group; the ratio of the targeting moiety to backbone monomers of is about 1:30 to 1:40 (e.g., 1:33); and the ratio of the MMAE to mannose is about 1:1 to 1:3 (e.g., 1:1).
• glucan backbone is a dextran; the molecular weight of the glucan backbone is about 6 kDa; the a, c, and d groups are interspersed; the end groups of the glucan backbone is a natural end group of glucose, such as a hydroxy end group; the ratio of the targeting moiety to backbone monomers of is about 1:33 to 1:40 (e.g., 1:37); and the ratio of the MMAE to mannose is about 1:3 to 1:5 (e.g., 1:4). 21 sf-5754346 16547-20003.40 III.
• compositions comprising the compound, including pharmaceutical compositions and formulations.
• the method described herein comprises the administration of the composition for the treatment of a disease.
• the disease is cancer.
• pharmaceutical formulations comprising the compound and additional agents for combination treatment or therapy.
• the pharmaceutical compositions and formulations generally include one or more optional pharmaceutically acceptable carriers or excipients.
• the composition includes at least one additional therapeutic agent.
• pharmaceutical formulation refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
• a “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
• a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
• the choice of carrier is determined in part by the method of administration. Accordingly, there are a variety of suitable formulations.
• the pharmaceutical composition can contain preservatives. Suitable preservatives may include, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. In some aspects, a mixture of two or more preservatives is used.
• the preservative or mixtures thereof are typically present in an amount of about 0.0001% to about 2% by weight of the total composition.
• Carriers are described, e.g., by Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
• Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10
• Buffering agents in some aspects are included in the compositions. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. In some aspects, a mixture of two or more buffering agents is used. The buffering agent or mixtures thereof are typically present in an amount of about 0.001% to about 4% by weight of the total composition. Methods for preparing administrable pharmaceutical compositions are known. Exemplary methods are described in more detail in, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).
• the formulation or composition may also contain more than one active ingredient useful for the particular indication, disease, or condition being treated with the compound or composition.
• active ingredients are suitably present in combination in amounts that are effective for the purpose intended.
• the pharmaceutical composition further includes other pharmaceutically active agents or drugs, such as chemotherapeutic agents, e.g., asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, temozolomide, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc.
• chemotherapeutic agents e.g., asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, temozolomide, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituxim
• the compound or composition is administered in the form of a salt, e.g., a pharmaceutically acceptable salt.
• Suitable pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids, for example, p-toluenesulphonic acid.
• the formulation or composition comprises doxorubicin, temozolomide, and/or paclitaxel.
• Active ingredients may be entrapped in microcapsules, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
• the pharmaceutical composition is formulated as an inclusion complex, such as cyclodextrin inclusion complex, or as a liposome.
• Liposomes can serve to target the host cells (e.g., T-cells or NK cells) to a particular tissue. Many methods are available for preparing liposomes, such as those described in, for example, Szoka et al., Ann. Rev. Biophys. Bioeng., 9: 467 (1980), and U.S.
• the pharmaceutical composition in some aspects can employ time-released, delayed release, and sustained release delivery systems such that the delivery of the composition occurs prior to, and with sufficient time to cause, sensitization of the site to be treated. Many types of release delivery systems are available and known. Such systems can avoid repeated administrations of the composition, thereby increasing convenience to the subject and the physician.
• the pharmaceutical composition in some embodiments contains the compound in amounts effective to treat or prevent the disease or condition, such as a therapeutically effective or prophylactically effective amount to treat a disease or disorder.
• Therapeutic or prophylactic efficacy in some embodiments is monitored by periodic assessment of treated subjects. For repeated administrations over several days or longer, depending on the condition, the treatment is repeated until a desired suppression of disease symptoms occurs.
• other dosage regimens may be useful and can be determined.
• the desired dosage can be delivered by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition. In some embodiments, administration by continuous infusion may be accomplished through use of a pump.
• the composition may be administered using standard administration techniques, formulations, and/or devices. Provided are formulations and devices, such as syringes and vials, for storage and administration of the compositions.
• Formulations include those for oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.
• the composition is administered parenterally.
• parenteral includes intravenous, intramuscular, subcutaneous, rectal, vaginal, intracranial, intrathoracic, and intraperitoneal administration.
• the composition is administered to a subject using peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection.
• compositions in some embodiments are provided as sterile liquid preparations, e.g., isotonic aqueous solutions, suspensions, emulsions, dispersions, or viscous compositions, which may in some aspects be buffered to a selected pH.
• sterile liquid preparations e.g., isotonic aqueous solutions, suspensions, emulsions, dispersions, or viscous compositions, which may in some aspects be buffered to a selected pH.
• Liquid preparations are normally easier to prepare than gels, other viscous compositions, and solid compositions. Additionally, liquid compositions are somewhat more convenient to administer, especially by injection. Viscous compositions, on the other hand, can be formulated within the appropriate viscosity range to provide longer contact periods with specific tissues.
• Liquid or viscous compositions can comprise carriers, which can be a solvent or dispersing medium containing, for example, water, 24 sf-5754346 16547-20003.40 saline, phosphate buffered saline, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol) and suitable mixtures thereof.
• saline phosphate buffered saline
• polyol for example, glycerol, propylene glycol, liquid polyethylene glycol
• Sterile injectable solutions can be prepared by incorporating the binding molecule in a solvent, such as in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, dextrose, or the like.
• the compositions can also be lyophilized.
• compositions can contain auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methylcellulose), pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard texts may in some aspects be consulted to prepare suitable preparations.
• auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methylcellulose), pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard texts may in some aspects be consulted to prepare suitable preparations.
• Various additives which enhance the stability and sterility of the compositions including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens
• Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
• Sustained-release preparations may be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules.
• the formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.
• any of the additional agents for combination therapy described herein can be prepared and administered as one or more pharmaceutical compositions comprising the compound.
• the combination therapy can be administered in one or more pharmaceutical compositions.
• IV. METHODS AND USES [0094] Provided herein are methods, such as methods of treatment, of using and uses of the compound and/or pharmaceutical compositions and formulations thereof, such as in the treatment or prevention of a disease or disorder. Also provided are methods of combination therapy comprising the compound and/or pharmaceutical composition for treatment or prevention of a disease or disorder. Also provided are methods of targeting tumor-associated macrophages (TAMs). In some embodiments, the methods of use may be for the targeting of 25 sf-5754346 16547-20003.40 macrophages for treatment of intracellular pathogens (M.
• TAMs tumor-associated macrophages
• the method disclosed herein may be used to target tumor-associated macrophages.
• the methods disclosed herein may to be used for treating cancer.
• the methods disclosed herein may be used for treating drug resistant cancer, cancer cells, and/or tumors (e.g. doxorubicin-resistant cancer, temolozide- resistant cancer).
• the method of treatment comprise the administration of a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to monomethyl auristatin E (MMAE).
• MMAE monomethyl auristatin E
• CD205 e.g soft tissue sarcomas or glioblastomas
• non- malignant tumors e.g., meningiomas hemangioblastomas or giant cell tumors
• chronic infectious diseases e.g.. tuberculosis
• a granulomatous disease e.g.. sarcoidosis
• nonmalignant tumors include, but are not limited to, meningioma of all grades (e.g., grade 1 meningioma, grade 2 meningioma, or grade 3 meningioma), schwannomas, schwannomatosis, neurofibromas, neurofibromatosis type 1 (NF1), or neurofibromatosis type 2 (NF2).
• the cancer can be any cell in a subject undergoing unregulated growth.
• the cancer can be any cancer cell capable of metastasis.
• the cancer can be a sarcoma, glioma, lymphoma, leukemia, carcinoma, blastoma, or germ cell tumor.
• the cancer is selected from the group consisting of: carcinoma, lymphoma, blastoma, sarcoma, glioma, leukemia, lymphoid malignancies, squamous cell cancer, epithelial squamous cell cancer, lung cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric cancer, stomach cancer, gastrointestinal cancer, squamous cell of the esophagus, hepatocellular carcinoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, gall bladder cancer, hepatoma, breast cancer (e.g., HR+/HER2- breast cancer, HR-/HER2- breast cancer, HR+/HER2+ breast cancer, or HR- /HER2+ breast cancer), colon cancer, rectal cancer, colorectal cancer, endometri
• the non-malignant tumor is meningiomas hemangioblastomas or giant cell 26 sf-5754346 16547-20003.40 tumors.
• the cancer is a brain metastases derived from a cancer.
• the cancer is a solid tumor.
• the cancer is a soft tissue sarcoma.
• the soft tissue sarcoma may be, but is not limited to, angiosarcoma, dermatofibrosarcoma protuberans, epithelioid sarcoma, gastrointestinal stromal tumor (GIST), Kaposi's sarcoma, leiomyosarcoma, liposarcoma, malignant peripheral nerve sheath tumors, myxofibrosarcoma, rhabdomyosarcoma, solitary fibrous tumor, synovial sarcoma, undifferentiated pleomorphic sarcoma (UPS), desmoid tumor, hemangiopericytoma, fibrosarcoma, vascular sarcoma, alveolar soft part sarcoma (ASPS), clear cell sarcoma and melanoma of soft parts, extraskeletal myxoid chondrosarcoma (EMC), Ewing sarcoma, or desmoplastic round cell tumors.
• GIST gastrointestinal stromal
• the cancer is undifferentiated pleomorphic sarcoma (UPS).
• UPS undifferentiated pleomorphic sarcoma
• the cancer is a glioma.
• the glioma may be an astrocytoma, ependymomas, or oligodendroglioma.
• the cancer is an astrocytoma.
• the cancer is a glioblastoma (glioblastoma multiforme).
• the methods described herein comprise the administration of a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to monomethyl auristatin E (MMAE) for the treatment of soft tissue sarcoma to a subject in need thereof.
• the methods described herein comprise the administration of a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to monomethyl auristatin E (MMAE) for the treatment of undifferentiated pleomorphic sarcoma (UPS) to a subject in need thereof.
• MMAE monomethyl auristatin E
• the methods described herein comprise the administration of a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to monomethyl auristatin E (MMAE) for the treatment of glioblastoma multiforme to a subject in need thereof.
• MMAE monomethyl auristatin E
• the cancer, cancer cell, and/or tumor are resistant to commonly administered therapies.
• the cancer, cancer cell, or tumor are resistant to commonly administered chemotherapeutic agents.
• the cancer, cancer cell, and/or tumor are resistant to inhibition by doxorubicin or temozolomide.
• the methods described herein comprise administration of the compound and/or pharmaceutical composition for the treatment of a drug-resistant cancer, cancer cells, 27 sf-5754346 16547-20003.40 and/or tumor to a subject in need thereof.
• the methods described herein comprise administration of the compound and/or pharmaceutical composition for the treatment of a doxorubicin-resistant cancer, cancer cells, and/or tumor to a subject in need thereof.
• the methods described herein comprise administration of the compound and/or pharmaceutical composition for the treatment of a temozolomide-resistant cancer, cancer cells, and/or tumor to a subject in need thereof.
• the methods described herein comprise the administration of a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to monomethyl auristatin E (MMAE) for the treatment of a doxorubicin-resistant cancer, cancer cells, and/or tumor to a subject in need thereof.
• the methods described herein comprise the administration of a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine- citrulline linker to monomethyl auristatin E (MMAE) for the treatment of a temozolomide- resistant cancer, cancer cells, and/or tumor to a subject in need thereof.
• the method of treatment comprises the administration of an effective amount of the compound and/or pharmaceutical composition for the treatment of autoimmune diseases, such as rheumatoid arthritis, lupus (SLE), or vasculitis.
• the method of treatment comprises the administration of an effective amount of the compound and/or pharmaceutical composition for treating an inflammatory disease, such as Crohn's disease, inflammatory bowel disease, or collagen-vascular diseases.
• the method of treatment comprises the administration of the compound and/or pharmaceutical composition for treating a macrophage-mediated disorder.
• the compositions disclosed herein may also be used to treat a lysosomal storage disease.
• a lysosomal storage disease includes, but is not limited to, Cholesterly ester storage disease, Wolman disease, Hunter syndrome, Hurler’s disease, Fabry disease, Gaucher disease, Krabb disease (globoid cell leukodystrophy) Metachromatic leukodystrophy, Niemann-Pick disease, Sandhoff disease, Tay-Sachs disease, Batten disease, Cystinosis, Danon disease, and Pompe disease.
• Cholesterly ester storage disease includes, but is not limited to, Cholesterly ester storage disease, Wolman disease, Hunter syndrome, Hurler’s disease, Fabry disease, Gaucher disease, Krabb disease (globoid cell leukodystrophy) Metachromatic leukodystrophy, Niemann-Pick disease, Sandhoff disease, Tay-Sachs disease, Batten disease, Cystinosis, Danon disease, and Pompe disease.
• Cholesterly ester storage disease includes, but is not limited to, Cholesterly ester storage disease, Wo
• the methods disclosed herein include administration of the compound or pharmaceutical composition via any suitable method to a subject, for example, by injection, e.g., intravenous or subcutaneous injections, intraocular injection, periocular injection, 28 sf-5754346 16547-20003.40 subretinal injection, intravitreal injection, trans-septal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjunctival injection, sub-Tenon's injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery.
• injection e.g., intravenous or subcutaneous injections, intraocular injection, periocular injection, 28 sf-5754346 16547-20003.40 subretinal injection, intravitreal injection, trans-septal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjunctival injection, sub-Tenon's injection, retrobulbar injection, peribulbar injection, or posterior
• the compound or composition is administered by parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration.
• Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, intracranial, intrathoracic, or subcutaneous administration.
• the method comprises administration of the compound or pharmaceutical composition parenterally into the parenchyma or into the circulation so that the disclosed compounds reach target tissues (e.g., where cancer cells may be located).
• the method comprises administration of the compound or pharmaceutical composition directly into or adjacent to a tumor mass.
• Parenteral administration of the compounds, if used, is generally characterized by injection.
• Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions.
• a revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained.
• Dosing and administration may depend in part on whether the administration is brief or chronic. Various dosing schedules include but are not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion. In some embodiments, a pump may be used for sustained administration.
• the appropriate dosage of the compound or pharmaceutical composition may depend on the type of disease to be treated, the severity and course of the disease, whether the compound or pharmaceutical composition is administered for preventive or therapeutic purposes, previous therapy, the subject's clinical history, and the discretion of the attending physician.
• the compound or pharmaceutical composition are in some embodiments suitably administered to the patient at one time or over a series of treatments.
• a dose of the compound or composition is administered to the subject as a single dose or is administered only one time within a period of two weeks, one month, three months, six months, 1 year or more.
• a dose of the compound or composition is administered to the subject over multiple administrations.
• the dose is administered to the subject once a day. In some embodiments, the dose is administered to the subject multiple times per day. In some embodiments, the dose is administered to the subject six times daily, five times daily, four times daily, three times daily, 29 sf-5754346 16547-20003.40 twice daily, once daily, every other day, three times a week, two times a week, at least once a week, once a week, once every two weeks, once every three weeks, once every month, once every two months, or once every three months. In certain embodiments, the dose is administered to the subject once every two weeks, once every three weeks, or once every month. B. Combination Therapy [0109] Also provided herein are methods of treating a disease or disorder (e.g.
• combination therapy comprising an effective amount of the compound and/or pharmaceutical composition and additional therapeutic agents or interventions to a subject in need thereof.
• the compound and/or pharmaceutical composition is administered simultaneously with the additional therapeutic agents or interventions.
• the compound and/or pharmaceutical composition is administered sequentially, in any order, with the additional therapeutic agents or interventions.
• the additional therapeutic agents or interventions can include, but are not limited to, chemotherapeutic agents, DNA hypomethylating agents, alkylating agents, topoisomerase inhibitors, therapeutic antibodies that specifically bind to cancer antigens, hematopoietic growth factors, cytokines, antibiotics, cox-2 inhibitors, CDK inhibitors, immunomodulators, anti-thymocyte globulin, immunosuppressants, corticosteroids or pharmacological derivatives thereof, radiation, surgery, and adjuvant therapy.
• the compound and/or pharmaceutical composition is administered in combination with a cytotoxic or therapeutic agent.
• the compound and/or pharmaceutical composition is administered in combination with a chemotherapeutic agent.
• the chemotherapeutic agent comprises temozolomide (TMZ), doxorubicin, and/or paclitaxel.
• the compound and/or pharmaceutical composition is administered with an adjuvant therapy.
• the compound and/or pharmaceutical composition is administered with radiation therapy.
• the combination therapy comprises the compound and/or pharmaceutical composition and one additional therapeutic agent or intervention.
• the combination therapy comprises the compound and/or pharmaceutical composition and more than one additional therapeutic agent or intervention.
• the methods disclosed herein comprise administration of the compound and/or pharmaceutical composition in combination with an effective amount of doxorubicin to a subject in need thereof.
• the methods disclosed herein 30 sf-5754346 16547-20003.40 comprise administration of the compound and/or pharmaceutical composition in combination with an effective amount of temozolomide to a subject in need thereof.
• the methods disclosed herein comprise administration of the compound and/or pharmaceutical composition in combination with paclitaxel to a subject in need thereof.
• the methods described herein comprise the administration of a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine- citrulline linker to MMAE in combination with an effective amount of doxorubicin to a subject in need thereof.
• the methods described herein comprise the administration of a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to MMAE in combination with an effective amount of temozolomide to a subject in need thereof.
• the methods described herein comprise the administration of a composition comprising a compound comprising a mannosylated dextran backbone connected by a valine-citrulline linker to MMAE in combination with an effective amount of paclitaxel to a subject in need thereof.
• the compound and/or pharmaceutical composition is co- administered with one or more additional therapeutic agents or in connection with another therapeutic intervention, either simultaneously or sequentially in any order.
• the compound and/or pharmaceutical composition is co-administered with another therapy sufficiently close in time such that the dose may enhance the effect of one or more additional therapeutic agents, or vice versa.
• the compound and/or pharmaceutical composition is administered prior to the one or more additional therapeutic agents.
• the compound and/or pharmaceutical composition is administered after to the one or more additional therapeutic agents.
• the containers may be formed from a variety of materials such as glass or plastic.
• the container has a sterile access port.
• Exemplary containers include an intravenous solution bags, vials, including those with stoppers pierceable by a needle for injection.
• the article of manufacture or kit may further include a package insert indicating that the compositions can be used to treat a particular 31 sf-5754346 16547-20003.40 condition such as a condition described herein (e.g., cancer).
• the article of manufacture or kit may further include another or the same container comprising a pharmaceutically-acceptable buffer. It may further include other materials such as other buffers, diluents, filters, needles, and/or syringes.
• the label or package insert may indicate that the composition is used for treating a disease, disorder or condition in an individual (e.g., cancer).
• the label or a package insert which is on or associated with the container, may indicate directions for reconstitution and/or use of the formulation.
• the label or package insert may further indicate that the formulation is useful or intended for subcutaneous, intravenous, or other modes of administration for treating or preventing an autoimmune disease, disorder or condition in an individual.
• the label or package insert can include instructions for use, for example instructions for administering the compound or the composition, in some aspects in accord with any of the methods or uses described herein.
• the container in some embodiments holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition.
• the article of manufacture or kit may include (a) a first container with a composition contained therein (i.e., first medicament), wherein the composition includes the compound; and (b) a second container with a composition contained therein (i.e., second medicament), wherein the composition includes a further agent, such as a cytotoxic or otherwise therapeutic agent, and which article or kit further comprises instructions on the label or package insert for treating the subject with the second medicament, in an effective amount.
• a further agent such as a cytotoxic or otherwise therapeutic agent
• starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product.
• protecting groups may be used to protect certain functional groups (amino, carboxy, or side 32 sf-5754346 16547-20003.40 chain groups) from reaction conditions, and that such groups are removed under standard conditions when appropriate.
• compositions of described herein can be synthesized according to the procedure as shown in Scheme A1.
• Scheme A1 33 sf-5754346 16547-20003.40
• Scheme A2 [0121] As can be seen in the above schemes, a glucan compound (such as a dextran or a cyclodextrin) is reacted with an activating agent.
• a, b, and c may each independently refer to an integer of 0, at least 1, at least 1, from about 1 to about 165, from about 16 to about 111, from about 5 to about 167, from about 50 to about 65, or from about 6 to about 16.
• glucan backbone in the above scheme may be linear, branched, circular, or combinations thereof.
• Groups not specified in the above schemes, such as any end groups to the glucan backbone, may be any end groups recognizable by one skilled in the art.
• an end group of the glucan backbone may be a hydroxy end group of the monomer.
• composition refers to any mixture of two or more products, substances, or compounds. It may be a solution, a suspension, liquid, powder, a paste, aqueous, non-aqueous or any combination thereof.
• alkyl refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbon atoms).
• Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”), having 1 to 10 carbon atoms (a “C 1 -C 10 alkyl”), having 6 to 10 carbon atoms (a “C 6 -C 10 alkyl”), having 1 to 6 carbon atoms (a “C1-C6 alkyl”), having 2 to 6 carbon atoms (a “C2-C6 alkyl”), or having 1 to 4 carbon atoms (a “C1-C4 alkyl”).
• 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.
• alkylene refers to the same residues as alkyl, but having bivalency.
• Particular alkylene groups are those having 1 to 20 carbon atoms (a “C 1 -C 20 alkylene”), having 1 to 10 carbon atoms (a “C 1 -C 10 alkylene”), having 6 to 10 carbon atoms (a “C 6 -C 10 alkylene”), having 1 to 6 carbon atoms (a “C1-C6 alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1-C3 alkylene”).
• alkylene examples include, but are not limited to, groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH 2 (CH 2 ) 5 CH 2 -), octylene (-CH 2 (CH 2 ) 6 CH 2 -), and the like.
• groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pent
• halo refers to elements of the Group 17 series having atomic number 9 to 85.
• Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc.
• perhaloalkyl refers to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is 36 sf-5754346 16547-20003.40 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).
• perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
• a perhaloalkoxy group is trifluoromethoxy (–OCF3).
• an optionally substituted group may be unsubstituted or substituted by 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 in which the substituents may be the same of different.
• an optionally substituted group has one substituent.
• an optionally substituted group has two substituents.
• an optionally substituted group has three substituents.
• an optionally substituted group has four substituents.
• 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.
• Example 1 Structure of Target 5, a targeted chemotherapeutic composed of a mannosylated dextran ligand linked to the toxin monomethyl auristatin E
• Target 5 A compound as described herein was synthesized.
• the compound (Target 5) consists of a mannosylated dextran backbone (in order to form a mannose binding site targeting moiety) connected by a valine-citrulline linker to monomethyl auristatin E (MMAE).
• MMAE monomethyl auristatin E
• the compound of Figure 1 may also be referred to as Compound A. 37 sf-5754346 16547-20003.40 Synthesis of Compound A I. Synthesis of Val-Cit-PAB-MMAE [0135] To Fmoc-Val-Cit-PAB-PNP (470 mg, 0.613 mmol) in DMF (12 ml) was added pyridine (5 ml), a solution of HOBt (80 mg, 0593 mmol) in DMF (5 ml), a solution of DIPEA (86 mg, 0.667 mmol) in DMF (5 ml), and a solution of MMAE (400 mg, 0.557 mmol) in DMF (12 ml). The mixture was stirred at room temperature for 2 days.
• Target 5-6k (900 mg) as a white solid.
• NMR for one mole of glucose units, the compound contains 3.1 mol% MMAE and 11.6 mol% mannose (and since the polymer has 37 glucose units in average, it has 1 MMAE unit and 4 mannose units).
• the average molecular weight of a repeating unit is ca. 234 g/mol, and the Mw is ca. 8600.
• Example 2 Administration of Target 5 shows strong anti-cancer efficacy in multiple murine soft tissue sarcoma (STS) tumor models
• STS murine soft tissue sarcoma
• Target 5 was administered twice weekly by lateral tail vein at 5mg/kg or 10 mg/kg. Saline was administered by tail vein and doxorubicin (4mg/kg) was injected intraperitoneally. [0145] As seen in Figure 2, Target 5 was able to reduce tumor volume in a dose-dependent manner. Mice administered 10mg/kg of Target 5 had diminished tumor volume comparable to mice treated with doxorubicin (FIG. 2A). Based on mouse stable weight gain, there is no significant toxicity from Target 5, however doxorubicin administration causes significant toxicity as illustrated in the decrease of body weight (FIG. 2B).
• Target 5 Intracranial Model [0146] The therapeutic effect of Target 5 was analyzed in a highly aggressive STS brain metastasis model. Luciferase-expressing HT1080 cells (HT1080-Luc) were implanted intracranially at day 0. At day 4, mice were enrolled into treatment groups having equivalent average tumor size as determined by mean bioluminescence intensities. Mice were administered saline or 10 mg/kg of Target 5 on days 4 and 7 and were imaged at day 10. As shown in FIG. 3, mice administered Target 5 (right panels) demonstrated marked reduction in tumor volume (as determined by a visible reduction in bioluminescence) after two doses as compared to mice administered saline (left panels) where the tumors increased in size.
• UPS is a doxorubicin-resistant subtype of STS.
• tumors reached a range of 72-294 mm 3 with an average of 150 mm 3 , mice were randomized to the respective treatment groups and dosed within 24 hrs.
• Target 5 is administered intravenously using 2 mg/kg; 4 mg/kg, 8 mg/kg, or 10 mg/kg all dosed twice weekly.
• Control mice are given saline intravenously twice a week. Tumor volume and body weight were measured twice weekly.
• mice were monitored and dosed for up to 14 days, until animals reach a tumor volume of 1,500 mm 3 , or humane endpoint, whichever occurred first.
• Target-5 exhibited a tumor-suppressive effect in a dose-dependent fashion in a 43 sf-5754346 16547-20003.40 doxorubicin-resistant sarcoma PDX model.
• Mice administered 4 mg/kg, 8 mg/kg, and 10 mg/kg of Target-5 demonstrated nearly equivalent reductions in tumor volume, indicating a broad therapeutic index for Target-5.
• the average body weight of mice was comparable between each treatment group.
• CBC complete blood count
• CRT0000.001 End of study complete blood count
• Values indicate the mean of four mice (chosen at random) from the saline control, 4 mg/kg Target-5, and 10 mg/kg Target-5 treatment groups. The comparison of mean values of analytes across treatment groups demonstrate broad tolerability to Target-5, even at highest dose.
• Table E2 CBC and chemistry panels [0149] Forty five (45) female nude mice were implanted with tumor fragments subcutaneously into the right rear flank. When tumors reached a range of 72-294 mm 3 with an average of 150 mm 3 , 30 mice were randomized to the respective treatment groups and dosed within 24 hrs.
• Target 5 is administered intravenously using 10 mg/kg dosed twice weekly. Control mice are given saline intravenously twice a week. Tumor volume and body weight were measured twice weekly. Mice were monitored and dosed for up to 26 days, until animals reach a tumor volume of 1,500 mm 3 , or humane endpoint, whichever occurred first. At the end of the 44 sf-5754346 16547-20003.40 study, or when animals reach humane endpoint, 3-4 tumors per group were resected and processed as FFPE.
• FIG. 4C shows that Target 5 administered at 10mg/kg per dose shows strong anti-cancer efficacy and was more effective at controlling tumor growth than doxorubicin in this doxorubicin-resistant model.
• U87MG human glioma cell line
• Target 5 was administered to the mice intravenously while temozolomide was administered by oral gavage.
• Figure 4 shows that Target 5 was able to reduce tumor volume in a dose-dependent manner (FIG. 5A) while having no significant toxicity as determined by an impact on mouse body weight (FIG. 5B).
• GL261 tumor cells are moderately resistant to temozolomide chemotherapy. Mice were administered saline, temozolomide (12.5 mg/kg by gavage), or various concentrations of Target 5 (5 mg/kg, 7.5 mg/kg, or 10 mg/kg by tail vein injection). Figure 5 shows the effect of Target 5 on GL261 tumor volume.
• Example 4 Effectiveness of Target 5 in inhibiting growth of temozolomide-resistant tumors in an immunocompetent intercranial glioma model
• the ability of Target 5 to target across the blood brain barrier and demonstrate anti-cancer efficacy of a temozolomide-resistant tumor in an immunocompetent intercranial glioma model is determined.
• fifty-five C57B/6 mice (includes overage) are purchased (equal #s male and female). The mice are 8-weeks-old at time of implantation and weigh >20 gm on date of implantation to ensure they have adequate reserve for the planned interventions.
• mice Recognizing the potential immunogenicity of GL261 luciferase lines (Sanchez et al., 2020), the non-transgenic GL261 model is used and anticancer efficacy via a Kaplan-Meier (K-M) survival study is evaluated.
• K-M Kaplan-Meier
• a PDX model based on high temozolomide IC-50 and MGMT methylation status is selected. Emphasis is on selection of models derived from patients with and without prior treatment. Pilot studies using both subcutaneous and intracranial implantation of the selected PDX lines in athymic mice to establish a predictive growth curve for subsequent studies are performed. The size of the tumor is measured twice a week by calipers for subcutaneous tumors and by MRI for intracranial tumors. [0157] Once the growth curve is established for the temozolomide-resistant PDX lines in athymic mice, subcutaneous anti-cancer efficacy studies using Target 5 on both PDX models is performed.
• Target 5 is administered intravenously using 5 mg/kg 2X/week; 10mg/kg 2X/week; or 6.7 mg/kg 3X/week.
• Mice treated with temozolomide are administered temozolomide at a dose of 10 mg/kg 2X/week, and control mice given saline intravenously twice a week. Animals remain on study until they reach moribundity, death, or tumor volume is 3 1500mm 3 .
• the anti- tumor effect of Target 5 of temozolomide-resistant tumors in a PDX model is assessed.
• a dosing regimen selected based on the efficacy of Target 5 in the subcutaneous model, is developed for an intracranial study using PDX models. Forty five (45) athymic mice per model (1.5X overage, equal #s male and female) are weighed 3x/week and tumor volume is measured once weekly via MRI. Volumetric measurements of tumor size are determined by MRI rather than rely on the more commonly used 2-D measurements. When >30 animals have tumors measuring >5mm 3 , mice are randomized and placed into study. Mice stay in study using moribundity or death as endpoints. Data includes K-M survival curves and tumor volumetrics.
• Target 5 is administered intravenously at 10 mg/kg and doxorubicin at 2 mg/kg twice a week.
• a saline control and a Target 5 without MMAE (10 mg/kg twice weekly) is also be administered.
• the dose for doxorubicin administered provides anti- cancer efficacy without dose-limiting toxicity.
• Example 7 Effectiveness of Target 5 in inhibiting synovial sarcoma, and leiomyosarcoma, and Ewing’s/PNET [0163]
• mice were sacrificed and plasma concentration of free MMAE were determined.
• Table E1 Free MMAE in circulation
• the pharmacokinetics of Target 5 are characterized by high exposure (C0 and AUCinf), very low clearance (Cl), moderate volume of distribution (Vss), long half-life (t1/2), and low variability. These data show very little free MMAE is present in the circulation of mice (0.2%).
• Example 9 Anti-cancer efficacy of Target 5 in a murine PDX sarcoma model (CRT0028.001) [0165] The anti-cancer efficacy of Target 5 in a second PDX model (CRT0028.001; a therapy-na ⁇ ve undifferentiated pleomorphic sarcoma) was examined. Seventeen (17) athymic mice (male and female) were implanted subcutaneously with CRT00288.001, an undifferentiated pleomorphic sarcoma (Certis Oncology Solutions, San Diego).
• FIG. 8A shows the mean tumor volumes for each group as a function of study day. The figure illustrates that 10 mg/kg of Target-5 exhibits a greater anti-tumor efficacy than 1 mg/kg of doxorubicin.
• FIG. 8B shows that mice treated with 10 mg/kg of Target-5 demonstrated 49 sf-5754346 16547-20003.40 stable body weight, a broad health indicator and tolerability measure for Target-5.
• Example 10 Engagement of CD206 in the absence of MMAE [0167] The effect of Target-5 lacking MMAE was evaluated.
• FIG. 9 shows that effect of saline, Compound B (Target-5 without MMAE), and Target-5 on tumor volume in GL261- bearing mice. Wildtype C57BL/6 mice (12 males and 12 females) were subcutaneously implanted with 5 x10 6 cells of the glioma cell line GL261. When the tumors reached a mean of 102 mm 3 , the mice were randomized into 3 treatment groups: the saline control, 10 mg/kg Compound B, and 9 mg/kg Target-5 (equivalent molar concentrations of each test group) and dosed 2x/week for 18 days.
• FIG. 9A depicts representative examples of GL261 tumors excised at end of study from saline-treated, Compound B- treated (10 mg/kg), and Target-5 treated (9 mg/kg) mice. Compound B and Target-5 doses are molar equivalent. Tumors were immuno-stained with anti- CD206 (Cell cat# 24595S Dilution: 1:1600).
• mice treated with Target-5 experienced marked reduction in tumor size compared to mice treated with Compound B, and strong CD206 expression indicating no downregulation of CD206 expression with Target-5 treatment.
• Example 11 Anti-cancer efficacy of Target 5 in a murine PDX myxofibrosarcoma model [0169] The anti-cancer efficacy of Target-5 in a sarcoma PDX model (myxofibrosarcoma)) was examined. Twenty one (21) athymic male mice were implanted with tumor fragments subcutaneously into the right rear flank.
• mice were randomized into three groups and were dosed 2x/week with either saline as a vehicle control, 10 mg/kg Target-5, or 1 mg/kg doxorubicin. As shown in FIG. 10, mice treated with Target-5 experienced lower tumor volume than mice treated with saline or doxorubicin in this model. These data indicate that Target-5 exhibits anti-cancer efficacy in a myxofibrosarcoma PDX model. 50 sf-5754346

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Molecular Biology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Gastroenterology & Hepatology (AREA)
• Immunology (AREA)
• Oncology (AREA)
• Biochemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=92501680

Family Applications (1)

Country Status (8)

Families Citing this family (1)

Family Cites Families (3)

• 2024
  • 2024-02-21 EP EP24760940.7A patent/EP4669335A1/de active Pending
  • 2024-02-21 KR KR1020257030689A patent/KR20250151447A/ko active Pending
  • 2024-02-21 WO PCT/US2024/016748 patent/WO2024178139A1/en not_active Ceased
  • 2024-02-21 JP JP2025549266A patent/JP2026507012A/ja active Pending
  • 2024-02-21 CN CN202480013904.XA patent/CN120731092A/zh active Pending
  • 2024-02-21 AU AU2024224437A patent/AU2024224437A1/en active Pending
  • 2024-02-21 IL IL322872A patent/IL322872A/en unknown
• 2025
  • 2025-08-21 MX MX2025009865A patent/MX2025009865A/es unknown

Also Published As

Similar Documents

Legal Events